Journal of Alzheimer's Disease - Volume 38, issue 1

Authors: Shi, Jiong | Han, Pengcheng | Kuniyoshi, Sandra M.

Article Type: Review Article

Abstract: Apolipoprotein E4 (ApoE4) has been considered to have detrimental effects on the age of onset and progression in Alzheimer's disease. Evidence continues to accumulate regarding the effects of ApoE isoforms in a number of other neurological diseases. Recent studies demonstrate an increase in cognitive deficits in ApoE4 patients with traumatic brain injury, cerebrovascular disease, and delirium. Evidence of the role ApoE isoforms played in cognition in multiple sclerosis has illuminated the neurodegenerative aspects of this disease. It further provides evidence of the effect neuroinflammation has in increasing susceptibility to cognitive decline in younger patients. Determining where these diverse diseases intersect …and diverge in their relationship to ApoE provides insight into the two-hit mechanism in cognitive decline. Show more

Keywords: Alzheimer's disease, aneurysm, apolipoprotein E, delirium, multiple sclerosis, stroke, traumatic brain injury

DOI: 10.3233/JAD-130623

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 1-9, 2014

Authors: Maruszak, Aleksandra | Pilarski, Adam | Murphy, Tytus | Branch, Nicholas | Thuret, Sandrine

Article Type: Review Article

Abstract: Alterations in hippocampal neurogenesis have been recognized as an integral part of Alzheimer's disease. Adult hippocampal neurogenesis is regulated by intrinsic and extrinsic factors; one of them is diet. This review provides an assessment of the current state of the field in hippocampal neurogenesis studies in Alzheimer's disease and focuses on the role of diet. The review highlights some of the key dietary compounds and interventions such as calorie restriction, fat, polyphenols, zinc, folate, alcohol and thiamine, and emphasizes the pathways that they modify.

Keywords: Alzheimer's disease, calorie restriction, diet, fatty acids, folate, neurogenesis, nutrients, polyphenols, thiamine, zinc

DOI: 10.3233/JAD-131004

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 11-38, 2014

Authors: Borghys, Herman | Jacobs, Tom | Van Broeck, Bianca | Dillen, Lieve | Dhuyvetter, Deborah | Gijsen, Harrie | Mercken, Marc

Article Type: Research Article

Abstract: Beta-secretase is the first cleavage enzyme of amyloid-β protein precursor (AβPP) in the amyloidogenic pathway, leading to the formation of the plaque forming Amyloid-β (Aβ)1-42 peptide. BACE (beta-site AβPP cleaving enzyme) 1 inhibition is therefore considered to be a promising disease modifying therapy for Alzheimer's disease. An early assessment of the in vivo activity of BACE inhibitors was done in dogs since AβPP processing is the same as in humans and this species easily enables longitudinal cerebrospinal fluid (CSF) sampling. Aβ changes in CSF compared to baseline are used to evaluate target engagement of the compounds. Levels of Aβ1-37 …, Aβ1-38 , Aβ1-40 , and Aβ1-42 in CSF are measured with immunoassay (Mesoscale electrochemiluminescence technology) and with an ultra high-performance liquid chromatography mass spectrometry (UPLC-MS/MS). Two experimental BACE inhibitors were evaluated. With the immunoassay, a dose dependent decrease is observed for all four Aβ peptides. Measurements with the UPLC-MS/MS are in line with the immunoassay for Aβ1-37 , Aβ1-38 , and Aβ1-40 , however, for Aβ1-42 , differences are sometimes observed when comparing to changes seen in the other peptides with UPLC-MS/MS and with immunoassay results. Generally lower concentrations are measured with immunoassay. The reason for these differences is still unknown. Aβ1-42 is more prone to form aggregates compared to the other peptides. One hypothesis could be that while the immunoassay only measures free Aβ, bound and aggregated Aβ peptides are at least partially dissolved with the UPLC-MS/MS method, since acetonitrile is added to the CSF samples. This increases variability in the concentration of Aβ peptide measured with UPLC-MS/MS, especially for Aβ1-42 , potentially masking the compound effect on Aβ1-42 levels. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, β-secretase, cerebrospinal fluid, dog

