Journal of Alzheimer's Disease - Volume 50, issue 2

Authors: Zhang, Ting | Li, He | Zhang, Junying | Li, Xin | Qi, Di | Wang, Nuo | Zhang, Zhanjun

Article Type: Research Article

Abstract: Epidemiological and clinical studies suggest that high serum cholesterol is a risk factor of dementia. However, the effects of cholesterol on cognition and brain remain largely unclear. This study aims to investigate the associations between serum total cholesterol (TC) and neuropsychological performance, and intrinsic functional networks in non-demented elderly. Among a cohort of 120 community-dwelling Beijing residents, 29 subjects in the high-TC group (1st quartile) and 31 in the low-TC group (4th quartile) were included in this study, and underwent a battery of neuropsychological tests and magnetic resonance imaging (MRI) scans, including T2- and T1-weighted imaging, and resting-state functional MRI. …No significant group difference was found in any of the neuropsychological tests used. Stronger connectivity in the default mode network was observed in the high-TC group compared to that in the low-TC group (p  <  0.001, uncorrected). While in the salience network (SN), the high-TC group showed lower connectivity in the anterior cingulate cortex and frontal regions, compared to the low-TC group (p  <  0.05, FWE corrected). Our findings suggest that in non-demented elderly persons, high serum cholesterol is associated with disruption of functional connectivity in the SN. The results not only deepen our understanding of how cholesterol affects the brain, but are also significant for selecting sensitive indicators for monitoring the impairments of cholesterol on the neural system. Show more

Keywords: Cognition, default mode network, functional connectivity, salience network, serum cholesterol

DOI: 10.3233/JAD-150810

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 455-463, 2016

Authors: Baiardi, Simone | Capellari, Sabina | Ladogana, Anna | Strumia, Silvia | Santangelo, Mario | Pocchiari, Maurizio | Parchi, Piero

Article Type: Research Article

Abstract: The Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex. Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients (4.9%) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall clinical …disease, a high prevalence of periodic sharp-wave complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG findings, and cerebrospinal fluid concentration below threshold for the diagnosis of “probable” CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups. While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene, our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings between cases according to the dominant PrPSc type (type 1 versus type 2). Show more

Keywords: Dementia, molecular typing, neurodegenerative diseases, occipital cortex, prion diseases, prion protein

DOI: 10.3233/JAD-150668

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 465-476, 2016

Authors: Bartolotti, Nancy | Segura, Laura | Lazarov, Orly

Article Type: Research Article

Abstract: The mechanism underlying impaired learning and memory in Alzheimer’s disease is not fully elucidated. The phosphorylation of cyclic-AMP response element binding protein (pCREB) in the hippocampus is thought to be a critical initiating step in the formation of long-term memories. Here, we tested CRE-driven gene expression following learning in mice harboring the familial Alzheimer’s disease-linked APPswe/PS1ΔE9 mutations using CRE-β galactosidase reporter. We show that young adult APPswe/PS1ΔE9 mice exhibit impaired recognition memory and reduced levels of pCREB, and its cofactors CREB binding protein (CBP) and p-300 following a learning task, compared to their wild type littermate counterparts. Impairments in learning-induced …activation of CREB in these mice are manifested by reduced CRE-driven gene transcription. Importantly, expression of the CRE-driven immediate early gene, Egr-1 (Zif268) is decreased in the CA1 region of the hippocampus. These studies implicate defective CREB-dependent plasticity in the mechanism underlying learning and memory deficits in Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, CBP, CRE, CREB, hippocampal plasticity, learning and memory

DOI: 10.3233/JAD-150650

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 477-489, 2016

Authors: Sugiyama, Kemmyo | Tomata, Yasutake | Kaiho, Yu | Honkura, Kenji | Sugawara, Yumi | Tsuji, Ichiro

