Journal of Alzheimer's Disease - Volume 23, issue 1

Authors: Nowicka, Aleksandra | Szczepankiewicz, Andrzej A. | Jaklewicz, Andrzej | Filipek, Anna | Barcikowska, Maria | Elbaum, Danek

Article Type: Short Communication

Abstract: Several neurodegenerative diseases, including Alzheimer's disease (AD), have etiology connected to abnormal protein self association. Copper-induced striking differences in amyloid-β40 aggregation, distinct from spontaneous self association, prompted us to study whether amyloid-β40 aggregation could be applied to differentiate between platelet poor plasma ultrafiltrates obtained from AD and control samples. We report, based on 20 AD and 18 age-matched controls, a significant difference in the concentration of short fibers induced by ultrafiltrated plasma from AD compared to control samples. The observed effect was independent of copper and other EDTA chelatable ions.

Keywords: Alzheimer's disease, amyloid-β, blood plasma, copper

DOI: 10.3233/JAD-2010-101137

Citation: Journal of Alzheimer's Disease, vol. 23, no. 1, pp. 1-5, 2011

Authors: Rossi, Giacomina | Piccoli, Elena | Benussi, Luisa | Caso, Francesca | Redaelli, Veronica | Magnani, Giuseppe | Binetti, Giuliano | Ghidoni, Roberta | Perani, Daniela | Giaccone, Giorgio | Tagliavini, Fabrizio

Article Type: Research Article

Abstract: Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder characterized by behavioural disturbances and cognitive decline. Here we describe an Italian family with FTLD showing remarkable phenotypic heterogeneity. Based on low plasma levels of progranulin, we analyzed the progranulin gene (GRN) in two patients with early onset and found the novel frame-shift mutation T278SfsX7. mRNA analysis confirmed the null effect of the mutation. The patients were homozygous for H1 MAPT haplotype, a disease modifier factor that can account for early age at onset. Being predictive for GRN null mutations, plasma progranulin dosage should be included in diagnostic work-up of dementia.

Keywords: Early onset, frontotemporal lobar degeneration, mutation, plasma dosage, progranulin

DOI: 10.3233/JAD-2010-101461

Citation: Journal of Alzheimer's Disease, vol. 23, no. 1, pp. 7-12, 2011

Authors: Sillén, Anna | Lilius, Lena | Forsell, Charlotte | Kimura, Toru | Winblad, Bengt | Graff, Caroline

Article Type: Research Article

Abstract: Two powerful genome-wide association studies have recently reported significant association between sporadic late-onset Alzheimer's disease (AD) and markers at the CLU locus in chromosome 8p. In this study, we have stratified our previously analyzed 109 Swedish AD families according to range in age at onset and performed whole-genome linkage analysis and subsequent fine-mapping in 8p21. The subgroup analyzed in the fine-mapping consisted of 28 families with AD, having a within-family onset-range not exceeding 8 years and an age at onset between 49 ≤ 70 years. A maximum non-parametric linkage peak (LOD = 3.5) was found between markers D8S1809 and 236c6-1. …Intriguingly this linked 9.5cM region contains clusterin (CLU), which is one of the two top susceptibility genes for AD. Our finding may be a reflection of linkage to the CLU susceptibility gene, in the same way as familial AD has previously been linked to the APOE locus. Show more

Keywords: 8p, age at onset, Alzheimer's disease, clusterin, dementia, linkage analysis

