Journal of Alzheimer's Disease - Volume 45, issue 1

Authors: Fernández-Montoya, Julia | Pérez, Mar

Article Type: Research Article

Abstract: Tauopathies, such as Alzheimer's disease (AD) and Frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), are characterized by tau accumulation. This accumulation could result from alterations in tau degradation by either the ubiquitin-proteasome system or the autophagy–lysosomal pathway. To analyze a possible alteration of the autophagy–lysosomal pathway in transgenic mice expressing human tau with three FTDP-17 missense mutations (TauVLW mice), we studied the lysosomal enzyme Cathepsin D. The hippocampi of TauVLW mice, where the human mutant tau accumulates, showed both increased Cathepsin D and partial colocalization of Cathepsin D with human mutant tau. At the ultrastructural level, …some multivesicular bodies showed human mutant tau-immunopositive vesicles. This finding could provide insights into the molecular mechanisms of tau degradation in human tauopathies. Show more

Keywords: Cathepsin D, FTDP-17, lysosomal system, mutated tau

DOI: 10.3233/JAD-140456

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 1-14, 2015

Authors: Bun, Shogyoku | Ikejima, Chiaki | Kida, Jiro | Yoshimura, Atsuko | Lebowitz, Adam Jon | Kakuma, Tatsuyuki | Asada, Takashi

Article Type: Research Article

Abstract: A number of studies have examined the effect of a single supplement against Alzheimer's disease (AD) with conflicting results. Taking into account the complex and multifactorial nature of AD pathogenesis, multiple supplements may be more effective. Physical activity is another prospect against AD. An open-label intervention study was conducted to explore a potential protective effect of multiple supplements and physical activity. Their interaction was also examined. Participants were community-dwelling volunteers aged 65 or older as of May 2001 in a rural area of Japan. Among 918 cognitively normal participants included in the analyses, 171 took capsules daily for three years …that contained n-3 polyunsaturated fatty acid, Ginkgo biloba leaf dry extracts, and lycopene. Two hundred and forty one participants joined the two-year exercise intervention that included a community center-based and a home-based exercise program. One-hundred and forty eight participated in both interventions. A standardized neuropsychological battery was administered at baseline in 2001, the first follow-up in 2004-2005, and the second in 2008-2009. The primary outcome was AD diagnosis at follow-ups. A complementary log-log model was used for survival analysis. A total of 76 participants were diagnosed with AD during follow-up periods. Higher adherence to supplementation intervention was associated with lower AD incidence in both unadjusted and adjusted models. Exercise intervention was also associated with lower AD incidence in the unadjusted model, but not in the adjusted model. We hypothesized that the combination of supplements acted in a complementary and synergistic fashion to bring significant effects against AD occurrence. Show more

Keywords: Alzheimer's disease, dietary supplements, exercise, Gingko biloba, intervention study, lycopene, n-3 PUFA

DOI: 10.3233/JAD-142232

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 15-25, 2015

Authors: Hsu, Phillip J. | Shou, Haochang | Benzinger, Tammie | Marcus, Daniel | Durbin, Tony | Morris, John C. | Sheline, Yvette I.

Article Type: Research Article

Abstract: The earliest sites of brain atrophy in Alzheimer's disease are in the medial temporal lobe, following widespread cerebral cortical amyloid deposition. We assessed 74 cognitively normal participants with clinical measurements, amyloid-β-PET imaging, MRI, and a newly developed technique for MRI-based hippocampal subfield segmentation to determine the differential association of amyloid deposition and hippocampal subfield volume. Compared to amyloid-negative participants, amyloid-positive participants had significantly smaller hippocampal tail, presubiculum, subiculum, and total hippocampal gray matter volumes. We conclude that, prior to the development of cognitive impairment, atrophy in particular hippocampal subfields occurs preferentially with amyloid-β accumulation.

