Journal of Alzheimer's Disease - Volume 45, issue 2

Authors: Pamphlett, Roger | Kum Jew, Stephen

Article Type: Research Article

Abstract: A marked loss of locus ceruleus (LC) neurons is a striking pathological feature of Alzheimer's disease (AD). LC neurons are particularly prone to taking up circulating toxicants such as heavy metals, and hyperphosphorylated tau (tauHYP ) appears early in these neurons. In an attempt to find out if both heavy metals and tauHYP could be damaging LC neurons, we looked in the LC neurons of 21 sporadic AD patients and 43 non-demented controls for the heavy metals mercury, bismuth, and silver using autometallography, and for tauHYP using AT8 immunostaining. Heavy metals or tauHYP were usually seen in …separate LC neurons, and rarely co-existed within the same neuron. The number of heavy metal-containing LC neurons did not correlate with the number containing tauHYP . Heavy metals therefore appear to occupy a mostly different population of LC neurons to those containing tauHYP , indicating that the LC in AD is vulnerable to two different assaults. Reduced brain noradrenaline from LC damage is linked to amyloid-β deposition, and tauHYP in the LC may seed neurofibrillary tangles in other neurons. A model is described, incorporating the present findings, that proposes that the LC plays a part in both the amyloid-β and tau pathologies of AD. Show more

Keywords: Alzheimer's disease, amyloid, disease model, environmental toxicant, heavy metals, locus ceruleus, locus coeruleus, mercury, noradrenaline, tau

DOI: 10.3233/JAD-142445

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 437-447, 2015

Authors: Varga, Edina | Juhász, Gábor | Bozsó, Zsolt | Penke, Botond | Fülöp, Lívia | Szegedi, Viktor

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most prevalent form of neurodegenerative disorders characterized by neuritic plaques containing amyloid-β peptide (Aβ) and neurofibrillary tangles. Evidence has been reported that Aβ1-42 plays an essential pathogenic role in decreased spine density, impairment of synaptic plasticity, and neuronal loss with disruption of memory-related synapse function, all associated with AD. Experimentally, Aβ1-42 oligomers perturb hippocampal long-term potentiation (LTP), an electrophysiological correlate of learning and memory. Aβ was also reported to perturb synaptic glutamate (Glu)-recycling by inhibiting excitatory-amino-acid-transporters. Elevated level of extracellular Glu leads to activation of perisynaptic receptors, including NR2B subunit containing NMDARs. These …receptors were shown to induce impaired LTP and enhanced long-term depression and proapoptotic pathways, all central features of AD. In the present study, we investigated the role of Glu-recycling on Aβ1-42 -induced LTP deficit in the CA1. We found that Aβ-induced LTP damage, which was mimicked by the Glu-reuptake inhibitor TBOA, could be rescued by blocking the NR2B subunit of NMDA receptors. Furthermore, decreasing the level of extracellular Glu using a Glu scavenger also restores TBOA or Aβ induces LTP damage. Overall, these results suggest that reducing ambient Glu in the brain can be protective against Aβ-induced synaptic disruption. Show more

Keywords: Alzheimer's disease, glutamate scavenger, glutamate-reuptake, long-term potentiation, NR2B, TBOA

DOI: 10.3233/JAD-142367

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 449-456, 2015

Authors: Gardini, Simona | Venneri, Annalena | Sambataro, Fabio | Cuetos, Fernando | Fasano, Fabrizio | Marchi, Massimo | Crisi, Girolamo | Caffarra, Paolo

Article Type: Research Article

Abstract: Semantic memory decline and changes of default mode network (DMN) connectivity have been reported in mild cognitive impairment (MCI). Only a few studies, however, have investigated the role of changes of activity in the DMN on semantic memory in this clinical condition. The present study aimed to investigate more extensively the relationship between semantic memory impairment and DMN intrinsic connectivity in MCI. Twenty-one MCI patients and 21 healthy elderly controls matched for demographic variables took part in this study. All participants underwent a comprehensive semantic battery including tasks of category fluency, visual naming and naming from definition for objects, actions …and famous people, word-association for early and late acquired words and reading. A subgroup of the original sample (16 MCI patients and 20 healthy elderly controls) was also scanned with resting state functional magnetic resonance imaging and DMN connectivity was estimated using a seed-based approach. Compared with healthy elderly, patients showed an extensive semantic memory decline in category fluency, visual naming, naming from definition, words-association, and reading tasks. Patients presented increased DMN connectivity between the medial prefrontal regions and the posterior cingulate and between the posterior cingulate and the parahippocampus and anterior hippocampus. MCI patients also showed a significant negative correlation of medial prefrontal gyrus connectivity with parahippocampus and posterior hippocampus and visual naming performance. Our findings suggest that increasing DMN connectivity may contribute to semantic memory deficits in MCI, specifically in visual naming. Increased DMN connectivity with posterior cingulate and medio-temporal regions seems to represent a maladaptive reorganization of brain functions in MCI, which detrimentally contributes to cognitive impairment in this clinical population. Show more