DOI: 10.3233/JAD-130599

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 39-48, 2014

Authors: Lee, Linda | Kosuri, Pallav | Arancio, Ottavio

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptides are constitutively produced in the brain throughout life via mechanisms that can be regulated by synaptic activity. Although Aβ has been extensively studied as the pathological plaque-forming protein species in Alzheimer's disease (AD), little is known about the normal physiological function(s) and signaling pathway(s). We previously discovered that physiologically-relevant, low picomolar amounts of Aβ can enhance synaptic plasticity and hippocampal-dependent cognition in mice. In this study, we demonstrated that astrocytes are cellular candidates for participating in this type of Aβ signaling. Using calcium imaging of primary astrocyte cultures, we observed that picomolar amounts of Aβ peptides can …enhance spontaneous intracellular calcium transient signaling. After application of 200 pM Aβ42 peptides, the frequency and amplitude averages of spontaneous cytosolic calcium transients were significantly increased. These effects were dependent on α7 nicotinic acetylcholine receptors (α7-nAChRs), as the enhancement effects were blocked by a pharmacological α7-nAChR inhibitor and in astrocytes from an α7 deficient mouse strain. We additionally examined evoked intercellular calcium wave signaling but did not detect significant picomolar Aβ-induced alterations in propagation parameters. Overall, these results indicate that at a physiologically-relevant low picomolar concentration, Aβ peptides can enhance spontaneous astrocyte calcium transient signaling via α7-nAChRs. Since astrocyte-mediated gliotransmission has been previously found to have neuromodulatory roles, Aβ peptides may have a normal physiological function in regulating neuron-glia signaling. Dysfunction of this signaling process may underlie glia-based aspects of AD pathogenesis. Show more

Keywords: α7 nicotinic acetylcholine receptor, amyloid-β, astrocyte, calcium imaging, glia, gliotransmission

DOI: 10.3233/JAD-130740

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 49-62, 2014

Authors: Kaerst, Lisa | Kuhlmann, Andre | Wedekind, Dirk | Stoeck, Katharina | Lange, Peter | Zerr, Inga

Article Type: Research Article

Abstract: Background: Dementia with Lewy bodies (DLB) is difficult to differentiate from other neuro-degenerative diseases. Patients are often mistaken to suffer from Parkinson’s disease (PD) or Alzheimer’s disease (AD) because of the overlapping clinical appearances concerning cognition and movement. Objective: We investigated the possibility for a valid differential diagnosis using cerebrospinal fluid (CSF) biomarkers. Methods: In the context of a large retrospective study, we analyzed data of patients suffering from degenerative, ischemic, or inflammatory CNS (central nervous system) diseases and identified those with DLB (n = 34), PD (n = 37), and AD (n = 47) for …further analyses. Results: We detected abnormalities in the CSF profiles of those patients with DLB while using a combination of decreased amyloid-β (Aβ)42 and increased tau levels. By stratification of data by disease severity, we observed a high sensitivity of this combination especially in the subgroup of patients with advanced stages, while the sensitivity in early forms was lower. In addition, with clinical deterioration, the abnormalities in the CSF profile became more pronounced. Conclusion: We conclude that DLB can be distinguished from PD, in spite of both being synucleinopathies, by CSF profiles using neurodegenerative marker analysis. The pathophysiology of increased tau and decreased Aβ levels in those conditions has to be elucidated further, since both proteins are known to be involved in the pathogenesis of AD, but no clear explanation has been postulated for DLB yet. Show more

Keywords: Alzheimer's disease, amyloid-β, cerebrospinal fluid, clinical diagnosis, dementia, dementia with Lewy bodies, Parkinson's disease, tau

DOI: 10.3233/JAD-130995

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 63-73, 2014

Authors: Carvalho, Cristina | Katz, Paige S. | Dutta, Somhrita | Katakam, Prasad V.G. | Moreira, Paula I. | Busija, David W.

