Journal of Alzheimer's Disease - Volume 29, issue 3

Authors: Delano-Wood, Lisa | Stricker, Nikki H. | Sorg, Scott F. | Nation, Daniel A. | Jak, Amy J. | Woods, Steven P. | Libon, David J. | Delis, Dean C. | Frank, Lawrence R. | Bondi, Mark W.

Article Type: Research Article

Abstract: Medial temporal lobe and temporoparietal brain regions are among the earliest neocortical sites to undergo pathophysiologic alterations in Alzheimer's disease (AD), although the underlying white matter changes in these regions is less well known. We employed diffusion tensor imaging to evaluate early alterations in regional white matter integrity in participants diagnosed with mild cognitive impairment (MCI). The following regions of interests (ROIs) were examined: 1) anterior cingulum (AC); 2) posterior cingulum (PC); 3) genu of the corpus callosum; 4) splenium of the corpus callosum; and 5) as a control site for comparison, posterior limb of the internal capsule. Forty nondemented …participants were divided into demographically-similar groups based on cognitive status (MCI: n = 20; normal control: n = 20), and fractional anisotropy (FA) estimates of each ROI were obtained. MCI participants showed greater posterior white matter (i.e., PC, splenium) but not anterior white matter (i.e., AC, genu) changes, after adjusting for age, stroke risk, and whole brain volume. FA differences of the posterior white matter were best accounted for by changes in radial but not axial diffusivity. PC FA was also significantly positively correlated with hippocampal volume as well as with performance on tests of verbal memory, whereas stroke risk was significantly correlated with genu FA and was unrelated to PC FA. When investigating subtypes of our MCI population, amnestic MCI participants showed lower PC white matter integrity relative to those with non-amnestic MCI. Findings implicate involvement of posterior microstructural white matter degeneration in the development of MCI-related cognitive changes and suggest that reduced FA of the PC may be a candidate neuroimaging marker of AD risk. Show more

Keywords: Aging, diffusion tensor imaging, memory, mild cognitive impairment, posterior cingulum, white matter

DOI: 10.3233/JAD-2012-102103

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 589-603, 2012

Authors: Reiner, Peggy | Jouvent, Eric | Duchesnay, Edouard | Cuingnet, Rémi | Mangin, Jean-François | Chabriat, Hugues | The Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Differences of cortical morphology between healthy controls (HC), amnestic mild cognitive impairment (MCI), and Alzheimer's disease (AD) have been repeatedly investigated using voxel-based morphometry (VBM). However, the results obtained using mainly VBM remain difficult to interpret as they can be explained by various mechanisms. The aim of the present study was to evaluate the differences of cortical morphology between HC, MCI, and AD patients using a new post-processing method based on reconstruction and identification of cortical sulci. Thirty HC, 33 MCI, and 30 AD patients were randomly selected from the ADNI database. For each subject, cortical sulci were reconstructed and …automatically identified using Brainvisa software. Depth and fold opening of nine large sulci were compared between HC, MCI, and AD patients. Fold opening of parietaloccipital fissure and intraparietal sulcus on both sides strongly differed between the 3 groups, with gradual increase from HC to MCI of about 1 mm and from MCI to AD of about 2 mm (right intraparietal: p = 0.005; left intraparietal: p = 0.004; right parietaloccipital: p = 0.003; left parietaloccipital: p = 0.0009). Results were left unchanged after adjustment for age, gender, and level of education. These variables were also strongly linked to neuropsychological scores, independent of age, gender, and level of education. In the present study, we found important regional differences of cortical morphology with gradual deterioration from HC to MCI to AD. The most important differences were found in parietaloccipital fissure and intraparietal sulcus. Further studies are needed to understand the involved underlying mechanisms. Show more

Keywords: Alzheimer's disease, cortex, cortical sulci, mild cognitive impairment, MRI

DOI: 10.3233/JAD-2012-111622

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 605-613, 2012

Authors: Moon, Minho | Hong, Hyun-Seok | Nam, Dong Woo | Baik, Sung Hoon | Song, Hyundong | Kook, Sun-Young | Kim, Yong Soo | Lee, Jeewoo | Mook-Jung, Inhee

