Journal of Alzheimer's Disease - Volume 36, issue 4

Authors: Kepe, Vladimir | Moghbel, Mateen C. | Långström, Bengt | Zaidi, Habib | Vinters, Harry V. | Huang, Sung-Cheng | Satyamurthy, Nagichettiar | Doudet, Doris | Mishani, Eyal | Cohen, Robert M. | Høilund-Carlsen, Poul F. | Alavi, Abass | Barrio, Jorge R.

Article Type: Review Article

Abstract: The rapidly rising prevalence and cost of Alzheimer's disease in recent decades has made the imaging of amyloid-β deposits the focus of intense research. Several amyloid imaging probes with purported specificity for amyloid-β plaques are currently at various stages of FDA approval. However, a number of factors appear to preclude these probes from clinical utilization. As the available “amyloid specific” positron emission tomography imaging probes have failed to demonstrate diagnostic value and have shown limited utility for monitoring therapeutic interventions in humans, a debate on their significance has emerged. The aim of this review is to identify and discuss critically …the scientific issues contributing to the extensive inconsistencies reported in the literature on their purported in vivo amyloid specificity and potential utilization in patients. Show more

Keywords: Amyloid imaging, amyloid ‘specific’ imaging probes, Amyvid, critical review, neuropathologic criteria, PIB, silent medial temporal lobe

DOI: 10.3233/JAD-130485

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 613-631, 2013

Authors: Khmeleva, Svetlana A. | Mezentsev, Yuri V. | Kozin, Sergey A. | Tsvetkov, Philipp O. | Ivanov, Alexis S. | Bodoev, Nikolay V. | Makarov, Alexander A. | Radko, Sergey P.

Article Type: Short Communication

Abstract: The interaction of the 16-mer synthetic peptide (Aβ16 ), which represents the metal-binding domain of the amyloid-β with DNA, was studied employing the surface plasmon resonance technique. It has been shown that Aβ16 binds to the duplex DNA in the presence of zinc ions and thus the metal-binding domain can serve as a zinc-dependent DNA-binding site of the amyloid-β. The interaction of Aβ16 with DNA most probably depends on oligomerization of the peptide and is dominated by interaction with phosphates of the DNA backbone.

Keywords: Alzheimer's disease, amyloid-β peptide, DNA, zinc

DOI: 10.3233/JAD-130122

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 633-636, 2013

Authors: Saydoff, Joel A. | Olariu, Ana | Sheng, Jin | Hu, Zhongyi | Li, Qin | Garcia, Rolando | Pei, Jiong | Sun, Grace Y. | von Borstel, Reid

Article Type: Research Article

Abstract: Uridine prodrug PN401 has been shown to have neuroprotective effects in models of Parkinson's disease and Huntington's disease. These age-related neurodegenerative diseases including Alzheimer's disease (AD) are associated with mitochondrial dysfunction, oxidative stress, and inflammation. Attenuation of these pathological factors in AD, in addition to amyloid fibrils and neurofibrillary tangles, is critical to prevent cognitive impairment. The effects of PN401 treatment were tested in the Tg2576 and Tg2576 X P301L (TAPP) mouse models of AD. Treatment with PN401 reduced impairments in the Tg2576 mice in contextual fear conditioning and novel object recognition. In the TAPP mice, PN401 reduced the impairments …in novel object recognition and social transmission of food preference. PN401 also improved motor behavior and reduced anxiety-like behavior in the TAPP mice. TAPP mouse hippocampal tau phosphorylation and lipid peroxidation were reduced by PN401 treatment. Increased tau phosphorylation was significantly correlated with worsening novel object recognition memory. PN401 did not affect amyloid plaque area in the AD mice. In other AD-related animal studies, PN401 treatment reduced blood-brain barrier damage due to intracortical LPS, elevation of serum TNFα due to systemic LPS, and hippocampal CA1 neuronal loss in the gerbil stroke model. Uridine dose-dependently protected cells from chemical hypoxia and ceramide, and decreased formation of reactive oxygen species and mitochondrial DNA damage due to hydrogen peroxide. These protective effects were achieved by raising uridine levels to at least 25–50 μM and serum uridine levels in this range in humans were obtained with oral PN401. Show more