Keywords: Alzheimer's disease, default mode network, functional MRI resting state, mild cognitive impairment, semantic memory

DOI: 10.3233/JAD-142547

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 457-470, 2015

Authors: Meißner, Julius N. | Bouter, Yvonne | Bayer, Thomas A.

Article Type: Research Article

Abstract: Pyroglutamate-modified amyloid-β (Aβ) at amino acid position three (AβpE3–42 ) is gaining considerable attention as a potential key player in the pathogenesis of Alzheimer's disease (AD). AβpE3–42 is abundant in AD brain and has a high aggregation propensity, stability, and cellular toxicity. The aim of the present work was to study the effect of AβpE3–42 expression on neuron loss and associated behavioral deficits using the TBA42 transgenic mouse model. Expression of pyroglutamate Aβ3–42 triggers hippocampal CA1 neuron loss and behavioral deficits in the TBA42 mouse model. Mice elicited significant neuron death (−35% at the age of 12 …months), deficits in the spatial reference memory, working memory, loss of anxiety, and severe motor deficits in an age-dependent manner. These results support a major pathological function of pyroglutamate Aβ in AD. Show more

Keywords: Hippocampus, motor deficits, N-truncated Aβ, spatial reference memory, stereology, transgenic mouse model, working memory

DOI: 10.3233/JAD-142868

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 471-482, 2015

Authors: Silveri, Maria Caterina | Ferrante, Ilaria | Brita, Anna Clelia | Rossi, Paola | Liperoti, Rosa | Mammarella, Federica | Bernabei, Roberto | Marini Chiarelli, Maria Vittoria | De Luca, Martina

Article Type: Research Article

Abstract: The aesthetic experience, in particular the experience of beauty in the visual arts, should have neural correlates in the human brain. Neuroesthetics is principally implemented by functional studies in normal subjects, but the neuropsychology of the aesthetic experience, that is, the impact of brain damage on the appreciation of works of art, is a neglected field. Here, 16 mild to moderate Alzheimer's disease patients and 15 caregivers expressed their preference on 16 works of art (eight representational and eight abstract) during programmed visits to an art gallery. A week later, all subjects expressed a preference rate on reproductions of the …same works presented in the gallery. Both patients and caregivers were consistent in assigning preference ratings, and in patients consistency was independent of the ability to recognize the works on which the preference rate had been given in an explicit memory task. Caregivers performed at ceiling in the memory task. Both patients and caregivers assigned higher preference ratings for representational than for abstract works and preference consistency was comparable in representational and abstract works. Furthermore, in the memory task, patients did not recognize better artworks they had assigned higher preference ratings to, suggesting that emotional stimuli (as presumably visual works of art are) cannot enhance declarative memory in this pathology. Our data, which were gathered in an ecological context and with real-world stimuli, confirm previous findings on the stability of aesthetic preference in patients with Alzheimer's disease and on the independence of aesthetic preference from cognitive abilities such as memory. Show more

Keywords: Aesthetic preference, Alzheimer's disease, art, dementia, emotional memory enhancement, memory, memory disorders, neuroesthetics

DOI: 10.3233/JAD-141434

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 483-494, 2015

Authors: Oliveira, Joana M. | Henriques, Ana Gabriela | Martins, Filipa | Rebelo, Sandra | da Cruz e Silva, Odete A.B.

