Journal of Alzheimer's Disease - Volume 51, issue 1

Authors: Niemantsverdriet, Ellis | Goossens, Joery | Struyfs, Hanne | Martin, Jean-Jacques | Goeman, Johan | De Deyn, Peter Paul | Vanderstichele, Hugo | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Intra- and inter-laboratory variability of cerebrospinal fluid (CSF) biomarker analyses remains an important issue. We investigated the clinical-diagnostic impact of CSF biomarker concentration shifts in mild cognitive impairment (MCI) and autopsy-confirmed Alzheimer’s disease (AD) dementia patients. MCI patients (n  = 85), autopsy-confirmed AD dementia patients (n  = 72), and cognitively healthy controls (n  = 100) were included in this prospective, longitudinal study. AD dementia patients were followed up until death, and controls were included from 1992 until 2003. In-house validated cutoff values of biomarkers were applied: Aβ1-42 <638.5 pg/mL, T-tau>296.5 pg/mL, P-tau181P >56.5 pg/mL. Both increments and decrements (from ± 5% …to ± 40% ) were added to the true (=observed) CSF biomarker values, imitating the anticipated differences in biomarker concentrations. Within certain limits, the clinical diagnostic performance of AD CSF biomarkers remains largely unchanged and clinical diagnostic accuracy deviated less than 8.2% from the reference when concentration shifts ranging between –20% and +20% were added to one of the three CSF biomarkers in MCI and autopsy-confirmed AD patients. Notwithstanding the fact that (pre- and post-)analytical parameters can affect the clinical classification, the present exploratory study provides evidence that for a specific context of use, the impact on clinical accuracy of biomarker concentration shifts might be lower than originally expected. In conclusion, induced shifts of ±20% in only one of the three biomarkers has limited impact on the clinical accuracy of AD CSF biomarkers in MCI and autopsy-confirmed AD patients when using the IWG-2 criteria. Show more

Keywords: Alzheimer’s disease, differential dementia diagnosis, cerebrospinal fluid, biomarkers, diagnostic accuracy, (pre-)analytical variability

DOI: 10.3233/JAD-150953

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 97-106, 2016

Authors: Tripathi, Ajai K. | Singh, Neena

Article Type: Research Article

Abstract: Hemin is known to induce endocytosis of prion-protein (PrPC ) from the neuronal plasma membrane, potentially limiting propagation of the disease causing PrP-scrapie (PrPSc ) isoform. Hemin is therefore an attractive disease-modifying option for sporadic Creutzfeldt-Jakob disease (sCJD), a human prion disorder with no effective treatment. The hemin-PrPC interaction is also of interest in cerebral-hemorrhage (CH), a condition where potentially toxic hemin molecules come in contact with neuronal PrPC . Interestingly, PrPC is upregulated in penumbric neurons surrounding CH and is known to confer neuroprotection in a dose-dependent manner. The underlying mechanism, however, is not clear. Here, we …report that hemin binds PrPC on diverse cell lines, resulting in its aggregation or degradation in a cell-type specific manner. Surprisingly, the hemin-PrPC interaction upregulates Hb synthesis in hematopoietic cells, a response reversed by deleting the hemin-binding octa-peptide repeat region of PrPC . A similar response is noted in brain organotypic cultures where exposure to hemin induces significantly more α -globin in wild-type (PrP+/+ ) relative to PrP-knock-out (PrP–/– ) samples. Furthermore, red blood cells and brain tissue from PrP–/– mice show significantly less α -globin relative to PrP+/+ controls, indicating a positive effect of PrPC on Hb synthesis under physiological conditions as well. Surprisingly, levels of α -globin are significantly higher in sCJD brain tissue relative to controls, suggesting compensatory upregulation of Hb synthesis by surviving neurons or misregulation in diseased brains. These observations reveal a unique function of PrPC that is likely to impact the therapeutic management of CH and sCJD. Show more