Keywords: Amyloid accumulation, cognitively normal elderly, hippocampal subfield volumes, presubiculum, subiculum

DOI: 10.3233/JAD-141743

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 27-33, 2015

Authors: Jongbloed, Wesley | Bruggink, Kim A. | Kester, Maartje I. | Visser, Pieter-Jelle | Scheltens, Philip | Blankenstein, Marinus A. | Verbeek, Marcel M. | Teunissen, Charlotte E. | Veerhuis, Robert

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ)-oligomers are neurotoxic isoforms of Aβ and are a potential diagnostic biomarker for Alzheimer's disease (AD). Objectives: 1) Analyze the potential of Aβ-oligomer concentrations in cerebrospinal fluid (CSF) to diagnose and predict progression to AD in a large clinical study sample. 2) Monitor Aβ-oligomer concentrations over-time, both in early and advanced stages of AD. 3) Examine the relation between Aβ-oligomer levels in CSF and cognitive functioning. Methods: 24 non-demented, 61 mild cognitive impairment (MCI), and 64 AD patients who underwent lumbar puncture and cognitive testing at baseline and follow-up were selected from the memory …clinic based Amsterdam Dementia Cohort. CSF samples were analyzed for standard AD-biomarkers and Aβ-oligomer levels using a validated in-house Aβ-oligomer specific enzyme-linked immunosorbent assay. Aβ-oligomer levels were analyzed as indicators of disease progression (follow-up AD diagnosis) and cognitive decline, respectively. Results: Patient groups did not differ in Aβ-oligomer concentrations at baseline or follow-up. Baseline CSF Aβ-oligomer levels were similar in MCI patients that develop AD as in stable MCI patients. MCI and AD patients showed an annual decrease in Aβ-oligomer levels of 9.4% and 6.8%, respectively. A decrease in Aβ-oligomer levels over time was strongly associated with more severe cognitive decline in AD patients. Conclusion: Despite the limited diagnostic potential of Aβ-oligomer levels in CSF to differentiate between patient groups, and between MCI-AD and MCI-stable patients, changes in CSF Aβ-oligomer levels were related to cognitive decline. Therefore, CSF Aβ-oligomers may aid in the selection of patients with a more aggressive disease course. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, biological markers, cerebrospinal fluid, cognition, dementia, disease progression, mild cognitive impairment

DOI: 10.3233/JAD-142136

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 35-43, 2015

Authors: Cheung, Carol Yim-lui | Ong, Yi Ting | Hilal, Saima | Ikram, M. Kamran | Low, Sally | Ong, Yi Lin | Venketasubramanian, N. | Yap, Philip | Seow, Dennis | Chen, Christopher Li Hsian | Wong, Tien Yin

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder with emerging evidence that it is associated with retinal ganglion cell loss; however, few data exist to establish this association. Objective: To determine whether macular ganglion cell-inner plexiform layer (GC-IPL) and retinal nerve fiber layer (RNFL), as quantitatively measured by non-invasive in vivo spectral-domain optical coherence tomography (SD-OCT), are altered in patients with AD and mild cognitive impairment (MCI). Methods: Patients with AD and MCI were recruited from dementia/memory clinics, and cognitively normal controls were selected from the Singapore Epidemiology of Eye Disease program. SD-OCT (Cirrus HD-OCT, software …version 6.0.2, Carl Zeiss Meditec Inc, Dublin, CA) was used to measure the GC-IPL and RNFL thicknesses. Results: Compared with cognitively normal controls (n = 123), patients with AD (n = 100) had significantly reduced GC-IPL thicknesses in all six (superior, superonasal, inferonasal, inferior, inferotemporal, and superotemporal) sectors (mean differences from –3.42 to –4.99 µm, all p < 0.05) and reduced RNFL thickness in superior quadrant (–6.04 µm, p = 0.039). Patients with MCI (n = 41) also had significantly reduced GC-IPL thicknesses compared with controls (mean differences from –3.62 to –5.83 µm, all p < 0.05). Area under receiver operating characteristic curves of GC-IPL were generally higher than that of RNFL to discriminate AD and MCI from the controls. Conclusions: Our data strengthens the link between retinal ganglion cell neuronal and optic nerve axonal loss with AD, and suggest that assessment of macular GC-IPL can be a test to detect neuronal injury in early AD and MCI. Show more

Keywords: Alzheimer's disease, mild cognitive impairment, neurodegenerative disorder, optic nerve, retinal ganglion cell, spectral-domain optical coherence tomography