Article Type: Research Article

Abstract: We hypothesized that hyperglycemia-induced mitochondrial dysfunction and oxidative stress are closely associated with amyloid-β peptide (Aβ) toxicity in endothelial cells. Brain microvascular endothelial cells from rat (RBMEC) and mice (MBMEC) were isolated from adult Sprague-Dawley rats and homozygous db/db (Leprdb /Leprdb ) and heterozygous (Dock7m /Leprdb ) mice, and cultured under normo- and hyperglycemic conditions for 7 d followed by 24 h exposure to Aβ1-40 . Some experiments were also performed with two mitochondrial superoxide (O2 •− ) scavengers, MitoTempo and Peg-SOD. Cell viability was measured by the Alamar blue assay and mitochondrial membrane potential (ΔΨm) by confocal microscopy. Mitochondrial …O2 •− and hydrogen peroxide (H2 O2 ) production was assessed by fluorescence microscopy and H2 O2 production was confirmed by microplate reader. Hyperglycemia or Aβ1-40 alone did not affect cell viability in RBMEC. However, the simultaneous presence of high glucose and Aβ1-40 reduced cell viability and ΔΨm, and enhanced mitochondrial O2 •− and H2 O2 production. MitoTempo and PEG-SOD prevented Aβ1-40 toxicity. Interestingly, MBMEC presented a similar pattern of alterations with db/db cultures presenting higher susceptibility to Aβ1-40 . Overall, our results show that high glucose levels increase the susceptibility of brain microvascular endothelial cells to Aβ toxicity supporting the idea that hyperglycemia is a major risk factor for vascular injury associated with AD. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, brain endothelial cells, mitochondria, type 2 diabetes

DOI: 10.3233/JAD-130464

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 75-83, 2014

Authors: Bonakis, Anastasios | Economou, Nicholas-Tiberio | Paparrigopoulos, Thomas | Bonanni, Enrica | Maestri, Michelangelo | Carnicelli, Luca | Di Coscio, Elisa | Ktonas, Periklis | Vagiakis, Emmanouil | Theodoropoulos, Panagiotis | Papageorgiou, Sokratis G.

Article Type: Research Article

Abstract: Background: Conversely to other neurodegenerative diseases (i.e., Alzheimer’s disease, AD), sleep in frontotemporal dementia (FTD) has not been studied adequately. Although some evidence exists that sleep-wake disturbances occur in FTD, very little is known regarding sleep macrostructure and/or primary sleep disorders. Objective: To investigate these issues in this population and compare them to similar issues in AD and in healthy elderly (HE). Methods: Twelve drug-naïve behavioral-variant FTD (bvFTD) patients (7 men/5 women) of mean age 62.5 ± 8.6 years were compared to seventeen drug-naïve AD patients (8 men/9 women) of mean age 69.0 ± 9.9 years …and twenty drug-naïve HE (12 men/8 women) of mean age 70.2 ± 12.5 years. All participants were fully assessed clinically, through a sleep questionnaire, an interview, and video-polysomnography recordings. Results: The two patient groups were comparably cognitively impaired. However, compared to FTD patients, the AD patients had a statistically significant longer disease duration. Overall, the sleep profile was better preserved in HE. Sleep complaints did not differ considerably between the two patient groups. Sleep parameters and sleep macrostructure were better preserved in AD compared to FTD patients, regardless of primary sleep disorders, which occurred equally in the two groups. Conclusions: With respect to AD, FTD patients had several sleep parameters similarly or even more affected by neurodegeneration, but in a much shorter time span. The findings probably indicate a centrally originating sleep deregulation. Since in FTD patients sleep disturbances may be obvious from an early stage of their disease, and possibly earlier than in AD patients, physicians and caregivers should be alert for the early detection and treatment of these symptoms. Show more

Keywords: Alzheimer's disease, dementia, frontotemporal dementia, sleep

DOI: 10.3233/JAD-122014

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 85-91, 2014

Authors: Sun, Shu-Wei | Liang, Hsiao-Fang | Mei, Jennifer | Xu, Dan | Shi, Wei-Xing

