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