Keywords: α-Globin, hemin, neuronal hemoglobin, prion protein, sCJD

DOI: 10.3233/JAD-151039

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 107-121, 2016

Authors: Tong, Ming | Deochand, Chetram | Didsbury, John | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Background: T3D-959, a dual PPAR-δ /PPAR γ nuclear receptor agonist and former diabetes drug candidate, has been repositioned as an Alzheimer’s disease (AD)-modifying therapy. Objective: This study examines the effectiveness and mechanisms of T3D-959’s therapeutic effects using in vivo and ex vivo rat models of sporadic AD. Methods: A sporadic AD model was generated by intracerebral (i.c.) administration of streptozotocin (STZ). Control and i.c. STZ treated rats were gavaged with saline or T3D-959 (0.3 to 3.0 mg/kg/day) for 28 days. Spatial learning and memory were evaluated using the Morris water maze test. Frontal lobe …slice cultures generated 24 hours after i.c. STZ or vehicle were used to study early effects of T3D-959 (0.5–1.0 μM) on viability and molecular markers of AD. Results: T3D-959 significantly improved spatial learning and memory in i.c STZ-treated rats. Mechanistically, T3D-959 significantly improved culture viability and brain morphology, reduced levels of oxidative stress and Aβ, and normalized expression of phospho-tau, choline acetyltransferase, and myelin-associated glycoprotein. Protective effects occurred even at the lowest tested dose of T3D-959. Conclusions: Pre-clinical proof of concept has been demonstrated that T3D-959 can improve multiple pathologies of AD resulting in significant improvements in cognitive function and molecular and biochemical indices of neurodegeneration. These results support the theses that (1) effective disease modification in AD can be achieved by targeting relevant nuclear receptors, and (2) treating AD as a metabolic disease has the potential to be disease remedial. A Phase 2a trial of T3D-959 in mild-to-moderate AD patients has been initiated (ClinicalTrials.gov identifier NCT02560753). Show more

Keywords: Alzheimer’s disease, amyloid, PPAR agonist, slice culture, spatial learning and memory, Streptozotocin, T3D-959, Type 3 diabetes

DOI: 10.3233/JAD-151013

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 123-138, 2016

Authors: Clare, Linda | Quinn, Catherine | Jones, Ian Rees | Woods, Robert T.

Article Type: Research Article

Abstract: The self-regulatory model proposes that illness representations influence adjustment and coping in chronic conditions. Better understanding of the illness representations held by people with dementia could help with targeting information and support so as to optimize adjustment and coping. In this mixed-methods study of illness representations among people with mild to moderate Alzheimer’s, vascular, or mixed dementia we aimed to clarify the nature of the representations held, to determine whether specific profiles can be identified based on perceptions of the identity and cause of the condition, and to examine associations between these profiles and other participant characteristics. Data were collected …in the second wave of the Memory Impairment and Dementia Awareness Study (MIDAS). Sixty-four people with dementia, who had been told their diagnosis at a memory clinic, completed interviews and responded to questionnaires. In each case a carer was also interviewed. Cluster analysis based on responses about identity and cause identified three profiles. ‘Illness’ cluster participants saw themselves as living with an illness and used diagnostic labels, ‘ageing’ cluster participants did not use diagnostic labels and viewed their difficulties as related to ageing, and ‘no problem’ cluster participants considered that they did not have any difficulties. ‘Illness’ cluster participants had better cognition and better awareness, but lower mood, and perceived more practical consequences, than ‘ageing’ cluster participants. Holding an ‘illness’ model may not be advantageous. Rather than encouraging adoption of such a model, it may be preferable to target information and select interventions in line with the person’s representation profile. Show more

Keywords: Aging, awareness, coping behavior, dementia, diagnosis, psychological adjustment

DOI: 10.3233/JAD-150794

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 139-150, 2016

Authors: Nunez, Kavin | Kay, Jared | Krotow, Alexander | Tong, Ming | Agarwal, Amit R. | Cadenas, Enrique | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Background: Meta-analysis has shown that smokers have significantly increased risks for Alzheimer’s disease (AD), and neuroimaging studies showed that smoking alters white matter (WM) structural integrity. Objective: Herein, we characterize the effects of cigarette smoke (CS) exposures and withdrawal on WM myelin lipid composition using matrix assisted laser desorption and ionization-imaging mass spectrometry (MALDI-IMS). Methods: Young adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). Frontal lobe WM was examined for indices of lipid and protein oxidation and lipid …profile alterations by MALDI-IMS. Lipid ions were identified by MS/MS with the LIPID MAPS prediction tools database. Inter-group comparisons were made using principal component analysis and R-generated heatmap. Results: CS increased lipid and protein adducts such that higher levels were present in CS8 compared with CS4 samples. CS8 + R reversed CS8 effects and normalized the levels of oxidative stress. MALDI-IMS demonstrated striking CS-associated alterations in WM lipid profiles characterized by either reductions or increases in phospholipids (phosphatidylinositol, phosphatidylserine, phosphatidylcholine, or phosphatidylethanolamine) and sphingolipids (sulfatides), and partial reversal of CS’s inhibitory effects with recovery. The heatmap hierarchical dendrogram and PCA distinguished CS exposure, duration, and withdrawal effects on WM lipid profiles. Conclusion: CS-mediated WM degeneration is associated with lipid peroxidation, protein oxidative injury, and alterations in myelin lipid composition, including shifts in phospholipids and sphingolipids needed for membrane integrity, plasticity, and intracellular signaling. Future goals are to delineate WM abnormalities in AD using MALDI-IMS, and couple the findings with MRI-mass spectroscopy to improve in vivo diagnostics and early detection of brain biochemical responses to treatment Show more