Keywords: Alzheimer's disease, cognition, inflammation, lipid peroxidation, mitochondria, neurodegenerative diseases, stroke, uridine

DOI: 10.3233/JAD-130059

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 637-657, 2013

Authors: Sun, Fen | Mao, XiaoOu | Xie, Lin | Greenberg, David A. | Jin, Kunlin

Article Type: Research Article

Abstract: Neuroglobin is a neuronal protein with protective effects in animal models of stroke and Alzheimer's disease, but the relevance of these effects to Alzheimer's disease in humans is unknown. We measured neuroglobin levels by western blot and immunostained hippocampal sections for neuroglobin, cell-type protein markers, and amyloid-β, in brain tissue obtained at autopsy from patients with Alzheimer's disease. Neuroglobin levels were increased in early and moderately advanced Alzheimer's disease compared to controls, but declined to control levels in severe disease. In patients with Alzheimer's disease, neuroglobin was detected within neurons, as well as at extracellular sites associated with amyloid-β deposits. …We conclude that, as in transgenic mouse models, neuroglobin may influence the course of clinical Alzheimer's disease. Show more

Keywords: Alzheimer's disease, amyloid-β, hypoxia, neuroglobin, neuroprotection, stroke

DOI: 10.3233/JAD-130323

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 659-663, 2013

Authors: Poole, Sophie | Singhrao, Sim K. | Kesavalu, Lakshmyya | Curtis, Michael A. | Crean, StJohn

Article Type: Research Article

Abstract: The aim of this study was to establish a link between periodontal disease and Alzheimer's disease (AD) with a view to identifying the major periodontal disease bacteria (Treponema denticola, Tannerella forsythia, and Porphyromonas gingivalis) and/or bacterial components in brain tissue from 12 h postmortem delay. Our request matched 10 AD cases for tissue from Brains for Dementia Research alongside 10 non-AD age-related controls with similar or greater postmortem interval. We exposed SVGp12, an astrocyte cell line, to culture supernatant containing lipopolysaccharide (LPS) from the putative periodontal bacteria P. gingivalis. The challenged SVGp12 cells and cryosections from AD and control brains …were immunolabeled and immunoblotted using a battery of antibodies including the anti-P. gingivalis-specific monoclonal antibody. Immunofluorescence labeling demonstrated the SVGp12 cell line was able to adsorb LPS from culture supernatant on its surface membrane; similar labeling was observed in four out of 10 AD cases. Immunoblotting demonstrated bands corresponding to LPS from P. gingivalis in the SVGp12 cell lysate and in the same four AD brain specimens which were positive when screened by immunofluorescence. All controls remained negative throughout while the same four cases were consistently positive for P. gingivalis LPS (p = 0.029). This study confirms that LPS from periodontal bacteria can access the AD brain during life as labeling in the corresponding controls, with equivalent/longer postmortem interval, was absent. Demonstration of a known chronic oral-pathogen-related virulence factor reaching the human brains suggests an inflammatory role in the existing AD pathology. Show more

Keywords: Alzheimer's disease, lipopolysaccharide, periodontal disease, Porphyromonas gingivalis, postmortem

DOI: 10.3233/JAD-121918

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 665-677, 2013

Authors: Korff, Ane | Liu, Changqin | Ginghina, Carmen | Shi, Min | Zhang, Jing | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: In addition to amyloid-β (Aβ) and tau, α-synuclein, best known for its role in Parkinson's disease (PD), has been suggested to be involved in cognition and pathogenesis of Alzheimer's disease (AD). We investigate the potential of α-synuclein in cerebrospinal fluid (CSF) as a biomarker of cognitive decline in AD, and its prodromal phase, mild cognitive impairment (MCI). Using an established, sensitive Luminex assay, we measured α-synuclein levels in the CSF of a cohort of close to 400 healthy control, MCI, and AD subjects obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and factored in APOE genotype in data analysis. CSF …α-synuclein levels were significantly higher in the MCI (p = 0.005) and AD (p < 0.001) groups, compared to controls. However, receiver operating characteristic (ROC) curve analysis suggests that CSF α-synuclein level on its own only offered modest sensitivity (65%) and specificity (74%) as a diagnostic marker of AD, with an area under the curve (AUC) value of 0.719 for AD versus controls. The effect of APOE genotype, if any, was quite subtle. However, there was a significant correlation between α-synuclein and cognition (p = 0.001), with increased α-synuclein levels associated with decreased Mini-Mental State Exam scores. Our results support a role for α-synuclein even in MCI, the early phase of AD, in addition to being a potential contributor in MCI and AD diagnosis or monitoring of disease progression. Show more

