Volume 23, Number 1, January 2011

Pages 1-5
Short Communication
Aleksandra Nowicka, Andrzej A. Szczepankiewicz, Andrzej Jaklewicz, Anna Filipek, Maria Barcikowska,  Danek Elbaum
Ultrafiltrate of Blood Plasma Modulates Amyloid-β Aggregation
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.

Pages 7-12
Giacomina Rossi, Elena Piccoli, Luisa Benussi, Francesca Caso, Veronica Redaelli, Giuseppe Magnani, Giuliano Binetti, Roberta Ghidoni, Daniela Perani, Giorgio Giaccone, Fabrizio Tagliavini
A Novel Progranulin Mutation Causing Frontotemporal Lobar Degeneration with Heterogeneous Phenotypic Expression
Abstract: Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder characterized by behavioral 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.

Pages 13-20
Anna Sillén, Lena Lilius, Charlotte Forsell, Toru Kimura, Bengt Winblad, Caroline Graff
Linkage to the 8p21.1 Region Including the CLU Gene in Age at Onset Stratified Alzheimer’s Disease Families
Abstract: Three 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 9.5 cM 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.

Supplementary Data for Sillén et al. article (PDF)

Pages 21-35
Thimmappa S. Anekonda, Teri L. Wadsworth, Robert Sabin, Kate Frahler, Christopher Harris, Babett Petriko, Martina Ralle, Randy Woltjer, Joseph F. Quinn
Phytic Acid as a Potential Treatment for Alzheimer’s Pathology: Evidence from Animal and in vitro Models
Abstract: Alzheimer’s disease (AD) causes progressive, age-dependent cortical and hippocampal dysfunctions 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.

Pages 37-48
Nobuyuki Okamura, Masanori Mori, Shozo Furumoto, Takeo Yoshikawa, Ryuichi Harada, Satoshi Ito, Yosuke Fujikawa, Hiroyuki Arai, Kazuhiko Yanai, Yukitsuka Kudo (Handling Associate Editor: Victor Villemagne)
In vivo Detection of Amyloid Plaques in the Mouse Brain using the Near-Infrared Fluorescence Probe THK-265
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 650 nm 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 at the early stage after THK-265 administration. Furthermore, fluorescence intensity of THK-265 correlated with amyloid plaque burden in the brains of AβPP transgenic mice. These findings strongly indicate the usefulness of THK-265 as an NIRF imaging probe for noninvasive measurement of brain amyloid load.

Pages 49-59
Laura W. de Jong, Luca Ferrarini, Jeroen van der Grond, Julien R. Milles, Johan H.C. Reiber, Rudi G.J. Westendorp, Edward L.E.M. Bollen, Huub A.M. Middelkoop, Mark A. van Buchem
Shape Abnormalities of the Striatum in Alzheimer’s Disease
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.

Supplementary Data for de Jong et al. article (PDF)

Pages 61-77
Balmiki Ray*, Savita Bisht*, Amarnath Maitra, Anirban Maitra, Debomoy K. Lahiri *These authors contributed equally to this manuscript.
Neuroprotective and Neurorescue Effects of a Novel Polymeric Nanoparticle Formulation of Curcumin (NanoCurc®) in the Neuronal Cell Culture and AnimalModel: Implications for Alzheimer’s disease
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 can be used 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 are reasons behind its failure in some 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 (H2O2) mediated insults. NanoCurc® also rescues differentiated human SK-N-SH cells, which were previously insulted with H2O2.  In vivo, intraperitoneal (IP) NanoCurc® injection at a dose of 25 mg/kg twice daily in athymic mice resulted in a significant brain curcumin levels (0.32 μg/g). Biochemical study of NanoCurc®-treated athymic mice brain revealed decreased levels of H2O2, and caspase 3 and caspase 7 activities, 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 true therapeutic value of curcumin in AD.

Pages 79-85
Ezequiel Gleichgerrcht, Teresa Torralva, Daniel Martinez, María Roca, Facundo Manes (Handling Associate Editor: Donald Connor)
Impact of Executive Dysfunction on Verbal Memory Performance in Patients with Alzheimer’s Disease
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.

Pages 87-99
Feng Bai, Wei Liao, David R. Watson, Yongmei Shi, Yonggui Yuan, Alexander D. Cohen, Chunming Xie, Yi Wang, Chunxian Yue, Yuhuan Teng, Di Wu, Jianping Jia, Zhijun Zhang
Mapping the Altered Patterns of Cerebellar Resting-State Function in Longitudinal Amnestic Mild Cognitive Impairment Patients
Abstract: The cerebellum is known to be a relatively well preserved structure, but subtle alterations may occur early in Alzheimer’s disease (AD) evolution. Amnestic mild cognitive impairment (aMCI) patients appear to be particularly vulnerable to AD. However, little is currently known about the altered patterns of cerebellar function 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 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.

