Journal of Alzheimer's Disease - Volume 26, issue 2

Authors: Babiloni, Claudio | Lizio, Roberta | Carducci, Filippo | Vecchio, Fabrizio | Redolfi, Alberto | Marino, Silvia | Tedeschi, Gioacchino | Montella, Patrizia | Guizzaro, Antonio | Esposito, Fabrizio | Bozzao, Alessandro | Giubilei, Franco | Orzi, Francesco | Quattrocchi, Carlo C. | Soricelli, Andrea | Salvatore, Elena | Baglieri, Annalisa | Bramanti, Placido | Cavedo, Enrica | Ferri, Raffaele | Cosentino, Filomena | Ferrara, Michelangelo | Mundi, Ciro | Grilli, Gianpaolo | Pugliese, Silvia | Gerardi, Gianluca | Parisi, Laura | Vernieri, Fabrizio | Triggiani, Antonio I. | Pedersen, Jan T. | Hårdemark, Hans-Göran | Rossini, Paolo M. | Frisoni, Giovanni B.

Article Type: Research Article

Abstract: Resting state electroencephalographic (EEG) rhythms do not deteriorate with the increase of white matter vascular lesion in amnesic mild cognitive impairment (MCI) subjects [1], although white matter is impaired along Alzheimer's disease (AD). Here we tested whether this is true even in AD subjects. Closed-eye resting state EEG data were recorded in 40 healthy elderly (Nold), 96 amnesic MCI, and 83 AD subjects. White matter vascular lesions were indexed by magnetic resonance imaging recorded in the MCI and AD subjects (about 42% of cases following ADNI standards). The MCI subjects were divided into two sub-groups based on the median of …the white matter lesion, namely MCI+ (people with highest vascular load; n = 48) and MCI− (people with lowest vascular load; n = 48). The same was true for the AD subjects (AD+, n = 42; AD−, n = 41). EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha1 (8–10.5 Hz), alpha2 (10.5–13 Hz), beta1 (13–20 Hz), beta2 (20–30 Hz), and gamma (30–40 Hz). LORETA software estimated cortical EEG sources. When compared to Nold group, MCI and AD groups showed well known abnormalities of delta and alpha sources. Furthermore, amplitude of occipital, temporal, and limbic alpha 1 sources were higher in MCI+ than MCI− group. As a novelty, amplitude of occipital delta sources was lower in AD+ than AD− group. Furthermore, central, parietal, occipital, temporal, and limbic alpha sources were higher in amplitude in AD+ than AD− group. Amplitude of these sources was correlated to global cognitive status (i.e., Mini Mental State Evaluation score). These results suggest that in amnesic MCI and AD subjects, resting state posterior delta and alpha EEG rhythms do not deteriorate with the increase of white-matter vascular lesion. These rhythms might be more sensitive to AD neurodegenerative processes and cognitive status rather than to concomitant lesions to white matter. Show more

Keywords: Alzheimer's disease, Alzheimer's disease neuroimaging initiative, amnesic mild c cognitive impairment, electroencephalographic rhythms, low resolution brain electromagnetic tomography, magnetic resonance imaging, resting state, white matter vascular lesion

DOI: 10.3233/JAD-2011-101710

Citation: Journal of Alzheimer's Disease, vol. 26, no. 2, pp. 331-346, 2011

Authors: Humbert, Ianessa A. | McLaren, Donald G. | Malandraki, Georgia | Johnson, Sterling C. | Robbins, JoAnne

Article Type: Research Article

Abstract: Frontal cortical activation is elicited when subjects have been instructed not to initiate a sensorimotor task. The goal of this preliminary fMRI study was to examine BOLD response to a “Do Not Swallow” instruction (an intentional “off-state”) in the context of other swallowing tasks in 3 groups of participants (healthy young, healthy old, and early Alzheimer's disease (AD)). Overall, the older group had larger, bilaterally active clusters in the cortex, including the dorsomedial prefrontal cortex during the intentional swallowing off-state; this region is commonly active in response inhibition studies. Disease-related differences were evident where the AD group had significantly greater …BOLD response in the insula/operculum than the old. These findings have significant clinical implications for control of swallowing across the age span and in neurodegenerative disease. Greater activation in the insula/operculum for the AD group supports previous studies where this region is associated with initiating swallowing. The AD group may have required more effort to “turn off” swallowing centers to reach the intentional swallowing off-state. Show more

Keywords: Alzheimer's disease, cognitive aging, deglutition, fMRI

DOI: 10.3233/JAD-2011-110380

Citation: Journal of Alzheimer's Disease, vol. 26, no. 2, pp. 347-354, 2011

Authors: Lee, Sangmook | Hall, Garth F. | Shea, Thomas B.