Keywords: α-Synuclein, Alzheimer's disease, biomarkers, cerebrospinal fluid, mild cognitive impairment

DOI: 10.3233/JAD-130458

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 679-688, 2013

Authors: Nation, Daniel A. | Wierenga, Christina E. | Clark, Lindsay R. | Dev, Sheena I. | Stricker, Nikki H. | Jak, Amy J. | Salmon, David P. | Delano-Wood, Lisa | Bangen, Katherine J. | Rissman, Robert A. | Liu, Thomas T. | Bondi, Mark W.

Article Type: Research Article

Abstract: Background: Reduced regional cerebral blood flow (rCBF) is a well-established finding in Alzheimer’s disease (AD), although fewer studies have examined the role of increased regional cerebrovascular resistance. By calculating the ratio of mean arterial pressure to rCBF, it is possible to estimate an index of regional cerebrovascular resistance (CVRi) that may be a sensitive measure of occult cerebrovascular disease. Objective: To compare probable AD patients to mild cognitive impairment (MCI) and normal control (NC) participants on CVRi, the ratio of mean arterial pressure to rCBF. Methods: Eighty-one participants (12 AD, 23 MCI, 46 NC) were compared …on CVRi using voxel-wise analyses. Region-of-interest analyses examined correlations between subcortical CVRi and both cognition and white matter lesion (WML) volume. Results: Voxel-wise analyses revealed CVRi elevation in AD relative to NCs (subcortical, medial temporal, posterior cingulate, precuneus, inferior parietal, superior temporal) and MCI (subcortical, posterior cingulate). MCI participants exhibited intermediate CVRi values within cortical and medial temporal areas. Significant CVRi clusters were larger and more widespread than those of parallel CBF analyses. Among MCI and AD participants, subcortical CVRi elevation was associated with lower Dementia Rating Scale score (r = −0.52, p = 0.001, for both thalamus and caudate), and caudate CVRi correlated with WML volume (r = 0.45, p = 0.001). Conclusions: Cortical and subcortical CVRi is elevated in AD, particularly within the caudate and thalamus, where it is associated with decreased cognitive performance and increased WMLs. Findings suggest CVRi may play a role in cognitive decline and cerebrovascular disease in MCI and AD. Show more

Keywords: Alzheimer's disease, cerebral blood flow, cerebrovascular resistance, mild cognitive impairment

DOI: 10.3233/JAD-130086

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 689-698, 2013

Authors: Cholerton, Brenna | Larson, Eric. B. | Baker, Laura D. | Craft, Suzanne | Crane, Paul K. | Millard, Steven P. | Sonnen, Joshua A. | Montine, Thomas J.

Article Type: Research Article

Abstract: Many cognitively normal older adults have underlying neuropathologic changes of Alzheimer's disease (AD), vascular brain injury (VBI), or Lewy body disease (LBD), which confer an increased risk of dementia. The current study focused on the association between multiple neuropathologic indices and performance on specific cognitive domains in a community sample of older adults. Of 438 participants in the Adult Changes in Thought population-based study of brain aging who were autopsied, 363 subjects had cognitive testing at their final study visit and were included. Associations were measured between performance on the Cognitive Abilities Screening Instrument prior to death and neuropathologic endpoints, …including AD neuropathologic changes, LBD, cerebral amyloid angiopathy, and measures of VBI. Braak stage for neurofibrillary tangles, lower brain weight, and VBI as measured by cerebral cortical microvascular lesions (μVBI) explained a significant proportion of the variance associated with global cognitive test performance (R2 = 0.31, p < 0.0001) both in the entire sample and when analysis was restricted to non-demented subjects (R2 = 0.23, p < 0.0001). Specific cognitive domains were differentially related to neuropathologic lesion type: memory and executive function with AD pathologic changes and cortical μVBI, executive function with subcortical μVBI, and visuospatial construction with LBD. Thus, neuropathologic lesions of LBD and μVBI are associated with poorer cognitive performance over and above AD neuropathologic changes in subjects without dementia in this cohort. These findings underscore that cognitive impairment is a complex convergent trait that has important implications for clinical investigation and medical management of older adults. Show more