DOI: 10.3233/JAD-2010-101359

Citation: Journal of Alzheimer's Disease, vol. 23, no. 1, pp. 13-20, 2011

Authors: Anekonda, Thimmappa S. | Wadsworth, Teri L. | Sabin, Robert | Frahler, Kate | Harris, Christopher | Petriko, Babett | Ralle, Martina | Woltjer, Randy | Quinn, Joseph F.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) causes progressive, age-dependent cortical and hippocampal dysfunction leading to abnormal intellectual capacity and memory. We propose a novel protective treatment for AD pathology with phytic acid (inositol hexakisphosphate), a phytochemical found in food grains and a key signaling molecule in mammalian cells. We evaluated the protective and beneficial effects of phytic acid against amyloid-β (Aβ) pathology in MC65 cells and the Tg2576 mouse model. In MC65 cells, 48–72-hour treatment with phytic acid provided complete protection against amyloid precursor protein-C-terminal fragment-induced cytotoxicity by attenuating levels of increased intracellular calcium, hydrogen peroxide, superoxide, Aβ oligomers, and moderately upregulated the …expression of autophagy (beclin-1) protein. In a tolerance paradigm, wild type mice were treated with 2% phytic acid in drinking water for 70 days. Phytic acid was well tolerated. Ceruloplasmin activity, brain copper and iron levels, and brain superoxide dismutase and ATP levels were unaffected by the treatment. There was a significant increase in brain levels of cytochrome oxidase and a decrease in lipid peroxidation with phytic acid administration. In a treatment paradigm, 12-month old Tg2576 and wild type mice were treated with 2% phytic acid or vehicle for 6 months. Brain levels of copper, iron, and zinc were unaffected. The effects of phytic acid were modest on the expression of AβPP trafficking-associated protein AP180, autophagy-associated proteins (beclin-1, LC3B), sirtuin 1, the ratio of phosphorylated AMP-activated protein kinase (PAMPK) to AMPK, soluble Aβ1-40 , and insoluble Aβ1-42 . These results suggest that phytic acid may provide a viable treatment option for AD. Show more

Keywords: Amyloid-β, amyloid-β protein precursor, antioxidant, autophagy, beclin-1, phosphorylated AMP-activated protein kinase, sirtuin 1

DOI: 10.3233/JAD-2010-101287

Citation: Journal of Alzheimer's Disease, vol. 23, no. 1, pp. 21-35, 2011

Authors: Okamura, Nobuyuki | Mori, Masanori | Furumoto, Shozo | Yoshikawa, Takeo | Harada, Ryuichi | Ito, Satoshi | Fujikawa, Yosuke | Arai, Hiroyuki | Yanai, Kazuhiko | Kudo, Yukitsuka

Article Type: Research Article

Abstract: Noninvasive detection of amyloid-β (Aβ) deposits in the brain would be beneficial for an early and presymptomatic diagnosis of Alzheimer's disease (AD). We developed THK-265 as a candidate near-infrared fluorescence (NIRF) probe for the in vivo detection of amyloid deposits in the brain. The maximal emission wavelength of THK-265 was greater than 650nm and it showed high quantum yield and molar absorption coefficients. A fluorescence binding assay showed its high binding affinity to Aβ fibrils (Kd = 97 nM). THK-265 clearly stained amyloid plaques in AD neocortical brain sections and showed a moderate log p value (1.8). After intravenous administration …of THK-265 in amyloid-β protein precursor (AβPP) transgenic mice, amyloid deposits in the brain were clearly labeled with THK-265. Furthermore, in vivo NIRF imaging demonstrated significantly higher fluorescence intensity in the brains of AβPP transgenic mice than in those of wild-type mice. As THK-265 showed profound hyperchromic effect upon binding to Aβ fibrils, good discrimination between AβPP transgenic and wild-type mice was demonstrated even early after THK-265 administration. Furthermore, the fluorescence intensity of THK-265 correlated with amyloid plaque burden in the brains of AβPP transgenic mice. These findings strongly support the usefulness of THK-265 as an NIRF imaging probe for the noninvasive measurement of brain amyloid load. Show more

Keywords: Alzheimer's disease, amyloid, amyloid-β protein, fluorescence, molecular imaging

DOI: 10.3233/JAD-2010-100270

Citation: Journal of Alzheimer's Disease, vol. 23, no. 1, pp. 37-48, 2011

Authors: de Jong, Laura W. | Ferrarini, Luca | van der Grond, Jeroen | Milles, Julien R. | Reiber, Johan H.C. | Westendorp, Rudi G.J. | Bollen, Edward L.E.M. | Middelkoop, Huub A.M. | van Buchem, Mark A.