Article Type: Research Article

Abstract: Epidemiological studies of the association between coffee consumption and dementia have yielded inconsistent results. Therefore, we investigated the association between coffee consumption and incident risk of dementia in an elderly Japanese population. 23,091 subjects aged ≥65 y living in Ohsaki City, northeastern Japan, responded to the baseline survey in 2006. Of these, we analyzed 13,137 subjects who gave informed consent and were not disabled at baseline. The outcome was the incidence of disabling dementia defined by usage of the Long-term Care Insurance database. We used the Cox proportional hazards regression model for multivariate analysis. During 5.7 y of follow-up period, …we identified 1,107 cases of incident dementia. Overall, coffee consumption was significantly associated with a lower risk of incident dementia. The multivariate-adjusted HRs for the incidence of dementia according to coffee consumption categories (never, occasionally, 1-2 cups/d, and ≥3 cups/d) were 1.00, 0.73 (95% CI, 0.62–0.86), 0.72 (95% CI, 0.61–0.84), and 0.82 (95% CI, 0.65–1.02; p for trend = 0.009), respectively. In addition, this significant inverse association was more remarkable among women, non-smokers, and non-drinkers. Coffee consumption is significantly associated with a lower risk of incident dementia. Show more

Keywords: Coffee, cohort, dementia, elderly, Japan

DOI: 10.3233/JAD-150693

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 491-500, 2016

Authors: Jin, Huafeng | Chen, Tingting | Li, Guoxi | Wang, Conghui | Zhang, Baofeng | Cao, Xinyuan | Sha, Sha | Wan, Qi | Chen, Ling

Article Type: Research Article

Abstract: Background: Simvastatin (SV) has been reported to improve dementia and slow progression of Alzheimer’s disease (AD), however there are conflicting reports. Objective & Methods: Intracerebroventricular injection of aggregated Aβ1-42 in mice (Aβ1-42 -mice) caused spatial cognitive deficits, long-term potentiation (LTP) impairment, and death of hippocampal pyramidal cells. The present study focused on exploring the dose-dependent effects of SV (10–80 mg/kg) on Aβ1-42 -impaired spatial memory and the underlying mechanisms. Results: The treatment of Aβ1-42 -mice with SV for continuous 15 days could attenuate the spatial cognitive deficits and recover the LTP induction in a “U” type …dose-dependent manner. The death of pyramidal cells in Aβ1-42 -mice was significantly reduced by the SV-treatment at 20 mg/kg, but not at a dose of 10 or 40 mg/kg, even was aggravated at a dose of 80 mg/kg. Hippocampal NMDA receptor (NMDAr) NR2B phosphorylation (phospho-NR2B) was elevated in Aβ1-42 -mice, which was further dose-dependently increased by SV-treatment. Replenishment of isoprenoid farnesyl pyrophosphate (FPP) by applying farnesol (FOH) could abolish the SV-increased phospho-NR2B in Aβ1-42 -mice, but had no effect on the Aβ1-42 -enhanced phospho-NR2B. NMDAr antagonist blocked the neurotoxicity of Aβ1-42 and SV (80 mg/kg) in Aβ1-42 -mice, whereas FOH only inhibited SV (80 mg/kg)-neurotoxicity. The SV-treatment in Aβ1-42 -mice corrected the decrease in hippocampal Akt phosphorylation. The PI3K inhibitor abolished the SV (20 mg/kg)-neuroprotection in Aβ1-42 -mice. Conclusion: SV-treatment in Aβ1-42 -mice exerts dose-dependent neuroprotection and neurotoxicity by reducing FPP to enhance the phosphorylation of NR2B and Akt. Show more

Keywords: Amyloid–β 1–42, hippocampus, long-term potentiation, memory, NMDA receptor, simvastatin