Keywords: Alzheimer’s disease, cigarette smoke, imaging mass spectrometry, MALDI, mouse model, neurodegeneration, tobacco, white matter

DOI: 10.3233/JAD-150916

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 151-163, 2016

Authors: Frenkel-Pinter, Moran | Tal, Sharon | Scherzer-Attali, Roni | Abu-Hussien, Malak | Alyagor, Idan | Eisenbaum, Tal | Gazit, Ehud | Segal, Daniel

Article Type: Research Article

Abstract: Tauopathies, such as Alzheimer’s disease (AD), are a group of disorders characterized neuropathologically by intracellular toxic accumulations of abnormal protein aggregates formed by misfolding of the microtubule-associated protein tau. Since protein self-assembly appears to be an initial key step in the pathology of this group of diseases, intervening in this process can be both a prophylactic measure and a means for modifying the course of the disease for therapeutic purposes. We and others have shown that aromatic small molecules can be effective inhibitors of aggregation of various protein assemblies, by binding to the aromatic core in aggregation-prone motifs and preventing …their self-assembly. Specifically, we have designed a series of small aromatic naphthoquinone-tryptophan hybrid molecules as candidate aggregation inhibitors of β -sheet based assembly and demonstrated their efficacy toward inhibiting aggregation of the amyloid-β peptide, another culprit of AD, as well as of various other aggregative proteins involved in other protein misfolding diseases. Here we tested whether a leading naphthoquinone-tryptophan hybrid molecule, namely NQTrp, can be repurposed as an inhibitor of the aggregation of the tau protein in vitro and in vivo . We show that the molecule inhibits the in vitro assembly of PHF6, the aggregation-prone fragment of tau protein, reduces hyperphosphorylated tau deposits and ameliorates tauopathy-related behavioral defect in an established transgenic Drosophila model expressing human tau. We suggest that NQTrp, or optimized versions of it, could act as novel disease modifying drugs for AD and other tauopathies. Show more

Keywords: AcPHF6 peptide, Drosophila, neurodegeneration, NQTrp compound, protein aggregation, tau protein, tauopathies

DOI: 10.3233/JAD-150927

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 165-178, 2016

Authors: Xu, Zhi-Qiang | Huang, Huang | Chen, Ya-Li | Gao, Yun-Ying | Xu, Jun | Marshall, Charles | Cai, Zhi-You | Xiao, Ming

Article Type: Research Article

Abstract: Extensive loss of hippocampal neurons serves a pathological basis for irreversible cognitive impairment in patients with Alzheimer’s disease (AD). However, this characteristic cannot be replicated by transgenic mouse models, and its underlying mechanisms are unclear. Here, we present evidence that different expression patterns of amyloid-β protein precursor (AβPP) secretases in human and mouse hippocampal neurons are a decisive cause of species difference in the susceptibility to Aβ pathogenesis. Cell bodies of both pyramidal and granular neurons did not appear to undergo Aβ deposits in the 10-month-old transgenic mutant human AβPP/presenilin-1 (PS1) mice. They expressed high levels of non-amyloidogenic α -secretase, …and its neuroprotective products soluble AβPPα , but low levels of amyloidogenic β-secretase and γ -secretase, and a neurotoxic product, Aβ42 peptide. Unlike those found in the mouse, human hippocampal neuronal cell bodies expressed β-secretase and γ -secretase, but not α -secretase, which could increase Aβ generation, thus undergoing death in response to various pathological conditions. Increased hippocampal neuronal apoptosis at 48 h following local microinjection of α -secretase antibody ADAM10 into the hippocampus of AβPP/PS1 mice further suggests that high α -secretase expression in mouse neuronal cell bodies is a factor in the paucity of neuronal loss in AD-like pathology. Therefore, selective down-regulation of brain α -secretase in transgenic AD models will better replicate the disease spectrum, including decreased brain soluble AβPPα levels and massive neuronal loss in AD patients, and be beneficial for preclinical therapeutic evaluation of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β metabolism, AβPP/PS1 mice, hippocampus

DOI: 10.3233/JAD-150634

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 179-195, 2016

Authors: Chang, Lirong | Zhang, Yali | Liu, Jinping | Song, Yizhi | Lv, Angchu | Li, Yan | Zhou, Wei | Yan, Zhen | Almeida, Osborne F.X. | Wu, Yan

