Journal of Alzheimer's Disease - Volume 20, issue 1

Authors: Lanni, Cristina | Racchi, Marco | Stanga, Serena | Mazzini, Giuliano | Ranzenigo, Alberto | Polotti, Renzo | Memo, Maurizio | Govoni, Stefano | Uberti, Daniela

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) is a syndrome defined as cognitive decline, but not sufficient to meet the criteria for any specific dementia. Although subjects with MCI may have an increased risk to develop AD, this clinical state encompasses several subtypes of cognitive dysfunction of different etiologies, none of which necessarily progresses to AD. The current inability of clinical criteria to accurately identify this at-risk group for AD development is fuelling the interest in biomarkers able to supplement clinical approaches. We recently described a blood-based cytofluorimetric method for conformationally altered p53 protein detection that allows the discrimination of AD patients from …control subjects and patients affected by other dementias. The same protein also predicted progression to AD in preclinical patients with MCI two years before clinical diagnosis of AD was made. Herein, we describe these findings and discuss the potential of the test in diagnosing AD. Show more

Keywords: cytofluorimetric approach, mild cognitive impairment, risk factor, unfolded blood p53

DOI: 10.3233/JAD-2010-1347

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 97-104, 2010

Authors: Sharman, Matthew J. | Shui, Guanghou | Fernandis, Aaron Z. | Lim, Wei Ling F. | Berger, Tamar | Hone, Eugene | Taddei, Kevin | Martins, Ian J. | Ghiso, Jorge | Buxbaum, Joseph D. | Gandy, Sam | Wenk, Markus R. | Martins, Ralph N.

Article Type: Research Article

Abstract: It is known that apolipoprotein E (ApoE) is essential for normal lipid metabolism. ApoE is the major apolipoprotein in the central nervous system and plays a key role in neurobiology by mediating the transport of cholesterol, phospholipids, and sulfatides. We therefore examined APOE ε2, ε3, and ε4 knock-in mice, using electrospray ionization mass spectrometry to determine if APOE genotype or age leads to altered levels in the brain of a number of glycerophospholipids (phosphatidylinositol, PI; phosphatidylethanolamine, PE; phosphatidic acid, PA, phosphatidylserine, PS; phosphatidylcholine, PC), sphingolipids (sphingomyelin, SM; ceramide, Cer), cholesterol, and triacylglycerols. We observed slight changes within individual PI, PE, …PC, Cer, and SM lipid levels in APOE ε2 and ε4 mice compared to APOE ε3 mice. However, overall, we did not observe any major effects in APOE ε4 knock-in mice for the levels of the glycerophospholipids measured, as compared to APOE ε2 and ε3 mice. Our findings indicate that variations in ApoE isoforms do not per se affect bulk lipid homeostasis in the brain. These findings indicate that APOE ε4 is not associated with disturbances in brain sterol or sphingolipids in the absence of environmental factors. Show more

Keywords: Alzheimer's disease, APOE genotype, cholesterol, glycerophospholipids, lipidomics, sphingolipids

DOI: 10.3233/JAD-2010-1348

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 105-111, 2010

Authors: Leon, Wanda Carolina | Canneva, Fabio | Partridge, Vanessa | Allard, Simon | Ferretti, Maria Teresa | DeWilde, Arald | Vercauteren, Freya | Atifeh, Ramtin | Ducatenzeiler, Adriana | Klein, William | Szyf, Moshe | Alhonen, Leena | Cuello, A. Claudio

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a neurodegenerative pathology in which amyloid-β (Aβ) peptide accumulates in different brain areas leading to deposition of plaques and a progressive decline of cognitive functions. After a decade in which a number of transgenic (Tg) mouse models mimicking AD-like amyloid-deposition pathology have been successfully generated, few rat models have been reported that develop intracellular and extracellular Aβ accumulation, together with impairment of cognition. The generation of a Tg rat reproducing the full AD-like amyloid pathology has been elusive. Here we describe the generation and characterization of a new transgenic rat line, coded McGill-R-Thy1-APP, developed to express …the human amyloid-β precursor protein (AβPP) carrying both the Swedish and Indiana mutations under the control of the murine Thy1.2 promoter. The selected mono-transgenic line displays an extended phase of intraneuronal Aβ accumulation, already apparent at 1 week after birth, which is widespread throughout different cortical areas and the hippocampus (CA1, CA2, CA3, and dentate gyrus). Homozygous Tg animals eventually produce extracellular Aβ deposits and, by 6 months of age, dense, thioflavine S-positive, amyloid plaques are detected, associated with glial activation and surrounding dystrophic neurites. The cognitive functions in transgenic McGill-R-Thy1-APP rats, as assessed using the Morris water maze task, were found already altered as early as at 3 months of age, when no CNS plaques are yet present. The spatial cognitive impairment becomes more prominent in older animals (13 months), where the behavioral performance of Tg rats positively correlates with the levels of soluble Aβ (trimers) measured in the cortex. Show more

