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

Authors: De Bartolo, Paola | Cutuli, Debora | Ricceri, Laura | Gelfo, Francesca | Foti, Francesca | Laricchiuta, Daniela | Scattoni, Maria Luisa | Calamandrei, Gemma | Petrosini, Laura

Article Type: Research Article

Abstract: The “cholinergic hypothesis” of dementia posits that the progressive loss of basal forebrain cholinergic neurons and the consequent decrease of acetylcholine levels in the deafferented projection sites are correlated with degree of cognitive decline in dementia. It has also been proposed that early dysfunction of the basal forebrain (BF) cholinergic system may be a risk factor for subsequent cognitive decline and possibly dementia. To characterize how age when BF cholinergic system is lesioned affects behavioral performances and morphology of neocortical neurons, seven-day-old rats were bilaterally i.c.v. injected with 192 IgG-saporin. In adulthood, these animals were subjected to spatial and associative …tests. Subsequently, the morphology of parietal pyramidal neurons was assessed. The same behavioral and morphological evaluations were made in 80-day-old rats tested three weeks after bilateral i.c.v. injections of 192 IgG-saporin. The behavioral consequences of both cholinergic depletions were markedly similar. While both groups of lesioned animals exhibited very subtle deficits in the Morris water maze, they were significantly impaired in spatial discrimination in the open field and the radial maze. Paralleling behavioral data, the results of the morphological analysis revealed comparable increases in number and density of spines in apical and basal dendrites in layer-III parietal pyramidal neurons following both neonatal and adult cholinergic depletions. The present results demonstrate that the consequences of abnormal maturation of the cholinergic system are not substantially different from those evoked by cholinergic dysfunction in adulthood and provide a developmental psychobiological perspective of the neuronal foundations of the impaired cognitive functions. Show more

Keywords: Age effect, Alzheimer's disease, cholinergic lesion, 192 IgG-saporin, neuronal morphology, pyramidal neurons, rat, spatial function

DOI: 10.3233/JAD-2010-1355

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 207-227, 2010

Authors: García-Matas, Silvia | de Vera, Núria | Aznar, Arantxa Ortega | Marimon, Josep M. | Adell, Albert | Planas, Anna M. | Cristòfol, Rosa | Sanfeliu, Coral

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a devastating age-related neurodegenerative disease. Age is the main risk factor for sporadic AD, which is the most prevalent type. Amyloid-β peptide (Aβ) neurotoxicity is the proposed first step in a cascade of deleterious events leading to AD pathology and dementia. Glial cells play an important role in these changes. Astrocytes provide vital support to neurons and modulate functional synapses. Therefore, the toxic effects of Aβ on astrocytes might promote neurodegenerative changes that lead to AD. Aging reduces astrocyte antioxidant defenses and induces oxidative stress. We studied the effects of Aβ42 on cultures of human …astrocytes in the presence or absence of the following pro-oxidant agents: buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, and FeSO4 , which liberates redox active iron. Pro-oxidant conditions potentiated Aβ toxicity, as shown by the generation of free radicals, inflammatory changes, and apoptosis. Similar treatments were assessed in rats in vivo. A combination of Aβ40 and Aβ42 or Aβ42 alone was infused intracerebroventricularly for 4 weeks. Other animal groups were also infused with BSO and FeSO4 . A long-term analysis that ended 4 months later showed greater cognitive impairment in the Morris water maze task, which was induced by Aβ plus pro-oxidant agent treatments. Pro-oxidant agents also potentiated brain tissue pathology. This was demonstrated in histological studies that showed highly increased astrocyte reactivity in AD-vulnerable areas, Aβ deposits, and oxidative damage of AD-sensitive hippocampal neurons. To increase our understanding of AD, experimental models should be used that mimic age-related brain changes, in which age-related oxidative stress potentiates the effects of Aβ. Show more

Keywords: Amyloid-β peptide, human astrocyte cultures, inflammation, iron, oxidative stress, rat model of Alzheimer's disease