DOI: 10.3233/JAD-150782

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 501-516, 2016

Authors: Hatami, Asa | Monjazeb, Sanaz | Glabe, Charles

Article Type: Research Article

Abstract: Recently we reported that several monoclonal antibodies that recognize linear segments of amyloid-β (Aβ) also recognize amyloid fibrils, but not monomers of unrelated sequences, indicating that recognition of a linear sequence segment is not a reliable indicator of sequence specificity. We asked whether any of the commonly used commercially available Aβ antibodies also recognize fibrils of unrelated sequence. Here we report that 4G8, which recognizes residues 18–23 of the Aβ sequence and is widely believed to be sequence-specific, also recognizes fibrils formed from α-synuclein and islet amyloid polypeptide (IAPP). The recognition of amyloid fibrils is aggregation-dependent because 4G8 does not …recognize α-synuclein or IAPP monomer. 4G8 also stains fibrillar α-synuclein aggregates in human multiple system atrophy brain where it colocalizes with anti-α-synuclein monoclonal antibody LB509 immunoreactivity. We also found that LB509 recognizes Aβ fibrils, but not monomer, indicating that generic epitope-reactive antibodies are also produced in response to α-synuclein immunization. Taken together, our results indicate that generic fibril conformational epitope specificity may be a pervasive property among monoclonal antibodies raised against amyloid-forming antigens and that the specificity of their immunoreactivity should be rigorously established and otherwise interpreted with caution. Show more

Keywords: Amyloid, amyloid-beta, conformation, monoclonal antibody, IAPP, synuclein

DOI: 10.3233/JAD-150696

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 517-525, 2016

Authors: Yamashita, Shinji | Kiko, Takehiro | Fujiwara, Hironori | Hashimoto, Michio | Nakagawa, Kiyotaka | Kinoshita, Mikio | Furukawa, Katsutoshi | Arai, Hiroyuki | Miyazawa, Teruo

Article Type: Research Article

Abstract: Aside from accumulation of amyloid-β (Aβ) peptide in the brain, Alzheimer’s disease (AD) has been reported as being associated with peroxidation of major phospholipids (e.g., phosphatidylcholine (PtdCho)) and degradation of antioxidative phospholipids (e.g., ethanolamine plasmalogen (PlsEtn)). In addition to its presence in the brain, Aβ is also found in blood; however, there is still little information about the levels of PtdCho hydroperoxide (PCOOH) and PlsEtn in the blood of patients with AD. In this study, by assuming a possible interaction among Aβ, PCOOH, and PlsEtn in blood circulation, we evaluated the levels of these molecules and correlations in blood samples …that had been obtained from our former AD study for PCOOH measurement (Kiko et al., J Alzheimers Dis 28 , 593-600, 2012). We found that when compared to controls, plasma from patients with AD showed lower concentrations of PlsEtn species, especially PlsEtn bearing the docosahexaenoic acid (DHA) moiety. In addition, lower PlsEtn and higher PCOOH levels were observed in red blood cells (RBCs) of patients with AD. In both AD and control blood samples, RBC PCOOH levels tended to correlate with plasma levels of Aβ40 , and each PlsEtn species showed different correlations with plasma Aβ. These results, together with in vitro data suggesting Aβ aggregation due to a decrease in levels of PlsEtn having DHA, led us to deduce that Aβ is involved in alterations in levels of PCOOH and PlsEtn species observed in the blood of patients with AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, phospholipid hydroperoxide, plasmalogen

DOI: 10.3233/JAD-150640

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 527-537, 2016

Authors: Morenas-Rodríguez, Estrella | Cervera-Carles, Laura | Vilaplana, Eduard | Alcolea, Daniel | Carmona-Iragui, María | Dols-Icardo, Oriol | Ribosa-Nogué, Roser | Muñoz-Llahuna, Laia | Sala, Isabel | Belén Sánchez-Saudinós, M. | Blesa, Rafael | Clarimón, Jordi | Fortea, Juan | Lleó, Alberto