Keywords: Alzheimer's disease, amyloid-β oligomers, cognitive impairment, intracellular amyloid-β, transgenic rat

DOI: 10.3233/JAD-2010-1349

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 113-126, 2010

Authors: Mandal, Pravat K. | Simplaceanu, Virgil | Fodale, Vincenzo

Article Type: Research Article

Abstract: Amyloid-β peptide (Aβ) oligomerization has a profound role in Alzheimer's disease pathophysiology. Biophysical studies have shown that smaller sized inhaled anesthetics promote oligomerization by inducing perturbation of three critical amino acid residues (G29, A30, and I31) located in the helix-loop-helix domain of Aβ. In this present experimental study, using state-of-the-art nuclear magnetic resonance, we have monitored the influence of a larger sized intravenous anesthetic, diazepam, as well as diazepam co-administered with halothane, on Aβ. It was concluded that diazepam (in isolation) does not interact with the G29, A30, and I31 residues, and no Aβ oligomerization occurs in the presence of …0.101 mM diazepam, even after 63 days. However, when diazepam was co-administered with halothane, profound Aβ oligomerization is observed. These results strengthen the hypothesis that the presence of smaller molecular sized anesthetic is instrumental in promoting Aβ oligomerization even when co-administered with a larger sized anesthetic, namely diazepam. An erratum for this article can be found in Journal of Alzheimer's Disease 20(4), 2010, p. 1261. https://dx.doi.org/10.3233/JAD-2010-01425 Show more

Keywords: Amyloid-β, amyloid-β oligomerization, aqueous halothane, diazepam, inhaled anesthetics, intravenous anesthetics, NMR

DOI: 10.3233/JAD-2010-1350

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 127-134, 2010

Authors: Balakrishnan, Karthikeyan | Andrei-Selmer, Luminita-Cornelia | Selmer, Thorsten | Bacher, Michael | Dodel, Richard

Article Type: Research Article

Abstract: Intravenous immunoglobulins (IVIG) are currently used for therapeutic purposes in autoimmune disorders. Recently, we demonstrated the presence of naturally occurring antibodies against amyloid-β (nAbs-Aβ) within the pool of IVIG. In this study, we compared different brands of IVIG for nAbs-Aβ and have found differences in the specificity of the nAbs-Aβ towards Aβ1–40 and Aβ1–42 . We analyzed the influence of a pH-shift over the course of antibody storage using ELISA and investigated antibody dimerization at acidic and neutral pH as well as differences in the IgG subclass distributions among the IVIG using both HPLC and a nephelometric assay. Furthermore, …we investigated the epitope region of purified nAbs-Aβ. The differences found in Aβ specificity are not directly proportionate to the binding nature of these antibodies when administered in vivo. This information, however, may serve as a guide when choosing the commercial source of IVIG for therapeutic applications in Alzheimer's disease. Show more

Keywords: Alzheimer's disease, amyloid-β specific nAbs, immunotherapy for AD, IVIG

DOI: 10.3233/JAD-2010-1353

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 135-143, 2010

Authors: Wang, Ze-Fen | Yin, Jun | Zhang, Yao | Zhu, Ling-Qiang | Tian, Qing | Wang, Xiao-Chuan | Li, Hong-Lian | Wang, Jian-Zhi