Article Type: Research Article

Abstract: Hyperphosphorylation of tau is closely associated with its aggregation by as yet undefined mechanisms. We attempted herein to further investigate the interrelationships between tau aggregation and phosphorylation by inhibition and activation of cdk5 and GSK3β in cells expressing normal tau and a mutant form of tau (3PO-tau), which generates intracellular aggregates while retaining microtubule-binding capacity). Aggregates were routinely observed in cells expressing 3PO-tau, but never in cells expressing normal tau, whether or not cdk5 or GSK3β was overexpressed. In addition, in cells expressing 3PO-tau, both the percentage of cells with aggregates, as well as the size of aggregates, was increased …following overexpression of cdk5 or GSK3β, decreased following treatment with pharmacological agents (roscovitine and lithium) active against these kinases, and increased following treatment with the phosphatase inhibitor okadaic acid. These findings collectively indicate that phosphorylation potentiates aggregation in the presence of one or more key tau mutations. These findings confirm and extend prior studies in which overexpression of the cdk5 activator p35, or GSK3β, induced phosphorylation, mislocalization and/or aggregation of tau. Show more

Keywords: Aggregation, caspase, cdk5, cleavage, GSK3β, lithium, okadaic acid, phosphorylation, PP2A, roscovitine, tau

DOI: 10.3233/JAD-2011-102016

Citation: Journal of Alzheimer's Disease, vol. 26, no. 2, pp. 355-364, 2011

Authors: Song, Fei | Poljak, Anne | Valenzuela, Michael | Mayeux, Richard | Smythe, George A. | Sachdev, Perminder S.

Article Type: Research Article

Abstract: Plasma amyloid-β (Aβ) levels have been proposed as biomarkers of Alzheimer's disease (AD), but studies have produced inconsistent results. We present a meta-analytic review of cross-sectional studies that examined plasma Aβ levels in AD and cognitively normal subjects, and longitudinal studies that used baseline plasma Aβ levels to predict conversion from normal cognition to AD. Medline and EMBASE databases were searched to generate an initial list of relevant studies, and selected authors approached for additional data. Twelve cross- sectional studies (n = 1483) and seven longitudinal (n = 3920) met the inclusion criteria for meta-analysis. Random effects model was used …to calculate the weighted mean difference (WMD) by Review Manager Version 4.2. In longitudinal studies, cognitively normal individuals who converted to AD had higher baseline Aβ1-40 and Aβ1-42 levels (WMD: 10.29, z = 3.80, p = 0.0001 and WMD: 8.01, z = 2.76, p = 0.006, respectively), and non-significantly increased Aβ1-42 /Aβ1-40 ratio (WMD: 0.03, z = 1.65, p = 0.10). In cross sectional studies, compared to cognitively normal individuals, AD patients had marginally but non-significantly lower Aβ1-42 levels (WMD:−2.84, z = 1.73, p = 0.08), but Aβ1-40 levels were not significantly different (WMD: 3.43, z = 0.40, p = 0.69). Our systematic review suggests a model of differential longitudinal changes in plasma Aβ levels in cognitively stable individuals versus those who go on to develop AD dementia. Baseline Aβ1-40 and Aβ1-42 levels in cognitively normal elderly individuals might be predictors of higher rates of progression to AD, and should be further explored as potential biomarkers. Show more

Keywords: Alzheimer's disease, amyloid-β, meta-analysis, plasma

DOI: 10.3233/JAD-2011-101977

Citation: Journal of Alzheimer's Disease, vol. 26, no. 2, pp. 365-375, 2011

Authors: Peuralinna, Terhi | Tanskanen, Maarit | Mäkelä, Mira | Polvikoski, Tuomo | Paetau, Anders | Kalimo, Hannu | Sulkava, Raimo | Hardy, John | Lai, Shiao-Lin | Arepalli, Sampath | Hernandez, Dena | Traynor, Bryan J. | Singleton, Andrew | Tienari, Pentti J. | Myllykangas, Liisa