Pages 101-108
James Scott Miners1, Sean Morris1, Seth Love, Patrick Gavin Kehoe (Handling Associate Editor: Dengshun Wang) 1These authors contributed equally to this manuscript.
Accumulation of Insoluble Amyloid-β in Down’s Syndrome is Associated with Increased BACE-1 and Neprilysin Activities
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.

Supplementary Data for Miners et al. article (PDF)

Pages 109-119
Birgitte Boonstra Booij, Torbjørn Lindahl, Peter Wetterberg, Nina Voss Skaane, Solve Sæbø, Guri Feten, Phil D Rye, Lena Iren Kristiansen, Nina Hagen, Marianne Jensen, Ken Bårdsen, Bengt Winblad, Praveen Sharma, Anders Lönneborg
A Gene Expression Pattern in Blood for the Early Detection of Alzheimer’s Disease
Abstract: A whole genome screen was performed using oligonucleotide microarray analysis on blood from a large clinical cohort of Alzheimer’s disease (AD) patients and control subjects as clinical sample. Blood samples for total RNA extraction were collected in PAXgene tubes, and gene expression analysis performed on the AB1700 Whole Genome Survey Microarrays. When comparing the gene expression of 94 AD patients and 94 cognitive healthy controls, a Jackknife gene selection based method and Partial Least Square Regression (PLSR) was used to develop a disease classifier algorithm, which gives a test score indicating the presence (positive) or absence (negative) of AD. This algorithm, based on 1239 probes, was validated in an independent test set of 63 subjects comprising 31 AD patients, 25 age-matched cognitively healthy controls, and 7 young controls. This algorithm correctly predicted the class of 55/63 (accuracy 87%), including 26/31 AD samples (sensitivity 84%) and 29/32 controls (specificity 91%). The positive likelihood ratio was 8.9 and the area under the receiver operating characteristic curve (ROC AUC) was 0.94. Furthermore, the algorithm also discriminated AD from Parkinson’s disease in 24/27 patients (accuracy 89%). We have identified and validated a gene expression signature in blood that classifies AD patients and cognitively healthy controls with high accuracy and show that alterations specific for AD can be detected distant from the primary site of the disease.

Supplementary Data for Booij et al. article (PDF)

Pages 121-129
Phil. D. Rye*, Birgitte Boonstra Booij*, Gisle Grave, Torbjørn Lindahl, Lena Kristiansen, Hilde-Marie Andersen, Peter O. Horndalsveen, Harald A. Nygaard, Mala Naik, Dagne Hoprekstad, Peter Wetterberg, Christer Nilsson, Dag Aarsland, Praveen Sharma, Anders Lönneborg *Authors contributed equally to the manuscript
A Novel Blood Test for the Early Detection of Alzheimer’s Disease
Abstract: Despite a variety of testing approaches, it is often difficult to make an accurate diagnosis of Alzheimer’s disease (AD), especially at an early stage of the disease. Diagnosis is based on clinical criteria as well as exclusion of other causes of dementia but a definitive diagnosis can only be made at autopsy. We have investigated the diagnostic value of a 96-gene expression array for detection of early AD. Gene expression analysis was performed on blood RNA from a cohort of 203 probable AD and 209 cognitively healthy age matched controls. A disease classification algorithm was developed on samples from 208 individuals (AD=103; controls=105) and was validated in two steps using an independent initial test set (n=74; AD=32; controls=42) and another second test set (n=130; AD=68; controls=62). In the initial analysis, diagnostic accuracy was 71.6 ±10.3%, with sensitivity 71.9 ±15.6 % and specificity 71.4 ±13.7 %. Essentially the same level of agreement was achieved in the two independent test sets. High agreement (24/30; 80%) between algorithm prediction and subjects with available cerebrospinal fluid biomarker was found. Assuming a clinical accuracy of 80%, calculations indicate that the agreement with underlying true pathology is in the range 85%-90%. These findings suggest that the gene expression blood test can aid in the diagnosis of mild to moderate AD, but further studies are needed to confirm these findings.

Supplementary Data for Rye et al. article (PDF)

Pages 131-141
Alberto Pilotto, Grazia D’Onofrio, Edoardo Benelli, Antonio Zanesco, Ana Cabello, M. Carmen Margelí, Sophia Wanche-Politis, Kostas Seferis, Daniele Sancarlo, Dimitrios Kilias on behalf of the HOPE Investigators (Handling Associate Editor: Vincenza Frisardi)
Information and Communication Technology Systems to Improve Quality of Life and Safety of Alzheimer’s Disease Patients: A Multicenter International Survey
Abstract: In the frame of the European Commission funded Smart Home for Elderly People (HOPE) Project, relatives/caregivers of 223 Alzheimer’s Disease (AD) patients were recruited in Italy,  Spain, and Greece for a multicenter international survey on the potential role of Information and Communication Technology  system (ICT-systems) for AD patients. A five-minute video on HOPE ICT-systems was shown, and all relatives/caregivers completed a 13-item questionnaire that evaluated the potential role of: A) ICT-systems in improving quality of life, care, and safety; B) devices for monitoring personal movements, medication use, and ambient environmental conditions; C) devices to improve communication, home-based rehabilitation, and reduction of specific risks; and D) possible agreement in using ICT-systems by AD patients. Relatives/caregivers reported that ICT-systems could be very useful to improve: A) quality of life (66.4%), care (56.1%), and safety (87.0%); B) monitoring bed rest and movements (80.7%), medication use (87.4%), and ambient environmental conditions (85.2%); and C) emergency communication (83.4%). Relatives/caregivers reported that ICT-systems could be significantly more useful for AD patients aged 75-84 than patients aged <75 or ≥85 years (p<0.0001) and with moderate than mild or severe dementia (p<0.0001). Relatives/caregivers aged ≥50 years and with low educational level considered ICT-systems more useful than relatives/caregivers aged<50 years (p<0.0001) and with high educational level (p<0.0001). In conclusion, relatives/caregivers considered that HOPE ICT-system could be useful to improve the management of AD patients.