Article Type: Research Article

Abstract: Background: Progranulin is implicated in frontotemporal dementia (FTD), but its role in other neurodegenerative disorders is unknown. Objective: To investigate the levels of progranulin (PGRN) in cerebrospinal fluid (CSF) in different neurodegenerative dementias and their correlation with levels in plasma in cognitively normal subjects. Methods: We measured PGRN in CSF in 229 patients with amnestic mild cognitive impairment, Alzheimer’s disease dementia, sporadic FTD, dementia with Lewy bodies, corticobasal syndrome, or progressive supranuclear palsy. We also measured PGRN in CSF and plasma in 74 cognitively normal individuals. We examined the correlation between PGRN levels in CSF and …diagnosis, cortical thickness, genetic factors and other CSF biomarkers. We also investigated the correlation between plasma and CSF levels of PGRN in cognitively normal individuals. Results: CSF levels did not differ across diagnoses or correlate with cortical thickness. Polymorphism rs5848 in GRN influenced CSF PGRN levels, but APOE ɛ 4 allele did not. Amyloid-β 42 , t-tau, p-tau, and YKL-40 levels correlated weakly with PGRN in CSF. We found a weak correlation (r  = 0.362) between plasma and CSF PGRN levels in cognitively normal individuals. Conclusions: Our findings do not support a diagnostic value of CSF PGRN in neurodegenerative diseases. Our data confirm that levels of PGRN in plasma do not reflect accurately levels in CSF in cognitively normal controls. These data should be considered in clinical trials aiming to increase PGRN. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarker, cerebrospinal fluid, dementia, plasma, progranulin, tau

DOI: 10.3233/JAD-150746

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 539-546, 2016

Authors: Oulhaj, Abderrahim | Jernerén, Fredrik | Refsum, Helga | Smith, A. David | de Jager, Celeste A.

Article Type: Research Article

Abstract: A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged ≥70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured. Final scores …for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD. Show more

Keywords: Alzheimer’s disease, B vitamins, clinical dementia rating scale, cognition, omega–3 fatty acids

DOI: 10.3233/JAD-150777

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 547-557, 2016

Authors: Ibarria, Marta | Alegret, Montserrat | Valero, Sergi | Morera, Amèrica | Guitart, Marina | Cañabate, Pilar | Moreno, Mariola | Lara, Susana | Diego, Susana | Hernández, Joan | Tantinyá, Natàlia | Vera, Maribel | Hernández, Isabel | Becker, James T. | Ruíz, Agustín | Boada, Mercè | Tárraga, Lluís

Article Type: Research Article

Abstract: Background: The existing pharmacological treatments for Alzheimer’s disease (AD) can only slow the progression of symptoms or delay admission to long-term care facilities. The beneficial effects of non-drug treatments are poorly studied. Objective: To describe the effects of an Integrated Psychostimulation Program (IPP) in patients with mild-moderate AD treated with acetylcholinesterase inhibitors; and to identify factors related to greater benefit of the IPP. Methods: 206 patients (mean age = 75.9 years; MMSE = 19.6) were evaluated before starting the IPP and 3, 6, 9, and 12 months later. Measures included: Mini-Mental State Examination (MMSE), Cognitive Subscale of Alzheimer’s Disease Assessment …Scale (ADAS-Cog), Rapid Disability Rating Scale (RDRS-2), and Neuropsychiatric Inventory Questionnaire (NPI-Q). Results: Patients remained cognitively stable (MMSE/ADAS-Cog) for more than 6 months and significantly worsened at 9-month and 12-month follow-ups, without clinically significant functional changes (RDRS-2) or psychiatric symptoms(NPI-Q). The mean annual change on MMSE and ADAS-Cog were 2.06 and 3.56 points, respectively, lower than the annual decline demonstrated previously in similar patients (2.4 and 4.5, respectively). 42.7% of patients maintained or improved global cognitive scores between baseline and 12-month follow-up. The patients who maintained cognitive functions were older than those who did not (77.5 versus 74.7 years). Conclusions: The IPP may be an effective treatment to maintain cognition, functionality, and psychiatric symptoms in AD patients pharmacologically treated, and older age seems to increase beneficial effects of IPP. Show more

Keywords: Alzheimer’s disease, cognition, cognitive stimulation, dementia, functionality, Integral Psychostimulation Program, non-pharmacological therapy

DOI: 10.3233/JAD-150455

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 559-566, 2016