Article Type: Research Article

Abstract: It has been a puzzle why the tangle-bearing neurons in Alzheimer's disease (AD) brain do not die preferentially of apoptosis even though they are actually challenged by multiple proapoptotic factors. Recently, we have reported that phosphorylation of tau can antagonize apoptosis induced by exogenous apoptotic inducers. Amyloid-β (Aβ), a recognized endogenous proapoptotic factor, is significantly increased in the AD brains, however, it is not known whether tau could abate the Aβ-potentiated apoptosis. Here, we observed that the cells bearing high level of Aβ were more vulnerable than the controls to H2 O2 -induced apoptosis, and this effect of Aβ was …associated with decrease of Bcl-2, elevation of Bax and cytosolic cytochrome-c, as well as activation of caspase-3, suggesting that Aβ could potentiate the oxidant-induced cell apoptosis with involvement of mitochondria-caspase-3 pathway. More importantly, we also found that expression of tau that became hyperphosphorylated could reduce the Aβ-potentiated apoptosis with simultaneous preservation of Bcl-2 and suppression of Bax, cytosolic cytochrome-c, and caspase-3 activity, implying that overexpression of tau that became hyperphosphorylated can attenuate the Aβ-potentiated cell apoptosis through mitochondria-caspase-3 pathway. These findings provide an explanation of the chronic nature of neurodegeneration of neurons with neurofibrillary pathology of abnormal hyperphosphorylated tau in AD and related tauopathies. Show more

Keywords: Alzheimer's disease, amyloid-β, apoptosis, hyperphosphorylation, mitochondria, tau

DOI: 10.3233/JAD-2010-1351

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 145-157, 2010

Authors: Imbimbo, Bruno P. | Giardino, Luciana | Sivilia, Sandra | Giuliani, Alessandro | Gusciglio, Marco | Pietrini, Vladimiro | Del Giudice, Elda | D'Arrigo, Antonello | Leon, Alberta | Villetti, Gino | Calzà, Laura

Article Type: Research Article

Abstract: The effects of compounds interfering with γ-secretase, the enzymatic complex responsible of the formation of the amyloid-β (Aβ) peptide from amyloid-β protein precursor (AβPP), on plaque deposition in transgenic mouse models of Alzheimer's disease are known but scanty data are available on the effects of these drugs on brain plasticity. We evaluated the effects of long-term treatment with CHF5074, a new γ-secretase modulator, on hippocampal neurogenesis, cortical synaptophysin levels, and contextual memory in transgenic mice carrying the double Swedish mutation of AβPP (Tg2576). Six-month old Tg2576 mice were treated with CHF5074 (375 ppm in the diet) up to 15 months …of age. Age-matched control transgenic and wild-type mice received standard diet. Compared to wild-type animals, transgenic controls showed a significant decrease in the number of doublecortin-positive neuroblasts in dentate gyrus, synaptophysin intensity in the cortex, freezing to context in the contextual fear conditioning test. Compared to transgenic controls, CHF5074 treatment of Tg2576 mice resulted in a significant attenuation of the neurogenesis impairment in hippocampus (p = 0.036), normalization of synaptophysin levels in cortex (p < 0.001), attenuation of plaque burden in the cortex (p = 0.033), increases astroglial reaction around plaques (p = 0.001), and attenuation of activated microglia (p = 0.040). These effects were associated to a complete reversal of contextual memory deficit (p = 0.006). Contextual memory significantly correlated with synaptophysin immunoreactivity in the cortex (r = 0.548, p = 0.0038). Show more

Keywords: Amyloid-β, contextual memory, γ-secretase modulators, hippocampal neurogenesis, synaptophysin

DOI: 10.3233/JAD-2010-1366

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 159-173, 2010

Authors: Palmer, Katie | Di Iulio, Fulvia | Varsi, Ambra Erika | Gianni, Walter | Sancesario, Giuseppe | Caltagirone, Carlo | Spalletta, Gianfranco

Article Type: Research Article

Abstract: The aim of the study is to evaluate whether depression or apathy in patients with amnestic-mild cognitive impairment (MCI) increases the risk of progressing to Alzheimer's disease (AD). We investigated 131 consecutive memory-clinic outpatients with newly-diagnosed amnestic-MCI (mean age 70.8, SD = 6.5). Psychiatric disorders were diagnosed at baseline according to the criteria for depression and apathy in AD. Neuropsychiatric symptoms were assessed with the Neuropsychiatric Inventory (NPI). Follow-up examinations were conducted after six months and annually for four years. Neurologists diagnosed AD at follow-up using NINCDS-ADRDA criteria. Cox proportional hazard models with 95% confidence intervals were used to test …the hypothesis that apathy or depression increases the risk of developing AD. At baseline, 36.6% amnestic-MCI patients had a diagnosis of depression and 10.7} had apathy. Patients with both amnestic-MCI and an apathy diagnosis had an almost sevenfold risk of AD progression compared to amnestic-MCI patients without apathy (HR = 6.9; 2.3–20.6), after adjustment for age, gender, education, baseline global cognitive and functional status, and depression. Furthermore, the risk of developing AD increased 30% per point on the NPI apathy item (HR = 1.3; 1.1–1.4). There was no increased risk of developing AD in amnestic-MCI patients with either a diagnosis or symptoms of depression. In conclusion, apathy, but not depression, predicts which patients with amnestic-MCI will progress to AD. Thus, apathy has an important impact on amnestic-MCI and should be considered a mixed cognitive/psychiatric disturbance related to ongoing AD neurodegeneration. Show more

