Journal of Alzheimer's Disease - Volume 36, issue 3

Article Type: Editorial

DOI: 10.3233/JAD-139903

Citation: Journal of Alzheimer's Disease, vol. 36, no. 3, pp. 413-414, 2013

Authors: Cerami, Chiara | Marcone, Alessandra | Galimberti, Daniela | Villa, Chiara | Fenoglio, Chiara | Scarpini, Elio | Cappa, Stefano F.

Article Type: Short Communication

Abstract: Progranulin (GRN) mutations are typically associated with the behavioral variant of frontotemporal dementia and the non-fluent variant of primary progressive aphasia phenotypes. Hereby, we describe a patient affected by semantic variant of primary progressive aphasia (svPPA) with a highly positive family history of dementia, carrying a novel GRN missense variation in exon 11 [g.2897 C > T (p.Thr409Met)], predicted in silico to be damaging to protein structure and function. The variant was absent in 175 frontotemporal lobar degeneration (FTLD) patients and in 38 healthy subjects. This case confirms that GRN represents one of the most frequent FTLD genetic causes, suggesting …that a screening is indicated in the case of svPPA presentation. Show more

Keywords: Frontotemporal lobar degeneration, GRN mutation, semantic variant of primary progressive aphasia

DOI: 10.3233/JAD-130317

Citation: Journal of Alzheimer's Disease, vol. 36, no. 3, pp. 415-420, 2013

Authors: Eckerström, Carl | Olsson, Erik | Bjerke, Maria | Malmgren, Helge | Edman, Åke | Wallin, Anders | Nordlund, Arto

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a condition with increased risk for further cognitive decline. A considerable challenge lies in predicting which patients will eventually convert to dementia. Objective: To study prediction of dementia in MCI using neuropsychological tests, commonly used cerebrospinal fluid (CSF) biomarkers, and hippocampal volume. Methods: Twenty-one MCI patients converting to dementia, 21 stable MCI patients, and 26 controls were included in the study with a follow-up time of two years. The study participants underwent comprehensive examinations at inclusion: a neuropsychological assessment comprising 20 tests, MRI scanning with subsequent hippocampal volumetry, and CSF …analyses of T-tau, P-tau, and Aβ42 . Results: Neuropsychological tests, hippocampal volume, and the CSF markers Aβ42 , P-tau, and T-tau all predicted conversion from MCI to dementia. A combination of all classes of markers was the most successful at predicting dementia (AUC 0.96) with a memory test (RAVLT) as the best individual predictor (AUC 0.93). Similar findings are reported for the prediction of Alzheimer’s disease. Conclusion: Neuropsychological tests were the best individual predictors of dementia. A combination of markers improved the predictive ability with the combination of neuropsychological tests, CSF, and hippocampal volume as the best predictors of dementia. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, dementia, mild cognitive impairment, neuroimaging, neuropsychology

DOI: 10.3233/JAD-122440

Citation: Journal of Alzheimer's Disease, vol. 36, no. 3, pp. 421-431, 2013

Authors: Reckess, Gila Z. | Brandt, Jason | Luis, Cheryl A. | Zandi, Peter | Martin, Barbara | Breitner, John C. S. | For the ADAPT Research Group

Article Type: Research Article

Abstract: Compared with in-person assessment methods, telephone screening for dementia and other cognitive syndromes may improve efficiency of large population studies or prevention trials. We used data from the Alzheimer's Disease Anti-Inflammatory Prevention Trial to compare performance of a four-test Telephone Assessment Battery (TAB) that included the Telephone Interview for Cognitive Status (TICS) to that of a traditional in-person Cognitive Assessment Battery. Among 1,548 elderly participants with valid telephone and in-person screening results obtained within 90 days of each other, 225 persons were referred for a full cognitive diagnostic evaluation that was completed within six months of screening. Drawing on results …from this panel of 225 individuals, we used the Capture-Recapture method to estimate population numbers of cognitively impaired participants. The latter estimates enabled us to compare the performance characteristics of the two screening batteries at specified cut-offs for detection of dementia and milder forms of impairment. Although our results provide relatively imprecise estimates of the performance characteristics of the two batteries, a comparison of their relative performance suggests that, at selected cut-off points, the TAB produces results broadly comparable to in-person screening and may be slightly more sensitive in detecting mild impairment. TAB performance characteristics also appeared slightly better than those of the TICS alone. Given its benefits in time and cost when screening for cognitive disorders, telephone screening should be considered for large samples. Show more

Keywords: Alzheimer's disease, dementia, geriatric assessment, memory disorders, mild cognitive impairment, neuropsychology, prodromal period, telephone