Article Type: Research Article

Abstract: Postmortem studies show pathological changes in the striatum in Alzheimer's disease (AD). Here, we examine the surface of the striatum in AD and assess whether changes of the surface are associated with impaired cognitive functioning. The shape of the striatum (n. accumbens, caudate nucleus, and putamen) was compared between 35 AD patients and 35 individuals without cognitive impairment. The striatum was automatically segmented from 3D T1 magnetic resonance images and automatic shape modeling tools (Growing Adaptive Meshes) were applied for morphometrical analysis. Repeated permutation tests were used to identify locations of consistent shape deformities of the striatal surface in AD. …Linear regression models, corrected for age, gender, educational level, head size, and total brain parenchymal volume were used to assess the relation between cognitive performance and local surface deformities. In AD patients, differences of shape were observed on the medial head of the caudate nucleus and on the ventral lateral putamen, but not on the accumbens. The head of the caudate nucleus and ventral lateral putamen are characterized by extensive connections with the orbitofrontal and medial temporal cortices. Severity of cognitive impairment was associated with the degree of deformity of the surfaces of the accumbens, rostral medial caudate nucleus, and ventral lateral putamen. These findings provide evidence for the hypothesis that in AD primarily associative and limbic cerebral networks are affected. Show more

Keywords: Alzheimer's disease, caudate nucleus, corpus striatum, magnetic resonance imaging, nucleus accumbens, putamen, ventral striatum

DOI: 10.3233/JAD-2010-101026

Citation: Journal of Alzheimer's Disease, vol. 23, no. 1, pp. 49-59, 2011

Authors: Ray, Balmiki | Bisht, Savita | Maitra, Amarnath | Maitra, Anirban | Lahiri, Debomoy K.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques within the brain parenchyma followed by synaptic loss and neuronal death. Deposited Aβ reacts with activated microglia to produce reactive oxygen species (ROS) and cytochemokines, which lead to severe neuroinflammation. Curcumin is a yellow polyphenol compound found in turmeric, a widely used culinary ingredient that possesses anti-inflammatory and anti-cancer properties and may show efficacy as a potential therapeutic agent in several neuro-inflammatory diseases including AD. However, poor aqueous solubility and sub-optimal systemic absorption from the gastrointestinal tract may represent factors contributing to its failure in clinical trials. To increase …curcumin's bioavailability, a polymeric nanoparticle encapsulated curcumin (NanoCurc™) was formulated which is completely water soluble. NanoCurc™ treatment protects neuronally differentiated human SK-N-SH cells from ROS (H2 O2 ) mediated insults. NanoCurc™ also rescues differentiated human SK-N-SH cells, which were previously insulted with H2 O2 . In vivo, intraperitoneal (IP) NanoCurc™ injection at a dose of 25mg/kg twice daily in athymic mice resulted in significant curcumin levels in the brain (0.32 μg/g). Biochemical study of NanoCurc™-treated athymic mice revealed decreased levels of H2 O2 as well as caspase 3 and caspase 7 activities in the brain, accompanied by increased glutathione (GSH) concentrations. Increased free to oxidized glutathione (GSH:GSSH) ratio in athymic mice brain versus controls also indicated a favorable redox intracellular environment. Taken together, these results suggest that NanoCurc™ represents an optimized formulation worthy of assessing the therapeutic value of curcumin in AD. Show more

Keywords: Alzheimer's disease, caspase, curcumin, glutathione, GSH, NanoCurc™, neuropreservation, neuroprotection, oxidative stress, polymeric nanoparticle, reactive oxygen species

DOI: 10.3233/JAD-2010-101374

Citation: Journal of Alzheimer's Disease, vol. 23, no. 1, pp. 61-77, 2011

Authors: Gleichgerrcht, Ezequiel | Torralva, Teresa | Martinez, Daniel | Roca, María | Manes, Facundo

Article Type: Research Article

Abstract: It is currently accepted that there is a subset of patients diagnosed with Alzheimer's disease (AD) who show executive functioning (EF) impairments even in the earlier stages. These patients have been shown to present distinct psychiatric, behavioral, occupational, and even histopathological profiles. We assessed thirty patients with AD on two tasks of verbal memory (Logical Memory – LM, and the Rey Auditory-Verbal Learning Task – RAVLT), as well as classical tests of EF. AD patients were classified into either a spared EF (SEF) group if they showed impaired performance (z < −1.5 SD) in none or only one of the …executive tests, or into an impaired EF (IEF) group if they showed impaired performance on two or more tasks of EF. Their performance was compared with fourteen healthy controls. SEF showed significantly more years of education than IEF, but the groups did not differ significantly on age, gender, mood symptoms, or performance on general screening tests or attentional tasks. With education as a covariate, both AD groups differed from controls on all measures of memory, but a significant difference was found between SEF and IEF patients only on the recognition phases of both logical memory (p < 0.01) and RAVLT (p = 0.02). Recognition scores significantly correlated with performance on executive tasks. Early AD patients who preserve their EF seem to have an advantage in their ability to recognize information that has been previously presented over patients with impaired EF. Such advantage seems to be strongly associated with executive performance. Show more