DOI: 10.3233/JAD-2010-1365

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 229-245, 2010

Authors: Boada, Mercè | Antúnez, Carmen | López-Arrieta, Jesús | Galán, José Jorge | Morón, Francisco J. | Hernández, Isabel | Marín, Juan | Martínez-Lage, Pablo | Alegret, Montserrat | Carrasco, Jose M. | Moreno, Concha | Real, Luis M. | González-Pérez, Antonio | Tárraga, Lluís | Ruiz, Agustín

Article Type: Research Article

Abstract: CALHM1 gene coding non-synonymous SNP P86L (rs2986017) was reported to increase the risk of Alzheimer's disease (AD) in a recent study. We have investigated this genetic variant in 2470 individuals from Spain to conduct an independent replication study of the proposed SNP marker. By applying a recessive model, we observed weak evidence of an association between P86L mutation and late-onset AD (LOAD) susceptibility in our case-control study (OR = 1.38 C.I. = [1.01–1.89]). Meta-analysis of available studies also supports a recessive model for CALHM1 P86L variant and provides evidence of between study heterogeneity. Importantly, we found that adjusted mean age …at AD onset in P86L homozygous LOAD patients was significantly earlier that in the rest of patients (77.01 ± 6.1 for P86L homozygous carriers versus 79.0 ± 6.0 for the rest of patients, p = 0.002). We concluded that the CALMH1 gene may contribute to AD risk in our study population. The observed genetic model (recessive) and the estimated magnitude of the effect both imply that virtually all studies performed to date were markedly underpowered to detect this effect and underscore the importance of follow up, replication, and meta-analyses of promising genetic signals. Show more

Keywords: Alzheimer's disease, association, CALHM1, genotype, meta-analysis, molecular genetics, polymorphism

DOI: 10.3233/JAD-2010-1357

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 247-251, 2010

Authors: Mulder, Sandra D. | van der Flier, Wiesje M. | Verheijen, Jan H. | Mulder, Cees | Scheltens, Philip | Blankenstein, Marinus A. | Hack, C. Erik | Veerhuis, Robert

Article Type: Research Article

Abstract: Several studies have shown that reduced amyloid-β 1–42 (Aβ42 ) and increased tau levels in cerebrospinal fluid (CSF) reflect increased Alzheimer's disease (AD) pathology in the brain. β-site APP cleaving enzyme (BACE1) is thought to be the major β-secretase involved in Aβ production in the brain, and therefore we investigated the relation between BACE1 activity and CSF markers Aβ40 , Aβ42 , total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau) in CSF of control (n = 12), mild cognitive impairment (n = 18), and AD (n = 17) subjects. Patients were classified according to their Aβ42 , t-tau, …and p-tau CSF biomarker levels, with either an AD-like biomarker profile (two or three biomarkers abnormal: Aβ42 495 pg/ml in combination with t-tau > 356 pg/ml, and/or p-tau > 54 pg/ml) or a normal biomarker profile (⩽ one biomarker abnormal). This resulted in 19 subjects with an AD-like biomarker profile (66 ± 6 years, 53% female, and Mini-Mental Status Examination (MMSE) score: 23 ± 5) and 28 subjects with a normal biomarker profile (62 ± 11 years, 43% female, and MMSE score: 27 ± 4). Subjects with an AD-like biomarker profile had higher CSF BACE1 activity levels, compared to patients with a normal biomarker profile (20 pg/ml and 16 pg/ml respectively; p = 0.01), when controlled for age and gender. In the whole sample, BACE1 activity correlated with CSF levels of Aβ40 , t-tau, and p-tau (r = 0.38, r = 0.63, and r = 0.65; all p < 0.05), but not with Aβ42 . These data suggest that increased BACE1 activity in CSF relates to AD pathology in the brain. Show more

Keywords: Aβ40, Aβ42, Alzheimer's disease, BACE1 activity, CSF biomarker profile, p-tau, t-tau

DOI: 10.3233/JAD-2010-1367

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 253-260, 2010

Authors: Jin, Haifeng | Sanjo, Nobuo | Uchihara, Toshiki | Watabe, Kazuhiko | George-Hyslop, Peter St. | Fraser, Paul E. | Mizusawa, Hidehiro