Article Type: Research Article

Abstract: One of the major hallmarks of Alzheimer's disease (AD) is the extracellular deposition of amyloid-β (Aβ) as senile plaques in specific brain regions. Clearly, an understanding of the cellular processes underlying Aβ deposition is a crucial issue in the field of AD research. Recent studies have found that accumulation of intraneuronal Aβ (iAβ) is associated with synaptic deficits, neuronal death, and cognitive dysfunction in AD patients. In this study, we found that Aβ deposits had several shapes and sizes, and that iAβ occurred before the formation of extracellular amyloid plaques in the subiculum of 5XFAD mice, an animal model of …AD. We also observed pyroglutamate-modified Aβ (N3pE-Aβ), which has been suggested to be a seeding molecule for senile plaques, inside the Aβ plaques only after iAβ accumulation, which argues against its seeding role. In addition, we found that iAβ accumulates in calcium-binding protein (CBP)-free neurons, induces neuronal death, and then develops into senile plaques in 2-4-month-old 5XFAD mice. These findings suggest that N3pE-Aβ-independent accumulation of Aβ in CBP-free neurons might be an early process that triggers neuronal damage and senile plaque formation in AD patients. Our results provide new insights into several long-standing gaps in AD research, namely how Aβ plaques are formed, what happens to iAβ and how Aβ causes selective neuronal loss in AD patients. Show more

Keywords: 5XFAD mice, Alzheimer's disease, amyloid plaque, calcium-binding proteins, intraneuronal Aβ, pyroglutamate-modified Aβ

DOI: 10.3233/JAD-2011-111778

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 615-628, 2012

Authors: Zhuang, Lin | Wen, Wei | Trollor, Julian N. | Kochan, Nicole A. | Reppermund, Simone | Brodaty, Henry | Sachdev, Perminder

Article Type: Research Article

Abstract: The fornix is a major efferent tract of the hippocampus, a structure critical for normal memory function. However, the role of structural degradation of the fornix in memory dysfunction in mild cognitive impairment (MCI) has remained unclear. We used diffusion tensor tractography to measure microstructural properties of the fornix and the corticospinal tract (CST), as a control tract, in 206 cognitively normal subjects, 76 amnestic MCI (aMCI) and 51 non-amnestic MCI (naMCI) subjects. Hippocampal volumes were measured using deformation-based morphometry. We found significant fractional anisotropy reductions in the left fornix and radial diffusivity (RD) increases in bilateral fornices in aMCI, …but not in naMCI, compared with controls. No significant changes in the CST were found in aMCI subjects, but naMCI subjects showed significantly increased RD and axial diffusivity of the right CST, compared with controls. Increased left fornical RD measure was correlated with poor verbal memory performance in aMCI subjects. In addition, reduced microstructural integrity of the fornix was associated with hippocampal atrophy in aMCI. This study suggests that microstructural alteration of the fornix is a contributor to early episodic memory dysfunction in non-demented individuals. Show more

Keywords: Amnestic mild cognitive impairment, diffusion tensor tractography, fornix, hippocampus, non-amnestic mild cognitive impairment

DOI: 10.3233/JAD-2012-111766

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 629-639, 2012

Authors: Schmand, Ben | Eikelenboom, Piet | van Gool, Willem A. | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Using the database of the Alzheimer's Disease Neuroimaging Initiative, we examined the value of neuropsychological assessment, structural magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarkers, and FDG-PET scanning with respect to prediction of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). We tested the hypothesis that CSF biomarkers and FDG-PET would lose prognostic value when applied in patients older than 75 years, whereas MRI and neuropsychological testing would not. At baseline 175 patients had MCI, mostly amnestic. They were followed during a mean of 2.7 years, and 81 patients converted to AD after a mean of 1.6 years. …Logistic regression analyses showed that neuropsychological assessment and MRI variables predicted conversion with 63 to 67% classification success both in patients younger and older than 75 years, while CSF biomarkers attained this success rate only in patients younger than 75 years. For FDG-PET, this rate was 57% in the total sample. We conclude that the diagnostic yield of different techniques in predicting conversion from MCI to AD is moderate, and that it is affected by age of the subject under study. MRI and neuropsychological assessment remain informative in patients older than 75 years, unlike CSF biomarkers. Show more

Keywords: Alzheimer's disease, amyloid, cerebrospinal fluid, FDG-PET, mild cognitive impairment, MRI, neuropsychological tests, tau protein