DOI: 10.3233/JAD-141659

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 45-56, 2015

Authors: Gozes, Illana | Yeheskel, Adva | Pasmanik-Chor, Metsada

Article Type: Research Article

Abstract: The recent finding of activity-dependent neuroprotective protein (ADNP) as a protein decreased in serum of patients with Alzheimer's disease (AD) compared to controls, alongside with the discovery of ADNP mutations in autism and coupled with the original description of cancer mutations, ignited an interest for a comparative analysis of ADNP with other AD/autism/cancer-associated genes. We strive toward a better understanding of the molecular structure of key players in psychiatric/neurodegenerative diseases including autism, schizophrenia, and AD. This article includes data mining and bioinformatics analysis on the ADNP gene and protein, in addition to other related genes, with emphasis on recent literature. …ADNP is discovered here as unique to chordata with specific autism mutations different from cancer-associated mutation. Furthermore, ADNP exhibits similarities to other cancer/autism-associated genes. We suggest that key genes, which shape and maintain our brain and are prone to mutations, are by in large unique to chordata. Furthermore, these brain-controlling genes, like ADNP, are linked to cell growth and differentiation, and under different stress conditions may mutate or exhibit expression changes leading to cancer propagation. Better understanding of these genes could lead to better therapeutics. Show more

Keywords: Activity-dependent neuroportective protein, Alzheimer's disease, autism spectrum disorder, cancer

DOI: 10.3233/JAD-142490

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 57-73, 2015

Authors: Lovestone, Simon | Boada, Mercè | Dubois, Bruno | Hüll, Michael | Rinne, Juha O. | Huppertz, Hans-Jürgen | Calero, Miguel | Andrés, María V. | Gómez-Carrillo, Belén | León, Teresa | del Ser, Teodoro | for the ARGO investigators

Article Type: Research Article

Abstract: Background: The ARGO study was a phase II, double-blind, placebo controlled, four parallel arm trial of tideglusib in Alzheimer’s disease (AD). Objective: To prove the clinical efficacy of an inhibitor of glycogen synthase kinase-3 (GSK-3), in AD. Methods: Mild to moderate (Mini-Mental State Examination (MMSE) score, 14–26) AD patients on cholinesterase inhibitor and/or memantine treatment were administered tideglusib or placebo for 26 weeks. The ADAS-cog15 was the primary efficacy measure; function, cognition, behavior, and quality of life were assessed as secondary measures; cerebral atrophy in MRI and the levels of tau, amyloid-β, and BACE1 in …cerebrospinal fluid (CSF) were exploratory endpoints. Results: 306 AD patients were randomized to active (1000 mg QD: n = 86, 1000 mg QOD: n = 90, and 500 mg QD: n = 50) or placebo (n = 85) in 55 sites in four European countries. There were no statistically significant differences between either active and placebo arms in the efficacy variables. However, BACE1 in CSF significantly decreased with treatment in a small subgroup of patients. Participants with mild AD in the 500 mg QD group showed significant responses on ADAS-cog15 , MMSE, and word fluency. Diarrhea (14–18% in active, 11% placebo) and dose-dependent, mild to moderate, and fully reversible transaminase increase (9–16% in active, 3.5% placebo) were the most frequent adverse events. Conclusions: Short term (26 weeks) tideglusib was acceptably safe but produced no clinical benefit in this trial. However, given the non-linear dose response, especially in mildly affected patients, further dose finding studies in early disease stages and for longer duration are warranted to examine GSK-3 inhibition in AD patients. Show more

Keywords: Alzheimer's disease, GSK-3, pharmacological treatment, randomized controlled clinical trial, tideglusib

DOI: 10.3233/JAD-141959

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 75-88, 2015

Authors: Monacelli, Fiammetta | Borghi, Roberta | Cammarata, Sergio | Nencioni, Alessio | Piccini, Alessandra | Tabaton, Massimo | Odetti, Patrizio

Article Type: Research Article

Abstract: Autopsy studies have indicated brain accumulation of amyloid-β peptides as a common pathogenetic hallmark of amnestic cognitive impairment (aMCI) and overt Alzheimer's disease (AD). The pathogenesis of AD is still debated but recent reports have even designated AD as type III diabetes. This study aims to assess plasma levels of malondialdehyde, pentosidine, and insulin resistance in a group of aMCI patients, AD subjects, and age- and gender-matched controls, to confirm, beyond the accumulation of amyloid-β, the presence of a metabolic disorder, as a causative/contributive factor for AD. Patients were recruited and diagnosed as aMCI (n = 180), AD (n = …84), and age- and gender-matched controls (n = 62) at three different Italian memory clinics. Plasma insulin and glucose, plasma pentosidine and malondialdehyde (MDA), HOMA-IR and QUICKI score for insulin sensitivities indexes were collected at the basal visit. Plasma MDA levels were higher in the aMCI group who converted to AD compared to controls, stable aMCI subjects, and AD subjects (p < 0.01) respectively, while plasma pentosidine was higher compared to controls. The aMCI group showed a significant correlation between HOMA-IR, QUICKI, insulin, and MDA (p < 0.02). aMCI might be considered the early biochemical active disease stage where glycoxidation, hyperinsulinemia, and pro-amyloidogenic status are at the highest rate while overt AD might indicate the glycoxidative cascade dwindling, ending a process possibly started two decades earlier. Show more