Article Type: Research Article

Abstract: Background: Diffusion tensor imaging (DTI) suggests the presence of white matter abnormality at the prodromal stage in human Alzheimer’s disease (AD). Objective: To use a mouse model of AD to determine whether the white matter abnormality detected by in vivo DTI is associated with functional deficits and axon damage. Methods: Amyloid-β1-42 (Aβ1-42 ) was injected into the left lateral ventricle in mice. Two months after the injection, in vivo DTI and visual evoked potential (VEP) recordings were performed, followed by immunohistochemistry of phosphorylated neurofilament and myelin basic protein. Results: DTI of Aβ1-42 -treated …mice showed a significant increase of radial diffusivity in white matter including the optic nerves and tracts. The abnormality was associated with decreased amplitude and increased latency of VEP. Immunohistochemistry confirmed a significant loss of axons and myelin integrity. Conclusion: White matter damage induced by Aβ1-42 in mice can be detected non-invasively by DTI. Show more

Keywords: Amyloid-β1-42, diffusion tensor imaging, mice, optic nerve, white matter diseases

DOI: 10.3233/JAD-130236

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 93-101, 2014

Authors: Cummings, Jeffrey | Zhong, Kate | Bernick, Charles

Article Type: Research Article

Abstract: The Cleveland Clinic Lou Ruvo Center for Brain Health (LRCBH) is a unique clinical and translational research enterprise that stems from the passion of Larry Ruvo to honor his father, Lou, a victim of Alzheimer's disease (AD). To attract national attention to AD, Mr. Ruvo convinced architect Frank Gehry to construct the remarkable building complex of the LRCBH in Las Vegas, Nevada. Cleveland Clinic assumed responsibility for running the clinical and research aspects of the LRCBH. The care provided in this novel architectural setting is innovative and emphasizes patients first care with integration of caregiver programs and clinical research opportunities. …Standardization of care, outcomes measures, and process metrics provide a platform for assessing, studying, and exporting best practices in cognitive care. Clinical trials empower patients to help solve the diseases that afflict them. The combination of a passionate founder, dramatic architecture, clinical excellence, integrated care partner programs, and commitment to development of next generation treatments makes the LRCBH a unique model of integrated care and research. Show more

Keywords: Lou Ruvo center for brain health, cleveland clinic, clinical trials, Frank Gehry, Alzheimer's disease

DOI: 10.3233/JAD-130791

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 103-109, 2014

Authors: Shinto, Lynne | Quinn, Joseph | Montine, Thomas | Dodge, Hiroko H. | Woodward, William | Baldauf-Wagner, Sara | Waichunas, Dana | Bumgarner, Lauren | Bourdette, Dennis | Silbert, Lisa | Kaye, Jeffrey

Article Type: Research Article

Abstract: Oxidative stress, inflammation, and increased cholesterol levels are all mechanisms that have been associated with Alzheimer's disease (AD) pathology. Several epidemiologic studies have reported a decreased risk of AD with fish consumption. This pilot study was designed to evaluate the effects of supplementation with omega-3 fatty acids alone (ω-3) or omega-3 plus alpha lipoic acid (ω-3 + LA) compared to placebo on oxidative stress biomarkers in AD. The primary outcome measure was peripheral F2-isoprostane levels (oxidative stress measure). Secondary outcome measures included performance on: Mini-Mental State Examination (MMSE), Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL), and Alzheimer Disease …Assessment Scale-cognitive subscale (ADAS-cog). Thirty-nine AD subjects were randomized to one of three groups: 1) placebo, 2) ω-3, or 3) ω-3 + LA for a treatment duration of 12 months. Eighty seven percent (34/39) of the subjects completed the 12-month intervention. There was no difference between groups at 12 months in peripheral F2-isoprostane levels (p = 0.83). The ω-3 + LA and ω-3 were not significantly different than the placebo group in ADAS-cog (p = 0.98, p = 0.86) and in ADL (p = 0.15, p = 0.82). Compared to placebo, the ω-3 + LA showed less decline in MMSE (p < 0.01) and IADL (p = 0.01) and the ω-3 group showed less decline in IADL (p < 0.01). The combination of ω-3 + LA slowed cognitive and functional decline in AD over 12 months. Because the results were generated from a small sample size, further evaluation of the combination of omega-3 fatty acids plus alpha-lipoic acid as a potential treatment in AD is warranted. Show more