Article Type: Research Article

Abstract: Synaptic dysfunction during early stages of Alzheimer’s disease (AD) is triggered by soluble amyloid-β (Aβ) oligomers that interact with NMDA receptors (NMDARs). We previously showed that Aβ induces synaptic protein loss through NMDARs, albeit through undefined mechanisms. Accordingly, we here examined the contribution of individual NMDAR subunits to synaptotoxicity and demonstrate that Aβ exerts differential effects on the levels and distribution of GluN2A and GluN2B subunits of NMDAR in dendrites. Treatment of cultured hippocampal neurons with Aβ1-40 (10 μM, 1 h) induced a significant increase of dendritic and synaptic GluN2B puncta densities with parallel decreases in the puncta densities of …denritic and synaptic pTyr1472 -GluN2B. Conversely, Aβ significantly decreased dendritic and synaptic GluN2A and dendritic pTyr1325 -GluN2A puncta densities and increased synaptic pTyr1325 -GluN2A puncta densities. Unexpectedly, Aβ treatment resulted in a significant reduction of GluN2B and pTyr1472 -GluN2B protein levels but did not influence GluN2A and pTyr1325 -GluN2A levels. These results show that Aβ exerts complex and distinct regulatory effects on the trafficking and phosphorylation of GluN2A and GluN2B, as well as on their localization within synaptic and non-synaptic sites. Increased understanding of these early events in Aβ-induced synaptic dysfunction is likely to be important for the development of timely preventive and therapeutic interventions. Show more

Keywords: Alzheimer’s disease, amyloid beta, hippocampus, NMDA receptor subunits, synapse, tyrosine phosphorylation

DOI: 10.3233/JAD-150942

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 197-212, 2016

Authors: Huang, Chunxia | Ng, Olivia Tsz-Wa | Ho, Yuen-Shan | Irwin, Michael Garnet | Chang, Raymond Chuen-Chung | Wong, Gordon Tin-Chun

Article Type: Research Article

Abstract: Several studies suggest a relationship between anesthesia-induced tau hyperphosphorylation and the development of postoperative cognitive dysfunction. This study further characterized the effects of continuous propofol infusion on tau protein phosphorylation in rats, with or without temperature control. Propofol was administered intravenously to 8–10-week-old male Sprague-Dawley rats and infused to the loss of the righting reflex for 2 h continuously. Proteins from cortex and hippocampus were examined by western blot and immunohistochemistry. Rectal temperature was significantly decreased during propofol infusion. Propofol with hypothermia significantly increased phosphorylation of tau at AT8, AT180, Thr205, and Ser199 in cortex and hippocampus except Ser396. With temperature …maintenance, propofol still induced significant elevation of AT8, Thr205, and Ser199 in cortex and hippocampus; however, increase of AT180 and Ser396 was only found in hippocampus and cortex, respectively. Differential effects of propofol with or without hypothermia on multiple tau related kinases, such as Akt/GSK3β, MAPK pathways, or phosphatase (PP2A), were demonstrated in region-specific manner. These findings indicated that propofol increased tau phosphorylation under both normothermic and hypothermic conditions, and temperature control could partially attenuate the hyperphosphorylation of tau. Further studies are warranted to determine the long-term impact of propofol on the tau pathology and cognitive functions. Show more

Keywords: Hypothermia, propofol, protein kinases, tau phosphorylation

DOI: 10.3233/JAD-150645

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 213-226, 2016

Authors: Wang, Hui-Fu | Tan, Lan | Cao, Lei | Zhu, Xi-Chen | Jiang, Teng | Tan, Meng-Shan | Liu, Ying | Wang, Chong | Tsai, Richard M. | Jia, Jian-Ping | Yu, Jin-Tai | and Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The International Working Group (IWG) recently proposed the revised diagnostic criteria for Alzheimer’s disease (AD) to define and refine several types of AD, and to reclassify AD-related biomarkers into diagnostic and progression markers, but its performance is not known. Objective: This study was designed to describe the application of the revised IWG criteria in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, and to ascertain whether diagnostic and progression markers show significant differences in their relationships to AD severity and progression. Methods: Based on the requirements of the refined criteria, 857 ADNI subjects with memory evaluation …and at least one pathophysiological marker (CSF or amyloid imaging biomarkers) were eligible and reclassified in this study, and we calculated the associations of diagnostic (CSF and amyloid PET) and progression markers (MRI and fluorodeoxyglucose-PET) with AD severity and progression respectively. Results: The majority (84.2% ) of ADNI AD group (n  = 117) and 173 MCI (37.4% ) subjects in ADNI met the definition of typical AD; and 105 cognitively normal (41.0% ) individuals were diagnosed as asymptomatic AD. Furthermore, diagnostic and progression markers showed significant differences when correlated to AD severity and progression. Conclusion: A large proportion of AD dementia subjects were categorized as typical AD, and the revised criteria could identify typical AD from MCI status as well as asymptomatic AD at the asymptomatic stage. Moreover, the significant differences between diagnostic and progression markers further supported the new biomarkers categorization in the refined criteria. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease neuroimaging Initiative, diagnostic markers, international working group-2 criteria, progression markers

DOI: 10.3233/JAD-150824

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 227-236, 2016