Keywords: Alzheimer's disease, early biomarkers, insulin resistance, malondialdehyde, mild cognitive impairment, pentosidine

DOI: 10.3233/JAD-142511

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 89-95, 2015

Authors: Nishioka, Christopher | Poh, Christina | Sun, Shu-Wei | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Visual deficits are commonly seen in patients with Alzheimer's disease (AD), but postmortem histology has not found substantial damage in visual cortex regions, leading to the hypothesis that the visual pathway, from eye to the brain, may be damaged in AD. Diffusion tensor imaging (DTI) has been used to characterize white matter abnormalities. However, there is a lack of data examining the optic nerves and tracts in patients with AD. In this study, we used DTI to analyze the visual pathway in healthy controls, patients with mild cognitive impairment (MCI) and AD using scans provided by the Alzheimer's Disease Neuroimaging …Initiative (ADNI). We found significant increases in the total diffusivity and radial diffusivity and reductions in fractional anisotropy in optic nerves among AD patients. Similar but less extensive changes in these metrics were seen in MCI patients as compared to controls. The differences in DTI metrics between groups mirrored changes in the splenium of the corpus callosum, which has commonly been shown to exhibit white matter damage during AD and MCI. Our findings indicate that white matter damage extends to the visual system, and may help explain the visual deficits experienced by AD patients. Show more

Keywords: Alzheimer's disease, Alzheimer's Disease Neuroimaging Initiative, diffusion tensor imaging, human, mild cognitive impairment, optic nerve, optic tract, visual pathway

DOI: 10.3233/JAD-141239

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 97-107, 2015

Authors: Jingami, Naoto | Asada-Utsugi, Megumi | Uemura, Kengo | Noto, Rio | Takahashi, Makio | Ozaki, Akihiko | Kihara, Takeshi | Kageyama, Takashi | Takahashi, Ryosuke | Shimohama, Shun | Kinoshita, Ayae

Article Type: Research Article

Abstract: The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is sometimes complicated by concomitant Alzheimer's disease (AD) pathology. The purpose of the present study is to identify an iNPH-specific cerebrospinal fluid (CSF) biomarker dynamics and to assess its ability to differentiate iNPH from AD. Total tau (t-tau), tau phosphorylated at threonine 181 (p-tau), amyloid-β (Aβ) 42 and 40, and leucine-rich α-2-glycoprotein (LRG) were measured in 93 consecutive CSF samples consisting of 55 iNPH (46 tap test responders), 20 AD, 11 corticobasal syndrome, and 7 spinocerebeller disease. Levels of t-tau and p-tau were significantly decreased in iNPH patients especially in tap test …responders compared to AD. Correlation was observed between Mini-Mental State Examination scores and Aβ42 in AD (R = 0.44) and mildly in iNPH (R = 0.28). Although Aβ42/40 ratio showed no significant difference between iNPH and AD (p = 0.08), the levels of Aβ40 and Aβ42 correlated positively with each other in iNPH (R = 0.73) but much less in AD (R = 0.26), suggesting that they have discrete amyloid clearance and pathology. LRG levels did not differ between the two. Thus, our study shows that although CSF biomarkers of iNPH patients can be affected by concomitant tau and/or amyloid pathology, CSF t-tau and p-tau are highly useful for differentiation of iNPH and AD. Show more

Keywords: Alzheimer's disease, amyloid-β, analysis of covariate, idiopathic normal pressure hydrocephalus, leucine-rich α-2-glycoprotein, Mini-Mental State Examination, tap test, tau phosphorylated at threonine 181, total tau

DOI: 10.3233/JAD-142622

Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 109-115, 2015