Keywords: Alpha-lipoic acid, Alzheimer's disease, clinical trial, omega-3 fatty acids

DOI: 10.3233/JAD-130722

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 111-120, 2014

Authors: Kirste, Thomas | Hoffmeyer, André | Koldrack, Philipp | Bauer, Alexandra | Schubert, Susanne | Schröder, Stefan | Teipel, Stefan

Article Type: Research Article

Abstract: Background: Early detection of behavioral changes in Alzheimer’s disease (AD) would help the design and implementation of specific interventions. Objective: The target of our investigation was to establish a correlation between diagnosis and unconstrained motion behavior in subjects without major clinical behavior impairments. Method: We studied everyday motion behavior in 23 dyads with one partner suffering from AD dementia and one cognitively healthy partner in the subjects’ home, employing ankle-mounted three-axes accelerometric sensors. We determined frequency features obtained from the signal envelopes computed by an envelope detector for the carrier band 0.5 Hz to 5 Hz. …Based on these features, we employed quadratic discriminant analysis for building models discriminating between AD patients and healthy controls. Results: After leave-one-out cross-validation, the classification accuracy of motion features reached 91% and was superior to the classification accuracy based on the Cohen-Mansfield Agitation Inventory (CMAI). Motion features were significantly correlated with MMSE and CMAI scores. Conclusion: Our findings suggest that changes of everyday behavior are detectable in accelerometric behavior protocols even in the absence of major clinical behavioral impairments in AD. Show more

Keywords: Actigraphy, Alzheimer's disease, chronobiology phenomena, circadian rhythm disorders, Cohen-Mansfield Agitation Inventory, discriminant analysis, Fourier analysis, linear models, principal component analysis, psychomotor agitation

DOI: 10.3233/JAD-130272

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 121-132, 2014

Authors: Yu, Yang | Liu, Jin | Li, Shu-Qin | Peng, Lei | Ye, Richard D.

Article Type: Research Article

Abstract: Microglia and astrocytes in the brain play an important role in the development and progression of Alzheimer's disease (AD). Serum amyloid A (SAA) is a major acute-phase protein produced locally in the brain and colocalizes with senile plaques in AD patients. We investigated whether SAA plays a role in the development of AD. The viability of cultured primary microglia and astrocytes was measured by MTT; cell cycle and apoptosis analysis was also conducted. Cultured microglia and astrocytes were stimulated with 1 μM SAA for different periods of time (2, 4, 6, 12 h) or treated with 1 μM SAA with …or without 15 min pretreatment of MAPK or PI3K inhibitors. Total RNA was extracted for qPCR analysis. SAA induced morphological changes of primary microglia but not astrocytes. Interestingly, SAA increased the viability of microglia by inhibiting their apoptosis and reduced the viability of astrocytes by inducing G1 cell cycle arresting. SAA treatment increased the mRNA levels of IL-6, TNF-α, IL12p40, IL23p19, and IL-10, with higher potency in microglia than in astrocytes. However, SAA induced more iNOS mRNA in astrocytes than in microglia. SAA induced these cytokines and iNOS expression by activating the PI3K pathway in both glial cells, but selectively activated the JNK pathway in microglia and the NF-κB pathway in astrocytes. These results suggest that SAA can stimulate a different reactive phenotype in microglia and astrocytes, and SAA regulates cell viability differently in these two glial cells in part through the PI3K pathway. Show more

Keywords: Alzheimer's disease, astrocytes, glial cells, microglia, serum amyloid A