DOI: 10.3233/JAD-2012-111703

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 641-648, 2012

Authors: Kim, Nam-Gyoon

Article Type: Research Article

Abstract: The current study examined whether diminished sensitivity to dynamic occlusion in Alzheimer's disease (AD) contributes to reduced capacity to recover 3D shape from motion. Young controls, age-matched elderly controls, and AD patients participated in the study. Participants watched computer simulations of an object, depicted as either transparent or opaque, rotating about the vertical axis against a background rendered in random dot texture. Six geometric solids were graphically simulated, each rendered in three texture densities, against three different levels of background texture densities. Participants identified the displayed object by pointing to the matching wooden object. Young controls were most accurate (79%), …followed by elderly controls (61%) and AD patients (43%). Both control groups identified opaque objects better than transparent objects, but AD patients identified both objects equally poorly. These results demonstrate that dynamic occlusion (i.e., accretion and deletion of optical texture at the occluding edge) facilitates recovery of 3D shape from motion but such capacity is severely impaired in AD. The current results suggest the need for more research into dynamic occlusion, not only as source of information to recover 3D shape from motion, but also as a visual deficit in AD. Show more

Keywords: Alzheimer's disease, dynamic occlusion, projective correspondence, structure-from-motion, 3D shape perception

DOI: 10.3233/JAD-2012-111688

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 649-658, 2012

Authors: Lin, Gui Hua | Lee, Young-Jung | Choi, Dong-Young | Han, Sang Bae | Jung, Jae Kyung | Hwang, Bang Yeon | Moon, Dong Cheul | Kim, Youngsoo | Lee, Myung Koo | Oh, Ki-Wan | Jeong, Heon Sang | Leem, Jae Yoon | Shin, Hwa Kyoung | Lee, Jung Hwa | Hong, Jin Tae

Article Type: Research Article

Abstract: Neuroinflammation is implicated for amyloidogenesis. Sulfur compounds extracted from garlic have been shown to have anti-inflammatory properties. Previously, we have investigated that thiacremonone, a sulfur compound isolated from garlic has anti-inflammatory effects. To investigate thiacremonone's potential effect on anti-neuroinflammation and anti-amyloidogenesis, 4 week old ICR mice were given different doses of thiacremonone (1, 3, and 10 mg/kg) in drinking water for 1 month and received intraperitoneal injection of lipopolysaccharide (LPS) (250 μg/kg/day) at last 7 days of treatment. Our data show thiacremonone decreased LPS-induced memory impairment, glial activation, pro-inflammatory mediators' expression, and amyloidogenesis. In an in vitro study, we obtained …similar results, with thiacremonone (1, 2, and 5 μg/ml) effectively decreased LPS (1 μg/ml)-induced glial activation and inflammatory mediators generation which are implicated in amyloidogenesis. Our data also demonstrated that thiacremonone inhibited LPS-induced amyloidogenesis in cultured astrocytes and microglial BV-2 cells. NF-κB, a critical transcriptional factor regulating not only inflammation but also amyloid-β generation, was inhibited by thiacremonone via blocking of phosphorylation of IκBα in mice brain as well as cultured astrocytes and microglial BV-2 cells. These results indicated that the anti-inflammatory compound, thiacremonone, inhibited neuroinflammation and amyloidogenesis through inhibition of NF-κB activity, and thus could be applied for intervention of inflammation-related neurodegenerative disease including Alzheimer's disease. Show more

Keywords: Amyloidogenesis, neuroinflammation, NF-κb, thiacremonone

DOI: 10.3233/JAD-2012-111709

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 659-676, 2012

Authors: Lee, Young-Jung | Choi, Dong-Young | Lee, Yong Kyoung | Lee, Yoot Mo | Han, Sang Bae | Kim, Young Hee | Kim, Ki Ho | Nam, Sang-Yoon | Lee, Beom Jun | Kang, Jong-Koo | Yun, Young Won | Oh, Ki-Wan | Hong, Jin Tae