Article Type: Research Article

Abstract: Presenilin-1 (PSEN1) is a primary component of the γ-secretase complex, and total levels of its holoprotein and endoproteolytic fragments are tightly regulated. We examined the effects of several types of endoplasmic reticulum (ER) stress on quantitative changes in the levels of PSEN1 mRNA, holoprotein, and fragments. The ER stress-inducing chemical compounds tunicamycin, brefeldin-A, thapsigargin, and staurosporine were added to the culture media of various human cell lines. Tunicamycin treatment caused a doubling of PSEN1 holoprotein production in HEK293 cells and an increase in holoprotein production to approximately 180% in GOTO human neuroblastoma and KNS-42 human glioma cell lines, without changing …the amounts of PSEN1 N- or C-terminal fragments. The elevated holoprotein level in HEK293 cells was accompanied by an increase in PSEN1 mRNA expression. HEK293 cells that stably overexpressed PSEN1 holoprotein showed increased resistance to ER stress induced by tunicamycin, but they did not show resistance to ER stress caused by thapsigargin, a specific inhibitor of sarco ER calcium-ATPase (SERCA). In wild-type HEK293 cells under ER stress induced by tunicamycin, an increased amount of SERCA interacted with PSEN1 holoprotein. PSEN1 production varied among cell types and circumstances. The results suggested that the holoprotein forms a complex with the SERCA channel and participates in the regulation of intracellular calcium homeostasis. These findings provide support for the calcium hypothesis of Alzheimer's disease. Show more

Keywords: Endoplasmic reticulum stress, presenilin, PS1, PSEN1, PS2, PSEN2, sarco ER calcium-ATPase, SERCA, tunicamycin

DOI: 10.3233/JAD-2010-1360

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 261-273, 2010

Authors: Raychaudhuri, Mithu | Mukhopadhyay, Debashis

Article Type: Research Article

Abstract: The amyloid-β protein precursor (AβPP) is processed by various proteases located along the endosomal lysosomal pathway and any alteration in its trafficking would be important in the pathogenesis of Alzheimer's disease (AD). Our current study is based on the clinical evidence that an AβPP intracellular domain (AICD) “adaptor” protein, growth factor receptor protein binding protein 2 (Grb2), gets concentrated in neuronal cell bodies in AD patients. Here we show that both endogenous and exogenously transfected Grb2 interact with AβPP in Neuro 2A cells. Endogenous Grb2 partially co-localizes to late endosomal compartments along with AβPP and AICD. Increase in the concentration …of Grb2 confines it in enlarged late endosomes leading to more sequestration of AβPP and AICD within these compartments. This confinement of AβPP due to Grb2 overexpression affects its turnover by inhibiting its release via exosomal vesicles. As a consequence, the level of intracellular AβPP and AICD increases. The effect of Grb2 overexpression has been verified by knocking down Grb2 as well as by overexpressing Grb2 in Grb2 knocked down cells. Having established the Grb2-mediated trafficking of AICD and its impairment, the significance of its consequence has now become apparent in the downstream events of AD pathogenesis. Show more

Keywords: Amyloid-β protein precursor (AβPP), AβPP intracellular domain (AICD), endosomal-lysosomal pathway, exosome, Grb2