Article Type: Research Article

Abstract: Two histopathological hallmarks of Alzheimer's disease (AD), the tau rich neurofibrillary tangles and the senile plaques, predominating in amyloid-β (Aβ), have fueled research in distinct directions. Evidence suggests that Aβ triggers imbalanced activities of protein phosphatases and kinases thus affecting the phosphorylation state of tau in AD. The amyloid-β protein precursor (AβPP) itself appears to be hyperphosphorylated at different residues in AD brains, including at Thr668. The results reported in this manuscript show, for the first time, that Aβ42 can impact upon the AβPP phosphorylation state at the Thr668 residue. This novel finding supports a putative model, whereby Aβ …can modulate the phosphorylation state of AβPP regulating its processing and consequently its own production. Furthermore, the data presented shows that in primary cortical neurons, GSK3β and Cdk5 are involved in AβPP phosphorylation at this residue and that PP1 and PP2B participate in AβPP dephosphorylation. Consistent with other reports, Aβ was capable of increasing tau phosphorylation at the Ser396 and Ser262 residues. This peptide is therefore a strong candidate for promoting the cross talk between signaling pathways, which simultaneously result in AβPP and tau hyperphosphorylation. In closing, the Aβ effect on protein kinases and protein phosphatases may constitute an alternative mechanism by which the peptide is able to modulate the phosphorylation state of both AβPP and tau in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, protein phosphatases, protein phosphorylation, tau

DOI: 10.3233/JAD-142664

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 495-507, 2015

Authors: Meeker, Kole D. | Meabon, James S. | Cook, David G.

Article Type: Research Article

Abstract: The glutamate transporter GLT-1 (also called EAAT2 in humans) plays a critical role in regulating extracellular glutamate levels in the central nervous system (CNS). In Alzheimer's disease (AD), EAAT2 loss is associated with neuropathology and cognitive impairment. In keeping with this, we have reported that partial GLT-1 loss (GLT-1+/−) causes early-occurring cognitive deficits in mice harboring familial AD AβPPswe/PS1ΔE9 mutations. GLT-1 plays important roles in several molecular pathways that regulate brain metabolism, including Akt and insulin signaling in astrocytes. Significantly, AD pathogenesis also involves chronic Akt activation and reduced insulin signaling in the CNS. In this report we tested the …hypothesis that GLT-1 heterozygosity (which reduces GLT-1 to levels that are comparable to losses in AD patients) in AβPPswe/PS1ΔE9 mice would induce sustained activation of Akt and disturb components of the CNS insulin signaling cascade. We found that partial GLT-1 loss chronically increased Akt activation (reflected by increased phosphorylation at serine 473), impaired insulin signaling (reflected by decreased IRβ phosphorylation of tyrosines 1150/1151 and increased IRS-1 phosphorylation at serines 632/635 – denoted as 636/639 in humans), and reduced insulin degrading enzyme (IDE) activity in brains of mice expressing familial AβPPswe/PS1ΔE9 AD mutations. GLT-1 loss also caused an apparent compensatory increase in IDE activity in the liver, an organ that has been shown to regulate peripheral amyloid-β levels and expresses GLT-1. Taken together, these findings demonstrate that partial GLT-1 loss can cause insulin/Akt signaling abnormalities that are in keeping with those observed in AD. Show more

Keywords: Amyloid-β, EAAT2, excitotoxicity, GLT1, metabolism, SLC1A2

DOI: 10.3233/JAD-142304

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 509-520, 2015

Authors: Cretin, Benjamin | Di Bitonto, Laure | Blanc, Frederic | Magnin, Eloi

Article Type: Research Article

Abstract: Seizures can be an early symptom of Alzheimer's disease (AD) and can precede cognitive decline. Early epilepsy in AD can mimic transient epileptic amnesic syndrome (TEAS) or epileptic amnesic syndrome. We report the case of a patient who started a cerebrospinal fluid (CSF)-proven AD with partial seizures and TEAS that secondarily became a cortical posterior atrophy syndrome. CSF biomarkers showed a high amyloid production, amyloidopathy, and high level of total tau and p-Tau. This observation adds data to the complex AD-early epilepsy interactions and illustrates that atypical AD can cause a TEAS. Possible red flags for an underlying neurodegenerative process …in TEAS are discussed. Show more

Keywords: Alzheimer's disease, mild cognitive impairment, posterior cortical atrophy, temporal lobe epilepsy, transient epileptic amnesic syndrome

DOI: 10.3233/JAD-141953

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 521-526, 2015

Authors: Lachno, D. Richard | Evert, Barbara A. | Maloney, Kaia | Willis, Brian A. | Talbot, Jayne A. | Vandijck, Manu | Dean, Robert A.