Keywords: Alzheimer's disease, brain, cerebrovascular disorders, cognition, dementia, Lewy bodies, pathologic processes

DOI: 10.3233/JAD-130281

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 699-709, 2013

Authors: Grieder, Matthias | Crinelli, Raffaella M. | Jann, Kay | Federspiel, Andrea | Wirth, Miranka | Koenig, Thomas | Stein, Maria | Wahlund, Lars-Olof | Dierks, Thomas

Article Type: Research Article

Abstract: In Alzheimer's disease (AD) patients, episodic memory impairments are apparent, yet semantic memory difficulties are also observed. While the episodic pathology has been thoroughly studied, the neurophysiological mechanisms of the semantic impairments remain obscure. Semantic dementia (SD) is characterized by isolated semantic memory deficits. The present study aimed to find an early marker of mild AD and SD by employing a semantic priming paradigm during electroencephalogram recordings. Event-related potentials (ERP) of early (P1, N1) and late (N400) word processing stages were obtained to measure semantic memory functions. Separately, baseline cerebral blood flow (CBF) was acquired with arterial spin labeling. Thus, …the analysis focused on linear regressions of CBF with ERP topographical similarity indices in order to find the brain structures that showed altered baseline functionality associated with deviant ERPs. All participant groups showed semantic priming in their reaction times. Furthermore, decreased CBF in the temporal lobes was associated with abnormal N400 topography. No significant CBF clusters were found for the early ERPs. Taken together, the neurophysiological results suggested that the automatic spread of activation during semantic word processing was preserved in mild dementia, while controlled access to the words was impaired. These findings suggested that N400-topography alterations might be a potential marker for the detection of early dementia. Such a marker could be beneficial for differential diagnosis due to its low cost and non-invasive application as well as its relationship with semantic memory dysfunctions that are closely associated to the cortical deterioration in regions crucial for semantic word processing. Show more

Keywords: Alzheimer's disease, cerebral blood flow, event-related potential, magnetic resonance imaging, N400, semantic dementia, semantic memory, volumetry

DOI: 10.3233/JAD-121690

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 711-731, 2013

Authors: Rasmussen, Lucas | Delabio, Roger | Horiguchi, Lie | Mizumoto, Igor | Terazaki, Carlos-Renato | Mazzotti, Diego | Bertolucci, Paulo-Henrique | Pinhel, Marcela-Augusta | Souza, Dorotéia | Krieger, Henrique | Kawamata, Carlos | Minett, Thais | Smith, Marilia Cardoso | Payão, Spencer-Luiz

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease that takes the form of a local overexpression of cytokines and other inflammatory molecules. We investigated three single-nucleotide polymorphisms (SNP) of the interleukin 6 gene (IL-6) promoter region [−174G/C (rs 1800795), −572C/G (rs 1800796), and −597G/A (rs 1800797)] in 200 patients with late-onset AD and 165 elderly controls in a Brazilian case-control population sample. Genotyping was carried out from blood cells using PCR-RFLP techniques. Statistical analysis was performed to evaluate the Hardy-Weinberg equilibrium and to compare frequencies between groups. No association was found between any IL-6 polymorphism and AD; however the haplotype …composed of the −597 A allele and the −174G allele indicated a crude odds ratio (OR) of 0.15 (p = 0.0021) and a significantly adjusted OR (adjusted for the APOE E4 allele value) of 0.15 (p = 0.00294). Linkage disequilibrium was D' = 0.68 among the three SNPs. Our findings revealed a protective effect of AG (−597A, −174G) haplotype, which worked independently of the APOE E4 allele in our Brazilian population sample. Thus, the promoter region of IL-6 gene probably exerts an effect through gene linkage and/or gene interaction. Show more

Keywords: Association study, case-control study, haplotype, interleukin 6 gene, polymorphisms

DOI: 10.3233/JAD-122407

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 733-738, 2013