DOI: 10.3233/JAD-130818

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 133-144, 2014

Authors: Koran, Mary Ellen I. | Hohman, Timothy J. | Meda, Shashwath A. | Thornton-Wells, Tricia A. | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The genetic etiology of late-onset Alzheimer's disease (LOAD) has proven complex, involving clinical and genetic heterogeneity and gene-gene interactions. Recent genome wide association studies in LOAD have led to the discovery of novel genetic risk factors; however, the investigation of gene-gene interactions has been limited. Conventional genetic studies often use binary disease status as the primary phenotype, but for complex brain-based diseases, neuroimaging data can serve as quantitative endophenotypes that correlate with disease status and closely reflect pathological changes. In the Alzheimer's Disease Neuroimaging Initiative cohort, we tested for association of genetic interactions with longitudinal MRI measurements of the inferior …lateral ventricles (ILVs), which have repeatedly shown a relationship to LOAD status and progression. We performed linear regression to evaluate the ability of pathway-derived SNP-SNP pairs to predict the slope of change in volume of the ILVs. After Bonferroni correction, we identified four significant interactions in the right ILV (RILV) corresponding to gene-gene pairs SYNJ2-PI4KA, PARD3-MYH2, PDE3A-ABHD12B, and OR2L13-PRKG1 and one significant interaction in the left ILV (LILV) corresponding to SYNJ2-PI4KA. The SNP-SNP interaction corresponding to SYNJ2-PI4KA was identical in the RILV and LILV and was the most significant interaction in each (RILV: p = 9.13 × 10−12 ; LILV: p = 8.17 × 10−13 ). Both genes belong to the inositol phosphate signaling pathway which has been previously associated with neurodegeneration in AD and we discuss the possibility that perturbation of this pathway results in a down-regulation of the Akt cell survival pathway and, thereby, decreased neuronal survival, as reflected by increased volume of the ventricles. Show more

Keywords: Alzheimer's disease, Alzheimer's disease neuroimaging initiative, atrophy, epistasis, inositol, magnetic resonance imaging, neuroimaging

DOI: 10.3233/JAD-130989

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 145-154, 2014

Authors: Cano-Cuenca, Nieves | Solís-García del Pozo, Julián E. | Jordán, Joaquín

Article Type: Research Article

Abstract: Over the last few years, latrepirdine, a démodé antihistamine drug, has been proposed to be useful for treating neurodegenerative disorders such as Alzheimer's and Huntington's diseases, and more recently schizophrenia. The mechanisms and pharmacological targets that are responsible for the beneficial effects on neurodegenerative diseases remain unknown. But it has been proposed that latrepirdine may modulate several targets including voltage-gate Ca+2 channels, mitochondrial permeability pore transition, or several neurotransmitter receptors. Herein, we present a meta-analysis of randomized controlled trials to ascertain the efficacy and safety of latrepirdine on cognitive function. By doing a search in electronic databases, we found …five clinical trials in which the effect of latrepirdine on cognition function has been studied, and this was evaluated using MMSE, ADAS-cog, ADCS-ADL, and NPI scores. Latrepirdine generally presented a good safety profile; it was well tolerated when given alone or in combination with a variety of other drugs. We observed heterogeneous results between trials; latrepirdine failed to exert a significant beneficial effect although it tended to improve cognitive scores. The only significant benefit that we found was for the NPI score in Alzheimer's disease patients. Show more

Keywords: Alzheimer's disease, clinical trials, cognition function, dimebon, Huntington's disease, schizophrenia

DOI: 10.3233/JAD-130872

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 155-164, 2014

Authors: Silva, Patricia Natalia | Furuya, Tatiane Katsue | Braga, Ianna Lacerda | Rasmussen, Lucas Trevizani | Labio, Roger Willian | Bertolucci, Paulo Henrique | Chen, Elizabeth Suchi | Turecki, Gustavo | Mechawar, Naguib | Payão, Spencer Luiz | Mill, Jonathan | Smith, Marília Cardoso