DOI: 10.3233/JAD-2010-1371

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 275-292, 2010

Authors: Qiu, Chengxuan | Xu, Weili | Winblad, Bengt | Fratiglioni, Laura

Article Type: Research Article

Abstract: Numerous studies have linked individual vascular factors to dementia including Alzheimer's disease (AD). We investigated different vascular risk profiles in relation to dementia and AD among very old people. A standardized follow-up procedure was applied three times to a dementia-free cohort (n = 1270, age ⩾ 75) over a nine-year period to detect dementia and AD cases using the DSM-III-R criteria. We examined two vascular risk profiles, which were scored by counting the number of corresponding vascular factors: 1) atherosclerotic profile included systolic pressure ⩾ 160 mmHg, diabetes/prediabetes, and stroke; and 2) cerebral hypoperfusion profile constituted diastolic pressure < 70 …mmHg, pulse pressure < 70 mmHg, and heart failure. Data were analyzed with Cox proportional-hazards models controlling for major potential confounders. During the 6406 person-years of follow-up, 428 subjects developed dementia, including 328 AD cases. All components of vascular profiles were significantly or marginally associated with increased dementia risk. The risk of dementias was increased with increasing score of both risk profiles (p for trend ⩽ 0.001); subjects with a score ⩾ 2 in either profile had an approximately twofold-increased risk for dementia and AD. These data suggest that aggregation of atherosclerotic- and hypoperfusion-related vascular factors increases the risk of dementia in very old people. Severe cerebral atherosclerosis and insufficient perfusion are involved in the development of dementia including AD. Show more

Keywords: Alzheimer's disease, atherosclerosis, cerebral blood flow, cohort study, dementia, vascular factors

DOI: 10.3233/JAD-2010-1361

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 293-300, 2010

Authors: Cummings, Jeffrey | Emre, Murat | Aarsland, Dag | Tekin, Sibel | Dronamraju, Nalina | Lane, Roger

Article Type: Research Article

Abstract: Hallucinations in Alzheimer's disease (AD) may indicate greater cortical cholinergic deficits. Rivastigmine has shown larger treatment benefits versus placebo in dementia with Lewy bodies and Parkinson's disease dementia patients with hallucinations. In this retrospective, hypothesis-generating analysis, we investigated whether hallucinations in AD were associated with greater treatment benefits with rivastigmine. Data were pooled from two randomized, double-blind, 6-month, mild-to-moderate AD trials comparing rivastigmine with placebo. Co-primary efficacy parameters were the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). Efficacy data were analyzed for two sub-populations: those with and those without hallucinations at …baseline. Of 927 patients, 194 (21%) reported hallucinations at baseline. Hallucinators tended to have greater decline on placebo on all outcome measures. On the ADAS-cog, mean rivastigmine − placebo differences of 3.7 points in hallucinators and 2.2 points in non-hallucinators were reported at 6 months (both p < 0.001). In hallucinators, a significant rivastigmine − placebo difference of −1.0 points (a beneficial effect) was seen on the CIBIC-plus at 6 months (p < 0.001). Non-hallucinators showed a smaller significant treatment difference of −0.3 points (p < 0.05). Interaction testing suggested that differences in treatment effects were significant between hallucinators and non-hallucinators. Hallucinations predicted greater treatment responses to oral rivastigmine. Show more

Keywords: Alzheimer's disease, cholinesterase inhibitor, hallucinations, rivastigmine

DOI: 10.3233/JAD-2010-1362

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 301-311, 2010

Authors: Loskutova, Natalia | Honea, Robyn A. | Brooks, William M. | Burns, Jeffrey M.

Article Type: Research Article

Abstract: Accelerated bone loss is associated with Alzheimer's disease (AD). Although the central nervous system plays a direct role in regulating bone mass, primarily through the actions of the hypothalamus, there is little work investigating the possible role of neurodegeneration in bone loss. In this cross-sectional study, we examined the association between bone mineral density (BMD) and neuroimaging markers of neurodegeneration (i.e., global and regional measures of brain volume) in early AD and non-demented aging. Fifty-five non-demented and 63 early AD participants underwent standard neurological and neuropsychological assessment, structural MRI scanning, and dual energy x-ray absorptiometry. In early AD, voxel-based morphometry …analyses demonstrated that low BMD was associated with low volume in limbic grey matter (GM) including the hypothalamus, cingulate, and parahippocampal gyri and in the left superior temporal gyrus and left inferior parietal cortex. No relationship between BMD and regional GM volume was found in non-demented controls. The hypothesis-driven region of interest analysis further isolating the hypothalamus demonstrated a positive relationship between BMD and hypothalamic volume after controlling for age and gender in the early AD group but not in non-demented controls. These results demonstrate that lower BMD is associated with lower hypothalamic volume in early AD, suggesting that central mechanisms of bone remodeling may be disrupted by neurodegeneration. Show more