DOI: 10.3233/JAD-130113

Citation: Journal of Alzheimer's Disease, vol. 36, no. 3, pp. 433-443, 2013

Authors: Yang, Zhendong | Zhou, Xiangyu | Zhang, Qi

Article Type: Research Article

Abstract: Background/Objective: Memantine is approved as a treatment for moderate to severe Alzheimer’s disease (AD). However, recent studies report that memantine is harmful for AD patients in several ways. This paper will systematically review all the available studies to provide an update regarding memantine as a treatment for AD. Method: Two authors queried nine databases containing literature published prior to September 15, 2012 and determined eligible studies based on the inclusion criteria. We used Review Manager to pool similar data. The Cochrane Handbook was used to assess the bias of the included studies. The chi-squared test, sensitivity analysis, Egger’s …test, and funnel plots were used to determine the heterogeneity and report bias, respectively. Result: We obtained 889 studies and determined that 12 of those studies met the inclusion criteria. The pooled analysis showed that memantine had significant benefits for AD patients in terms of cognition and the clinician’s global impression. There were no significant benefits for AD patients in terms of mental state or activities of daily life. The results on brain volume and metabolism were controversial in two of the studies. Memantine did not significantly affect discontinuation caused by serious adverse events but did increase the risk for somnolence, weight gain, confusion, hypertension, nervous system disorders, and falling. Conclusion: Memantine is beneficial for AD patients with regards to cognition and clinician’s global impression but increases the risk for somnolence, weight gain, confusion, hypertension, nervous system disorders, and falling. Show more

Keywords: Alzheimer's disease, effectivity, memantine, safety

DOI: 10.3233/JAD-130395

Citation: Journal of Alzheimer's Disease, vol. 36, no. 3, pp. 445-458, 2013

Authors: Dursun, Erdinç | Gezen-Ak, Duygu | Yilmazer, Selma

Article Type: Research Article

Abstract: The inflammatory process in Alzheimer's disease (AD) has been suggested to include oxidative and nitrosative damage caused by elevated levels of nitric oxide (NO) and inducible nitric oxide synthase (iNOS). Here, we investigated iNOS expression in cortical neurons following amyloid-β (Aβ) treatment, vitamin D treatment, Aβ combined with vitamin D treatment, and vitamin D signaling disruption via silencing of nuclear (vitamin D receptor-VDR) or membrane vitamin D (1,25-MARRS) receptors. We observed that Aβ induced iNOS expression. Vitamin D prevented Aβ-induced cytotoxicity and iNOS upregulation in cortical neurons. Our silencing experiments suggest that vitamin D regulates iNOS via VDR, not 1,25-MARRS, …in cortical neurons. Consequently, VDR absence induces iNOS expression in either the absence or presence of Aβ. While our previous work demonstrates that Aβ pathology includes VDR suppression, our present work demonstrates that Aβ induces iNOS and that this effect is mediated via disruption of the vitamin D-VDR pathway. These data suggest the existence of crosstalk between Aβ pathology and VDR. Thus, vitamin D supplementation should be considered a candidate in both the treatment and prevention of AD. Show more

Keywords: 1,25-MARRS, Alzheimer's disease, amyloid-beta, iNOS, VDR, vitamin D

DOI: 10.3233/JAD-130416

Citation: Journal of Alzheimer's Disease, vol. 36, no. 3, pp. 459-474, 2013

Authors: Macklin, Eric A. | Blacker, Deborah | Hyman, Bradley T. | Betensky, Rebecca A.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) trials initiated during or before the prodrome are costly and lengthy because patients are enrolled long before clinical symptoms are apparent, when disease progression is slow. We hypothesized that design of such trials could be improved by: 1) selecting individuals at moderate near-term risk of progression to AD dementia (the current clinical standard) and 2) by using short-term surrogate endpoints that predict progression to AD dementia. We used a longitudinal cohort of older, initially non-demented, community-dwelling participants (n = 358) to derive selection criteria and surrogate endpoints and tested them in an independent national data set (n …= 6,243). To identify a “mid-risk” subgroup, we applied conditional tree-based survival models to Clinical Dementia Rating (CDR) scale scores and common neuropsychological tests. In the validation cohort, a time-to-AD dementia trial applying these mid-risk selection criteria to a pool of all non-demented individuals could achieve equivalent power with 47% fewer participants than enrolling at random from that pool. We evaluated surrogate endpoints measureable over two years of follow-up based on cross-validated concordance between predictions from Cox models and observed time to AD dementia. The best performing surrogate, rate of change in CDR sum-of-boxes, did not reduce the trial duration required for equivalent power using estimates from the validation cohort, but alternative surrogates with better ability to predict time to AD dementia should be able to do so. The approach tested here might improve efficiency of prodromal AD trials using other potential measures and could be generalized to other diseases with long prodromal phases. Show more

Keywords: Alzheimer's disease, clinical trials as topic, National Alzheimer's Coordinating Center Uniform Data Set, surrogate endpoint, survival analysis