Article Type: Research Article

Abstract: Alzheimer's disease (AD), the most common form of dementia, is characterized by memory deficits and deposition of amyloid-β (Aβ) in the brain. It has been known that neuroinflammation and oxidative stress are critical factors in the development of AD. 4-O-methylhonokiol, an extract from Magnolia officinalis, is known to have anti-inflammatory and anti-oxidative effects. Thus, we investigated the properties of 4-O-methylhonokiol against progression and development of AD in Tg2576 mice. Tg2576 mice models show memory impairment and AD-like pathological features including Aβ deposition. Oral administration of 4-O-methylhonokiol through drinking water (1 mg/kg in 0.0002% Tween 80) for 12 weeks not only …prevented memory impairment but also inhibited Aβ deposition. In addition, 4-O-methylhonokiol decreased β-secretase activity, oxidative lipid and protein damage levels, activation of astrocytes and microglia cells, and generation of IL-1β and TNF-α with increase of glutathione level in the brain. Our results showed that 4-O-methylhonokiol effectively prevented memory impairment by down-regulating β-secretase activity through inhibition of oxidative stress and neuroinflammatory responses in Tg2576 transgenic mice. Show more

Keywords: 4-O-methylhonokiol, Alzheimer's disease, β-secretase, neuroinflammation, oxidative stress

DOI: 10.3233/JAD-2012-111835

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 677-690, 2012

Authors: Cunnane, Stephen C. | Schneider, Julie A. | Tangney, Christine | Tremblay-Mercier, Jennifer | Fortier, Mélanie | Bennett, David A. | Morris, Martha Clare

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is generally associated with lower omega-3 fatty acid intake from fish but despite numerous studies, it is still unclear whether there are differences in omega-3 fatty acids in plasma or brain. In matched plasma and brain samples provided by the Memory and Aging Project, fatty acid profiles were quantified in several plasma lipid classes and in three brain cortical regions. Fatty acid data were expressed as % composition and as concentrations (mg/dL for plasma or mg/g for brain). Differences in plasma fatty acid profiles between AD, mild cognitive impairment (MCI), and those with no cognitive impairment (NCI) …were most apparent in the plasma free fatty acids (lower oleic acid isomers and omega-6 fatty acids in AD) and phospholipids (lower omega-3 fatty acids in AD). In brain, % DHA was lower only in phosphatidylserine of mid-frontal cortex and superior temporal cortex in AD compared to NCI (−14% and −12%, respectively; both p < 0.05). The only significant correlation between plasma and brain fatty acids was between % DHA in plasma total lipids and % DHA in phosphatidylethanolamine of the angular gyrus, but only in the NCI group (+0.77, p < 0.05). We conclude that AD is associated with altered plasma status of both DHA and other fatty acids unrelated to DHA, and that the lipid class-dependent nature of these differences reflects a combination of differences in intake and metabolism. Show more

Keywords: Alzheimer's disease, brain lipids, docosahexaenoic acid, free fatty acids, mild cognitive impairment, memory and aging project, oleic acid, omega-3 fatty acids, polyunsaturates, phospholipids

DOI: 10.3233/JAD-2012-110629

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 691-697, 2012

Authors: Di Maria, Emilio | Giorgio, Elisa | Uliana, Vera | Bonvicini, Cristian | Faravelli, Francesca | Cammarata, Sergio | Novello, Maria Cristina | Galimberti, Daniela | Scarpini, Elio | Zanetti, Orazio | Gennarelli, Massimo | Tabaton, Massimo

Article Type: Research Article

Abstract: The complex network of neurotrophic factors is supposed to play a role in neurodegeneration, but the effect of variations in their coding genes on susceptibility to sporadic Alzheimer's disease is not established. The mature form of nerve growth factor (NGF) derives from a precursor, proNGF, which was recently discovered to exert crucial functions in brain. We designed a case-control association study to test the hypothesis as to whether polymorphisms located in the proNGF genomic region influence the liability to Alzheimer's disease and its prodromal form, mild cognitive impairment. Three independent case-control samples, with individuals aged >60 years, were collected in …Italian Alzheimer Units. One polymorphism located in the proNGF region, rs6330, demonstrated a minor allele frequency >5% and was used in the association study. The minor allele of rs6330 was more frequent in patients from the three sample series as compared to respective normal controls. Multivariate logistic regression showed a significant association under the dominant model in one cohort (OR 1.83, 95% CI 1.00–3.54) and in the pooled case-control sample (OR 1.47, 95% CI 1.03–2.08). These findings further suggest that proNGF may play a role in Alzheimer-type neurodegeneration and that genetic variations in the NGF locus may influence the occurrence of sporadic, late-onset Alzheimer's disease. Show more

Keywords: Alzheimer's disease, APOE, association study, mild cognitive impairment, NGF, NGFB, proNGF

DOI: 10.3233/JAD-2012-112006

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 699-705, 2012