Keywords: Cognitive deficits, dementia, early detection, MCI, neuropsychiatric symptoms

DOI: 10.3233/JAD-2010-1352

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 175-183, 2010

Authors: Dougherty Jr., John H. | Cannon, Rex L. | Nicholas, Christopher R. | Hall, Lorin | Hare, Felicia | Carr, Erika | Dougherty, Andrew | Janowitz, Jennifer | Arunthamakun, Justin

Article Type: Research Article

Abstract: The computer self test (CST) is an interactive, internet-based instrument designed to assess functional cognitive domains impaired by Alzheimer's disease (AD) and mild cognitive impairment (MCI). This study consisted of 215 total subjects with a mean age of 75.24. The 84 cognitively impaired patients (excluding patients diagnosed as MCI) met all criteria set forth by NINCDS/ADRDA for the diagnosis of AD. Control participants consisted of 104 age-matched individuals who were cognitively unimpaired. All patients completed the CST prior to other routine neurocognitive procedures. The CST accurately classified 96% of the cognitively impaired individuals as compared to controls, while the Mini-Mental …Status Examination (MMSE) accurately classified 71% and the Mini-Cog 69% in the same respect. In addition, the CST accurately classified 91% of the six experimental groups (control, MCI, early AD, mild to moderate, moderate to severe, and severe) as compared to 54% for the MMSE and 48% for the Mini-Cog. In conclusions, the CST demonstrates a high degree of sensitivity and specificity and is capable of accurately identifying cognitive impairment in patients with variable degrees of cognitive abnormality. This interactive internet-based cognitive screening tool may aid in early detection of cognitive impairment in the primary care setting. The ease of use and interpretation may also provide the means to obtain an accurate baseline from which to monitor cognitive changes over time. Show more

Keywords: Alzheimer's disease, computerized cognitive screening, dementia, mild cognitive impairment

DOI: 10.3233/JAD-2010-1354

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 185-195, 2010

Authors: Meeus, Bram | Nuytemans, Karen | Crosiers, David | Engelborghs, Sebastiaan | Peeters, Karin | Mattheijssens, Maria | Elinck, Ellen | Corsmit, Ellen | De Deyn, Peter Paul | Van Broeckhoven, Christine | Theuns, Jessie

Article Type: Research Article

Abstract: The second most frequent form of neurodegenerative dementia after Alzheimer's disease is dementia with Lewy bodies (DLB). Since informative DLB families are scarce, little is presently known about the molecular genetic etiology of DLB. We recently mapped the first locus for DLB on chromosome 2q35-q36 in a multiplex Belgian family, DR246, with autopsy-proven DLB pathology in a region of 9.2 Mb. Here, we describe the ascertainment of additional DR246 family members and significant finemapping of the DLB locus to 3.3 Mb based on informative meiotic recombinants. Extensive sequencing of the 42 positional candidate genes within the DLB region did not …identify a simple pathogenic mutation that co-segregated with disease in family DR246. Also high resolution analysis of copy number variations in the DLB locus did not provide evidence for a complex mutation. In conclusion, we confirmed the DLB locus at 2q35-q36 as a genetic entity but candidate gene-based sequencing and copy number variation analysis did not identify the pathogenic mutation in family DR246. Other detection strategies will be needed to reveal the underlying mutation explaining the linkage of DLB to 2q35-q26. Possibly the disease mutation in this family acts through a more complex mechanism than generally envisaged for monogenic disorders. Nevertheless, identifying the first familial DLB gene is likely to contribute an entry point into the pathogenic cascades underlying DLB pathology. Show more

Keywords: Chromosome 2, dementia with Lewy bodies, mutation analyses, positional candidate genes

DOI: 10.3233/JAD-2010-1356

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 197-205, 2010