Article Type: Research Article

Abstract: The aim of this study was to validate assays for measurement of amyloid-β (Aβ) peptides in cerebrospinal fluid (CSF) specimens according to regulatory guidance and demonstrate their utility with measurements in specimens from Alzheimer's disease (AD) studies. Methods based on INNOTEST® β-AMYLOID(1-42) and prototype INNOTEST® β-AMYLOID(1-40) ELISA kits were developed involving pre-analytical sample treatment with Tween-20 for reliable analyte recovery. Validation parameters were evaluated by repeated testing of CSF pools collected and stored in the same manner as clinical specimens. Intra- and inter-assay coefficients of variation were ≤11% and relative accuracy was within ± 10% for …both analytes. Dilutional linearity was demonstrated for both analytes from a spiked CSF pool, but not from a non-spiked native CSF pool. Recovery of standard Aβ peptide spikes ranged from 77% to 93%. No interference was observed from the investigational drugs LY2811376, LY2886721, LY3002813, or semagacestat. Aβ1-40 and Aβ1-42 were stable in CSF for up to 8 hours at room temperature and during 5 freeze-thaw cycles from ≤−20°C and ≤−70°C. In frozen native CSF specimens, Aβ1-40 was mostly stable up to 3 years at ≤−70°C, whereas stability of Aβ1-42 was limited to 221 days. Dose-dependent changes in measured CSF Aβ were observed in healthy volunteers up to 36 hours after treatment with the β-site cleavage enzyme inhibitor LY2886721. In conclusion, rigorous validation tests have successfully demonstrated the strengths and operational limitations of these INNOTEST® -based assays. They have proved to be robust and reliable tools for pharmacodynamic evaluations of investigational AD therapeutics in clinical trials. Show more

Keywords: Alzheimer's disease, amyloid beta-peptide, biomarkers, cerebrospinal fluid, enzyme-linked immunosorbent assay, validation studies

DOI: 10.3233/JAD-141686

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 527-542, 2015

Authors: Ito, Kengo | Fukuyama, Hidenao | Senda, Michio | Ishii, Kazunari | Maeda, Kiyoshi | Yamamoto, Yasuji | Ouchi, Yasuomi | Ishii, Kenji | Okumura, Ayumu | Fujiwara, Ken | Kato, Takashi | Arahata, Yutaka | Washimi, Yukihiko | Mitsuyama, Yoshio | Meguro, Kenichi | Ikeda, Mitsuru | SEAD-J Study Group

Article Type: Research Article

Abstract: Background: 18 F-FDG-PET is defined as a biomarker of neuronal injury according to the revised National Institute on Aging–Alzheimer’s Association criteria. Objective: The objective of this multicenter prospective cohort study was to examine the value of 18 F-FDG-PET in predicting the development of Alzheimer’s disease (AD) in patients with mild cognitive impairment (MCI). Methods: In total, 114 patients with MCI at 9 participating institutions underwent clinical and neuropsychological examinations, MRI, and 18 F-FDG-PET at baseline. The cases were visually classified into predefined dementia patterns by three experts. An automated analysis for 18 F-FDG-PET was also performed …to calculate the PET score. Subjects were followed periodically for 3 years, and progression to dementia was evaluated. Results: In 47% of the patients with MCI, progression of symptoms justified the clinical diagnosis of “probable AD”. The PET visual interpretation predicted conversion to AD during 3-year follow-up with an overall diagnostic accuracy of 68%. Overall diagnostic accuracy of the PET score was better than that of PET visual interpretation at all follow-up intervals, and the optimized PET score threshold revealed the best performance at the 2-year follow-up interval with an overall diagnostic accuracy of 83%, a sensitivity of 70%, and a specificity of 90%. Multivariate logistic regression analysis identified the PET score as the most significant predictive factor distinguishing AD converters from non-converters. Conclusion: The PET score is the most statistically significant predictive factor for conversion from MCI to AD, and the diagnostic performance of the PET score is more promising for rapid converters over 2 years. Show more

Keywords: Alzheimer's disease, cerebral glucose metabolism, 18F-FDG-PET, mild cognitive impairment, prospective study

DOI: 10.3233/JAD-141338

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 543-552, 2015