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common form of dementia in elderly. Chaperones may have a crucial role in AD due to their involvement in protein quality control, folding, and degradation. In this study, we investigated the mRNA and promoter DNA methylation levels of two chaperones, HSPA8 and HSPA9, in postmortem brain tissue (entorhinal and auditory cortices and hippocampus) from healthy elderly and AD subjects as well as in peripheral blood of healthy elderly and AD patients. mRNA quantification was performed by qRT-PCR and DNA methylation by mass spectrometry. In the peripheral blood, we did not observe a significant difference …in HSPA8 and HSPA9 expression between elderly controls and AD. A significant downregulation of HSPA8 and HSPA9 was observed in AD across the three brain regions compared to the controls, suggesting their participation in AD pathogenesis. However, no important DNA methylation differences were observed, suggesting that other mechanism may be involved in controlling these genes expression. Show more

Keywords: epigenetics, gene expression, HSPA8, HSPA9, mRNA

DOI: 10.3233/JAD-130428

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 165-170, 2014

Authors: Chien, David T. | Szardenings, A. Katrin | Bahri, Shadfar | Walsh, Joseph C. | Mu, Fanrong | Xia, Chunfang | Shankle, William R. | Lerner, Alan J. | Su, Min-Ying | Elizarov, Arkadij | Kolb, Hartmuth C.

Article Type: Research Article

Abstract: Aggregates of hyperphosphorylated tau (PHF-tau), such as neurofibrillary tangles, are linked to the degree of cognitive impairment in Alzheimer's disease. We have recently reported early clinical results of a novel PHF-tau targeting PET imaging agent, [F18]-T807. Since then, we have investigated a second novel PHF-tau targeting PET imaging agent, [F18]-T808, with different pharmacokinetic characteristics, which may be favorable for imaging Alzheimer's disease and other tauopathies. Here, we describe the first human brain images with [F18]-T808.

Keywords: Alzheimer's disease, amyloid-β, brain imaging, mild cognitive impairment, molecular imaging, neurofibrillary tangles, PHF-tau, tau, tau aggregates, tauopathy

DOI: 10.3233/JAD-130098

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 171-184, 2014

Authors: Ito, Shingo | Ohtsuki, Sumio | Murata, Sho | Katsukura, Yuki | Suzuki, Hiroya | Funaki, Miho | Tachikawa, Masanori | Terasaki, Tetsuya

Article Type: Research Article

Abstract: Cerebral clearance of amyloid-β peptide (Aβ), which is implicated in Alzheimer's disease, involves elimination across the blood-brain barrier (BBB), and we previously showed that an insulin-sensitive process is involved in the case of Aβ1-40 . The purpose of this study was to clarify the molecular mechanism of the insulin-sensitive Aβ1-40 elimination across mouse BBB. An in vivo cerebral microinjection study demonstrated that [125 I]hAβ1-40 elimination from mouse brain was inhibited by human natriuretic peptide (hANP), and [125 I]hANP elimination was inhibited by hAβ1-40 , suggesting that hAβ1-40 and hANP share a common elimination process. Internalization of [125 …I]hAβ1-40 into cultured mouse brain capillary endothelial cells (TM-BBB4) was significantly inhibited by either insulin, hANP, other natriuretic peptides or insulin-degrading enzyme (IDE) inhibitors, but was not inhibited by phosphoramidon or thiorphan. Although we have reported the involvement of natriuretic peptide receptor C (Npr-C) in hANP internalization, cells stably expressing Npr-C internalized [125 I]hANP but not [125 I]hAβ1-40 , suggesting that there is no direct interaction between Npr-C and hAβ1-40 . IDE was detected in plasma membrane of TM-BBB4 cells, and internalization of [125 I]hAβ1-40 by TM-BBB4 cells was reduced by IDE-targeted siRNAs. We conclude that elimination of hAβ1-40 from mouse brain across the BBB involves an insulin- and ANP-sensitive process, mediated by IDE expressed in brain capillary endothelial cells. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, atrial natriuretic peptide, blood-brain barrier, brain capillary endothelial cells, insulin-degrading enzyme

DOI: 10.3233/JAD-122077

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 185-200, 2014

Authors: Tolppanen, Anna-Maija | Ngandu, Tiia | Kåreholt, Ingemar | Laatikainen, Tiina | Rusanen, Minna | Soininen, Hilkka | Kivipelto, Miia