Article Type: Research Article

Abstract: Cortical and cerebrovascular amyloid-β (Aβ) deposition is a hallmark of Alzheimer's disease (AD), but also occurs in elderly people not affected by dementia. The apolipoprotein E (APOE) ε4 is a major genetic modulator of Aβ deposition and AD risk. Variants of the amyloid-β protein precursor (AβPP) gene have been reported to contribute to AD and cerebral amyloid angiopathy (CAA). We analyzed the role of APOE and AβPP variants in cortical and cerebrovascular Aβ deposition, and neuropathologically verified AD (based on modified NIA-RI criteria) in a population-based autopsy sample of Finns aged ≥85 years (Vantaa85 + Study; n = 282). Our …updated analysis of APOE showed strong associations of the ε4 allele with cortical (p = 4.91 × 10−17 ) and cerebrovascular (p = 9.87 × 10−11 ) Aβ deposition as well as with NIA-RI AD (p = 1.62 × 10−8 ). We also analyzed 60 single nucleotide polymorphisms (SNPs) at the AβPP locus. In single SNP or haplotype analyses there were no statistically significant AβPP locus associations with cortical or cerebrovascular Aβ deposition or with NIA-RI AD. We sequenced the promoter of the AβPP gene in 40 subjects with very high Aβ deposition, but none of these subjects had any of the previously reported or novel AD-associated mutations. These results suggest that cortical and cerebrovascular Aβ depositions are useful quantitative traits for genetic studies, as highlighted by the strong associations with the APOE ε4 variant. Promoter mutations or common allelic variation in the AβPP gene do not have a major contribution to cortical or cerebrovascular Aβ deposition, or very late-onset AD in this Finnish population based study. Show more

Keywords: Alzheimer's disease, amyloid-β deposition, AβPP, APOE, cerebral amyloid angiopathy, neuropathology

DOI: 10.3233/JAD-2011-102049

Citation: Journal of Alzheimer's Disease, vol. 26, no. 2, pp. 377-385, 2011

Authors: Hook, Gregory | Hook, Vivian | Kindy, Mark

Article Type: Research Article

Abstract: The cysteine protease cathepsin B is a potential drug target for reducing brain amyloid-β (Aβ) and improving memory in Alzheimer's disease (AD), as reduction of cathepsin B in transgenic mice expressing human wild-type amyloid-β protein precursor (AβPP) results in significantly decreased brain Aβ. Cathepsin B cleaves the wild-type β-secretase site sequence in AβPP to produce Aβ, and cathepsin B inhibitors administered to animal models expressing AβPP containing the wild-type β-secretase site sequence reduce brain Aβ in a manner consistent with β-secretase inhibition. But such inhibitors could act either by direct inhibition of cathepsin B β-secretase activity or by off-target inhibition …of the other β-secretase, the aspartyl protease BACE1. To evaluate that issue, we orally administered a cysteine protease inhibitor, E64d, to normal guinea pigs or transgenic mice expressing human AβPP, both of which express the human wild-type β-secretase site sequence. In guinea pigs, oral E64d administration caused a dose-dependent reduction of up to 92% in brain, CSF, and plasma of Aβ40 and Aβ42 , a reduction of up to 50% in the C-terminal β-secretase fragment (CTFβ), and a 91% reduction in brain cathepsin B activity, but increased brain BACE1 activity by 20%. In transgenic AD mice, oral E64d administration improved memory deficits and reduced brain Aβ40 and Aβ42 , amyloid plaque, brain CTFβ, and brain cathepsin B activity, but increased brain BACE1 activity. We conclude that E64d likely reduces brain Aβ by inhibiting cathepsin B and not BACE1 β-secretase activity and that E64d therefore may have potential for treating AD patients. Show more

Keywords: Alzheimer disease, amyloid-β, BACE1, cathepsin B, guinea pig, memory deficits, oral E64d, transgenic mice

DOI: 10.3233/JAD-2011-110101

Citation: Journal of Alzheimer's Disease, vol. 26, no. 2, pp. 387-408, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-110421

Citation: Journal of Alzheimer's Disease, vol. 26, no. 2, pp. 409-411, 2011