DOI: 10.3233/JAD-122212

Citation: Journal of Alzheimer's Disease, vol. 36, no. 3, pp. 475-486, 2013

Authors: Veszelka, Szilvia | Tóth, Andrea E. | Walter, Fruzsina R. | Datki, Zsolt | Mózes, Emese | Fülöp, Lívia | Bozsó, Zsolt | Hellinger, Éva | Vastag, Monika | Orsolits, Barbara | Környei, Zsuzsanna | Penke, Botond | Deli, Mária A.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β peptides (Aβ) as perivascular deposits and senile plaques in the brain. The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) has been associated with decreased amyloid deposition and reduced risk in AD in several epidemiological trials; however the exact underlying molecular mechanism remains to be elucidated. The aim of the study was to test whether DHA can exert a direct protective effect on the elements of the neurovascular unit, such as neurons, glial cells, brain endothelial cells, and pericytes, treated with Aβ42 (15 μM). A dose-dependent high cellular …toxicity was found in viability assays in all cell types and on acute hippocampal slices after treatment with Aβ42 small oligomers prepared in situ from an isopeptide precursor. The cell morphology also changed dramatically in all cell types. In brain endothelial cells, damaged barrier function and increased para- and transcellular permeability were observed after peptide treatment. The production of reactive oxygen species was elevated in pericytes and endothelial and glial cells. DHA (30 μM) significantly decreased the Aβ42 -induced toxic effects in all cell types measured by viability assays, and protected the barrier integrity and functions of brain endothelial cells. DHA also decreased the elevated rhodamine 123 accumulation in brain endothelial cells pre-treated with Aβ42 indicating an effect on efflux pump activity. These results indicate for the first time that DHA can protect not only neurons but also the other elements of the neurovascular unit from the toxic effects of Aβ42 and this effect may be beneficial in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, blood-brain barrier, brain endothelial cells, docosahexaenoic acid, glia, neuron, neurovascular unit, pericyte, P-glycoprotein

DOI: 10.3233/JAD-120163

Citation: Journal of Alzheimer's Disease, vol. 36, no. 3, pp. 487-501, 2013

Authors: Monroy-Ramírez, Hugo C. | Basurto-Islas, Gustavo | Mena, Raul | Cisneros, Bulmaro | Binder, Lester I. | Avila, Jesús | Garcia-Sierra, Francisco

Article Type: Research Article

Abstract: Abnormal intracellular aggregation of tau protein is a pathological condition leading to neuronal death in Alzheimer's disease. Fibrillar and nonfibrillar aggregates of tau protein alter the normal functioning of neurons by disturbing important cellular processes and distinct membranous organelles. However, tau-caused alterations in the nuclear compartment are not totally established so far. In our study we evaluated whether tau protein and its Asp421 -truncated variant produce alterations in the normal architecture of the nucleus when expressed in cultured neuroblastoma cells. After 48 hours of transfection, significant deformity of the nuclear compartment with extensive lobulations along the nuclear envelope was observed …in SH-SY5Y cells expressing either full-length tau or Asp421 -truncated tau. This aberrant formation did not involve either nuclear fragmentation or cell death. The lobulated nuclei were devoid of tau protein, which mostly remained in the cytoplasm in a nonfibrillar state. Degradation of nuclear Lamins was not observed in tau-expressing SH-SY5Y cells, and a cell-cycle analysis did not show aberrant chromosome accumulation. Thus multiple division defects leading to multinucleation were discarded. The lobulated nuclei in tau-expressing SH-SY5Y cells seem to more resemble the multilobular phenotype of the nuclear envelope seen in Lamin-mutated cells from those pathological conditions leading to premature aging. Nevertheless, in our tau-expressing cells, the abnormal formation of cortical and perinuclear rings of tubulin generated by tau binding may be a more feasible mechanism of a nuclear-cytoskeleton generating force that causes the nuclear deformation. Show more

Keywords: Alzheimer's disease, confocal microscopy, Lamins, microtubules, nuclear architecture, tau pathology, truncated tau

DOI: 10.3233/JAD-122401

Citation: Journal of Alzheimer's Disease, vol. 36, no. 3, pp. 503-520, 2013

Authors: Wilson, Lachlan | Lardelli, Michael

Article Type: Research Article

Abstract: Aberrant proteolytic processing of amyloid-β protein precursor by γ-secretase complexes may result in an imbalance between production and clearance of the Aβ proteolytic product and promote neuronal dysfunction and death. Presenilin proteins form the catalytic core of γ-secretase complexes. The zebrafish, Danio rerio, is a versatile vertebrate model for investigating the molecular basis of Alzheimer's disease pathology. It possesses genes orthologous to human PSEN1 and PSEN2 (psen1 and psen2 respectively), and AβPP (appa and appb that are duplicates of an ancestral AβPP orthologue). Currently there is no in vivo assay appropriate for directly monitoring γ-secretase activity. Here, we describe such …an assay in which the level of a γ-secretase substrate (a modified form of Appa protein) is observed in zebrafish embryos by western immunoblotting relative to a co-expressed protein not subject to γ-secretase activity. We have used the assay to analyze the effects on γ-secretase activity of blocking translation of transcripts of zebrafish psen1 and/or psen2. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, assay, γ-secretase, morpholinos, presenilin, truncated protein, zebrafish

DOI: 10.3233/JAD-130332

Citation: Journal of Alzheimer's Disease, vol. 36, no. 3, pp. 521-534, 2013