Pages 143-146
Commentary
Vincenza Frisardi, Bruno P Imbimbo
Gerontechnology for Demented Patients: Smart Homes for Smart Aging
Abstract: In an aging world, maintaining good health and independence for as long as possible is essential. Instead of hospitalization or institutionalization, the elderly with chronic condition, especially with cognitive impairment, can be assisted in their own environment with numerous ‘smart’ devices that support them in their activity of daily living. A “smart home” is a residence equipped with technology that facilitates monitoring of residents aiming to improve quality of life and promotes physical independence, as well as to reduce caregiver burden. Several projects worldwide have been realized, but some ethical and legal issues are still unresolved and, at present, there is no evidence of the effects of smart homes on health outcomes. Randomized controlled trials are needed to understand lights and shadows of these projects, and this will be possible only with a widespread proliferation and penetration of smart homes in the social network.

Pages 147-159
Minho Moon, Jin Gyu Choi, Dong Woo Nam, Hyun-Seok Hong, Young-Ju Choi, Myung Sook Oh, Inhee Mook-Jung
Ghrelin Ameliorates Cognitive Dysfunction and Neurodegeneration in Intrahippocampal Amyloid-β1-42 Oligomer-Injected Mice
Abstract: Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by cognitive deficits, neuroinflammation, and loss of neurons. Recently, it has been shown that ghrelin, a 28 amino acid peptide hormone produced from the stomach and hypothalamus, has been reported as a potential therapeutic agent for several neurological disorders, including Parkinson’s disease (PD), stroke, epilepsy, multiple sclerosis, and spinal cord injury. Here we determined the effects of ghrelin on memory impairments and neuropathological changes in an AD mouse model induced by intrahippocampal injection of amyloid-β oligomers (AβO). We report that ghrelin: 1) rescues memory deficits in mice injected with AβO in the hippocampus; 2) decreases AβO-induced microgliosis in hippocampus; 3) attenuates hippocampal neuronal loss mediated by AβO; 4) prevents AβO-associated synaptic degeneration including cholinergic fiber loss. Taken together, our findings demonstrate that ghrelin can ameliorate AβO-induced cognitive impairment associated with neuroinflammation and neuronal loss. These results suggest that ghrelin may be a promising therapeutic agent for the treatment of AD.

Supplementary Data for Moon et al. article (PDF)

Pages 161-169
Monika Zilkova, Norbert Zilka, Andrej Kovac, Branislav Kovacech, Rostislav Skrabana, Michaela Skrabanova, Michal Novak
Hyperphosphorylated truncated protein tau induces caspase-3 independent apoptosis-like pathway in the Alzheimer’s Disease cellular model
Abstract: Neurofibrillary degeneration and neuronal loss represent key pathological hallmarks of Alzheimer’s disease (AD). It has been demonstrated that the decrease of total neuronal numbers correlated with the presence of neurofibrillary degeneration in AD brain. In order to unravel the mechanism leading to the cell death in AD, we developed a stably transfected human neuroblastoma cellular model with doxycycline-regulatable expression of AD truncated tau protein (AT tau, 151-391 4R). Cells expressing the longest tau isoform (Tau 40) were used as a control. We found that more than 80% of the total amount of AT tau and Tau 40 were phosphorylated. Strikingly, both AT tau and Tau 40 reduced the metabolic activity of the cells in a time-dependent manner (p<0.0001) suggesting that tau overexpression slows down cell proliferation. However, AT tau showed significantly higher toxicity than Tau40 (p<0.0001), which indicates that truncation leads to a toxic gain of function. The analysis of the type of the cell death revealed the characteristic features of apoptosis such as cell shrinkage, nuclear, and DNA fragmentation. However, we did not find either the activation of executive caspase (caspase-3) or the caspase cleavage products (PARP and fodrin). These results show that posttranslationally modified truncated tau protein induces caspase-3-independent apoptosis-like programmed cell death we termed tauoptosis.

Pages 171-172
Commentary
     John C. S. Breitner
     Apolipoprotein E, Alzheimer’s Disease, and Amyloid: Do We Have the Cart Before the Horse?

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