Keywords: Alzheimer's disease, dementia, executive functions, neuropsychology, verbal memory

DOI: 10.3233/JAD-2010-100990

Citation: Journal of Alzheimer's Disease, vol. 23, no. 1, pp. 79-85, 2011

Authors: Bai, Feng | Liao, Wei | Watson, David R. | Shi, Yongmei | Yuan, Yonggui | Cohen, Alexander D. | Xie, Chunming | Wang, Yi | Yue, Chunxian | Teng, Yuhuan | Wu, Di | Jia, Jianping | Zhang, Zhijun

Article Type: Research Article

Abstract: The cerebellum is known to be a relatively well preserved structure, but subtle alterations may occur early in the evolution of Alzheimer's disease (AD). Amnestic mild cognitive impairment (aMCI) patients appear to be particularly vulnerable to AD. However, little is currently known whether altered patterns of cerebellar function occur in aMCI patients. 26 aMCI patients and 18 well-matched healthy controls underwent a baseline resting-state functional magnetic resonance imaging (fMRI) scan. After a mean follow-up period of 20 months, the subjects who successfully completed baseline fMRI scans underwent a further follow-up scan, while spontaneous activation and functional connectivity of the cerebellum …were explored by using resting-state fMRI. Compared to controls, increased amplitude of low frequency fluctuation of the posterior cerebellar lobe may contribute to the underlying mechanisms affected, while greater decreased functional connections to the posterior cerebellar lobe were identified in the longitudinal study of aMCI patients. This suggests that abnormal functional connectivity of the cerebellum may offer a more sensitive and possibly preferred index of functional disturbance than regional activity measures in aMCI patients. The cerebellum may be partly related to the underlying mechanisms of aMCI, and it could help guide subsequent investigations designed to specify the precise functional role of cerebellum in aMCI patients. Show more

Keywords: Amnestic mild cognitive impairment, cerebellum, functional magnetic resonance imaging, functional connectivity, longitudinal

DOI: 10.3233/JAD-2010-101533

Citation: Journal of Alzheimer's Disease, vol. 23, no. 1, pp. 87-99, 2011

Authors: Miners, James Scott | Morris, Sean | Love, Seth | Kehoe, Patrick Gavin

Article Type: Research Article

Abstract: We previously reported age- and Alzheimer's disease (AD)-related increases in the activities of β-secretase (BACE-1) and Aβ-degrading enzymes including neprilysin (NEP) and angiotensin-converting enzyme (ACE) in the frontal cortex. We suggested that these increases were secondary to the accumulation of insoluble amyloid-β (Aβ) and a decline in soluble Aβ. We have further tested this hypothesis by examination of frontal cortex obtained postmortem from individuals with Down's syndrome (DS), in whom AD-like neuropathological changes occur in association with early-onset dementia. We measured total soluble and insoluble (guanidine-extractable) Aβ, BACE-1 activity, and the concentrations and activities of NEP and ACE in two …independent DS cohorts: an initial, Bristol cohort (9 DS cases, 8 controls matched for age-at-death) and a validation Newcastle cohort (20 DS, 18 controls with a wider spectrum of age-at-death). In both cohorts the level of insoluble (but not soluble) Aβ was significantly higher in DS than controls and was comparable to previously measured levels in AD. NEP protein concentration and activity were significantly increased in DS; a trend towards increased BACE-1 activity was observed in DS but did not reach statistical significance. Both NEP and BACE-1 correlated with the level of insoluble Aβ. The concentration of ACE in DS was elevated in the pilot cohort only and ACE activity was unchanged. These findings provide strong support that BACE-1 and NEP activities, but not ACE, increase in response to the accumulation of insoluble Aβ within the brain. Show more

Keywords: Alzheimer's disease, amyloid-β, angiotensin-converting enzyme, β-secretase, Down's syndrome, neprilysin

DOI: 10.3233/JAD-2010-101395

Citation: Journal of Alzheimer's Disease, vol. 23, no. 1, pp. 101-108, 2011