Keywords: Alzheimer's disease, bone density, hypothalamus, voxel-based morphometry

DOI: 10.3233/JAD-2010-1364

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 313-322, 2010

Authors: Zheng, Wei | Wang, Tao | Yu, Dan | Feng, Wan-Yu | Nie, Ying-Xue | Stoltenberg, Meredin | Danscher, Gorm | Wang, Zhan-You

Article Type: Research Article

Abstract: The presence of senile plaques containing abundant amyloid-β (Aβ) peptide is one of the major pathological hallmarks of Alzheimer's disease (AD). Recent studies support the notion that overexpression of zinc transporters (ZnT) is involved in zinc metabolic disturbances and Aβ aggregation in AD brains. Here we present data showing an elevated expression of zinc transporter 3 (ZnT3) protein, revealed by immunoblotting assay, in the cerebellum of the amyloid-β protein precursor (AβPP)/presenilin 1 (PS1) transgenic mouse. Confocal microscopic and autometallographic results showed that ZnT3 immunofluorescence and zinc ions were predominantly located in the amyloid plaques. ZnT3 protein was abundantly distributed throughout …the plaques, whereas zinc ions were mainly located in the peripheral parts of rosette-shaped plaques with a lightly stained center. Collectively, our results suggest that ZnT3 protein is involved in the Aβ aggregation in the cerebellum of the AβPP/PS1 mouse. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, cerebellum, ionic zinc, SLC30A3

DOI: 10.3233/JAD-2010-1363

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 323-331, 2010

Authors: Bartzokis, George | Lu, Po H. | Tishler, Todd A. | Peters, Douglas G. | Kosenko, Anastasia | Barrall, Katherine A. | Finn, J. Paul | Villablanca, Pablo | Laub, Gerhard | Altshuler, Lori L. | Geschwind, Daniel H. | Mintz, Jim | Neely, Elizabeth | Connor, James R.

Article Type: Research Article

Abstract: Prevalent gene variants involved in iron metabolism [hemochromatosis (HFE) H63D and transferrin C2 (TfC2)] have been associated with higher risk and earlier age at onset of Alzheimer's disease (AD), especially in men. Brain iron increases with age, is higher in men, and is abnormally elevated in several neurodegenerative diseases, including AD and Parkinson's disease, where it has been reported to contribute to younger age at onset in men. The effects of the common genetic variants (HFE H63D and/or TfC2) on brain iron were studied across eight brain regions (caudate, putamen, globus pallidus, thalamus, hippocampus, white matter of frontal lobe, genu, …and splenium of corpus callosum) in 66 healthy adults (35 men, 31 women) aged 55 to 76. The iron content of ferritin molecules (ferritin iron) in the brain was measured with MRI utilizing the Field Dependent Relaxation Rate Increase (FDRI) method. 47% of the sample carried neither genetic variant (IRON-) and 53% carried one and/or the other (IRON+). IRON+ men had significantly higher FDRI compared to IRON- men (p = 0.013). This genotype effect was not observed in women who, as expected, had lower FDRI than men. This is the first published evidence that these highly prevalent genetic variants in iron metabolism genes can influence brain iron levels in men. Clinical phenomena such as differential gender-associated risks of developing neurodegenerative diseases and age at onset may be associated with interactions between iron genes and brain iron accumulation. Clarifying mechanisms of brain iron accumulation may help identify novel interventions for age-related neurodegenerative diseases. Show more

Keywords: Alpha synuclein, amyloid, basal ganglia, chelation, dementia, diet, free radicals, gene, gray matter, iron, Lewy body, metal, myelin, oligodendrocytes, prevention, risk, tau, treatment

DOI: 10.3233/JAD-2010-1368

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 333-341, 2010

Authors: Landhuis, Esther

Article Type: Editorial

DOI: 10.3233/JAD-2010-1358

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 343-349, 2010

Article Type: Announcement

DOI: 10.3233/JAD-2010-1372

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 351-353, 2010