Article Type: Research Article

Abstract: Background: Obesity has been consistently associated with dementia. The role of certain risk factors of dementia may change during life, and the importance of having a life-course perspective has been acknowledged. Objective: The aim of this study was to investigate the association of midlife and late-life body mass index (BMI) with late-life dementia/Alzheimer’s disease (AD) and whether the association was independent of other obesity-related co-morbidities. Methods: The association between midlife BMI (mean age 50.2, SD 6.0) and late-life BMI (mean age 71.2, SD 4.0) and incident dementia later in life (mean age 75.7, SD 5.0) were …investigated among 1,304 participants of the longitudinal population-based Cardiovascular risk factors, Aging and Dementia (CAIDE) study, conducted in Eastern Finland. The duration of follow-up was 26 years. The diagnosis of dementia was based on DSM-IV criteria and the probable and possible AD on the NINCDS-ADRDA criteria. Results: Higher midlife BMI was associated with higher risk of incident dementia (adjusted HR, 95% CI 1.07, 1.00–1.14). However, decrease in BMI from midlife to late-life was associated with higher risk of dementia (1.14, 1.03–1.25 for one-unit decrease) and AD (1.20, 1.09–1.33). High late-life BMI was associated with lower risk of AD (0.89, 0.81–0.98) but the association with dementia was less evident (0.94, 0.86–1.03). Conclusion: Higher midlife BMI is related to higher risk of dementia and AD, independently of obesity-related risk factors and co-morbidities. Steeper decrease of BMI and low late-life BMI are associated with higher risk of dementia and AD. These findings highlight the importance of life-course perspective when assessing the association between BMI and cognition. Show more

Keywords: Alzheimer's disease, body mass index, dementia, obesity

DOI: 10.3233/JAD-130698

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 201-209, 2014

Authors: Heringa, Sophie M. | Reijmer, Yael D. | Leemans, Alexander | Koek, Huiberdina L. | Kappelle, L. Jaap | Biessels, Geert Jan | on behalf of the Utrecht Vascular Cognitive Impairment (VCI) Study Group

Article Type: Research Article

Abstract: Background: Cerebral microbleeds are a manifestation of small vessel disease and are common in patients with Alzheimer’s disease (AD). However, their clinical significance in this condition is uncertain. We hypothesized that microbleeds contribute to disturbances of the cerebral network in AD and as such may affect cognition. Objective: The goal of this study was to examine the relationship between microbleeds and brain networks in patients with amnestic mild cognitive impairment (aMCI) or early AD. Methods: Sixty-seven patients (77.9 ± 7.5 years) with aMCI (n = 29) or early AD (n = 38) underwent cognitive testing and …3Tesla MRI. Microbleeds were rated visually. Diffusion tensor imaging and graph theoretical analysis were used to reconstruct brain networks and to quantify network efficiency for each patient. Network measures were compared between patients without and with ⩾1 microbleeds and between patients without or with ≥3 microbleeds. In secondary analyses, cognitive functioning was compared between groups. Analyses were adjusted for age and gender, and additionally for other markers of small vessel disease and atrophy. Results: Network measures did not differ between patients with ≥1 microbleed (n = 26) and patients without microbleeds (n = 41). However, patients with ≥3 microbleeds (n = 11) showed significant white matter disruptions, longer path length, and less global efficiency than patients without microbleeds, independent of other markers of small vessel disease and atrophy. Cognitive functioning did not differ between patients without microbleeds and patients with ≥1 or ≥3 microbleeds. Conclusion: Multiple microbleeds are related to structural network disruption in patients with early AD, but their direct impact on cognitive functioning appears to be limited. Show more

Keywords: Alzheimer's disease, cerebral amyloid angiopathy, cerebral small vessel disease, cognition, diffusion tensor imaging, magnetic resonance imaging, microbleeds, mild cognitive impairment, network

DOI: 10.3233/JAD-130542

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 211-221, 2014

Article Type: Other

DOI: 10.3233/JAD-130543

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 223-225, 2014