Journal of Alzheimer's Disease - Volume 44, issue 2

Authors: Pal, Amit | Siotto, Mariacristina | Prasad, Rajendra | Squitti, Rosanna

Article Type: Review Article

Abstract: Copper is an essential micronutrient for physiological cell functioning and central nervous system (CNS) development. Indeed, it is a cofactor of many proteins and enzymes in a number of molecular pathways, including energy generation, oxygen transportation, hematopoiesis, cellular growth and metabolism, and signal transduction. This is because it serves as a catalyst of reduction-oxidation (redox) reactions in these processes. When copper is kept under control, bound to special proteins, it yields key properties. However, when it spirals out of control, it is exchanged among small compounds (it is loosely bound to them), and its redox activity makes it dangerous for …cell viability, promoting oxidative stress. Copper homeostasis in the CNS is securely synchronized, and perturbations in brain copper levels are known to underlie the pathoetiology of wide spectrum of common neurodegenerative disorders, including Alzheimer's disease. The main objective of this review is to provide some of the most relevant evidence gleaned from recent studies conducted on animal models and humans, and to discuss the evidence as it pertains to a new concept: Aberrant copper metabolism, which appears to have a genetic basis, is a modifiable risk factor accelerating Alzheimer's disease and initiation/progression of cognitive deficits in a percentage of susceptible persons. Show more

Keywords: Alzheimer's disease, ceruloplasmin, copper, metal, subtype

DOI: 10.3233/JAD-141194

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 343-354, 2015

Authors: Stone, Jonathan | Johnstone, Daniel M. | Mitrofanis, John | O'Rourke, Michael

Article Type: Review Article

Abstract: This review traces evidence that age-related dementia (Alzheimer's disease) results from the destructive impact of the pulse on cerebral vasculature. Evidence is reviewed that the neuropathology of the dementia is caused by the breakdown of small cerebral vessels (silent microbleeds), that the microbleeds result from pulse-induced damage to the cerebral vessels, and that pulse becomes increasingly destructive with age, because of the age-related stiffening of the aorta and great arteries, which causes an increase in the intensity of the pressure pulse. Implications for therapy are discussed, and evidence is reviewed that pulse-induced destruction of the brain, and of another highly …vascular organ, the kidney, are becoming the default forms of death, the way we die if we survive the infections, cardiovascular disease, and malignancies, which still, for a decreasing minority, inflict the tragedy of early death. Show more

Keywords: Alzheimer's disease, causes of death, dementia, pulse, vascular aging

DOI: 10.3233/JAD-141884

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 355-373, 2015

Authors: Zhang, Cheng | Rissman, Robert A. | Feng, June

Article Type: Short Communication

Abstract: Mitochondrial impairment as evidenced by decline in adenosine 5′-triphosphate (ATP) is associated with oxidative stress in Alzheimer's disease neuropathology and suggests that mitochondria may fail to maintain cellular energy, through reduced ATP production in neurons. To gain insights into the ATP characteristics of Alzheimer's disease transgenic (Tg) mice, we investigated ATP contents in the brain and whole blood of Tg mice at three ages (1-, 5-, and 24-months old). Overall, our results demonstrate that tissue ATP contents in Tg mice are significantly reduced, suggesting a decrease of tissue ATP production and mitochondrial dysfunction.

Keywords: Adenosine 5′-triphosphate (ATP) contents, Alzheimer's disease, Alzheimer's disease transgenic mouse model, oxidative stress

DOI: 10.3233/JAD-141890

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 375-378, 2015

Authors: Rueli, Rachel H.L.H. | Parubrub, Arlene C. | Dewing, Andrea S.T. | Hashimoto, Ann C. | Bellinger, Miyoko T. | Weeber, Edwin J. | Uyehara-Lock, Jane H. | White, Lon R. | Berry, Marla J. | Bellinger, Frederick P.

Article Type: Short Communication

Abstract: Subjects with Alzheimer's disease (AD) have elevated brain levels of the selenium transporter selenoprotein P (Sepp1). We investigated if this elevation results from increased release of Sepp1 from the choroid plexus (CP). Sepp1 is significantly increased in CP from AD brains in comparison to non-AD brains. Sepp1 localizes to the trans-Golgi network within CP epithelia, where it is processed for secretion. The cerebrospinal fluid from AD subjects also contains increased levels Sepp1 in comparison to non-AD subjects. These findings suggest that AD pathology induces increased levels of Sepp1 within CP epithelia for release into the cerebrospinal fluid to ultimately increase …brain selenium. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, choroid plexus, selenium, selenoprotein P, selenoproteins, Sepp1

DOI: 10.3233/JAD-141755

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 379-383, 2015

Authors: Wang, Jun | Tan, Lan | Wang, Hui-Fu | Tan, Chen-Chen | Meng, Xiang-Fei | Wang, Chong | Tang, Shao-Wen | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: In the past 20 years, substantial evidence from laboratory and epidemiologic studies have suggested that anti-inflammatory medications could defer or prevent the occurrence of Alzheimer's disease (AD). However, several studies do not corroborate these findings. Objective: To evaluate the association of anti-inflammatory drug use on the incidence of AD. Methods: Pubmed, Embase, and Cochrane Library databases were searched up to March 2014. Studies evaluating the association between use of anti-inflammatory drugs and AD risk were included. Relative risks (RRs) with 95% confidence intervals (CIs) were meta-analyzed using random effects models and were grouped by anti-inflammatory …type and duration of drug use. Results: In observational studies, use of non-steroidal anti-inflammatory drugs (NSAIDs) was significantly associated with a reduced risk of AD (RR, 0.72; 95%CI, 0.62–0.84) compared to no use of NSAIDs, especially in long term users (RR, 0.36; 95%CI, 0.17–0.74); the risks of AD were also lower in both aspirin (RR, 0.77; 95%CI, 0.63–0.95) and non-aspirin NSAID users (RR, 0.65; 95%CI, 0.47–0.88) compared with nonusers; whereas the use of corticosteroids showed no significant association (RR, 0.62; 95%CI, 0.26–1.46). In the single randomized controlled trial (RCT), NSAID use showed no significant effect on AD risk among dementia-free individuals (p > 0.05). Conclusion: Observational studies support the use of NSAIDs for prevention of AD, but RCT do not. Well-designed studies and innovative approaches are required to illuminate the exact relationship between NSAID use and AD risk. The appropriate dosage and duration of use to benefit and the safety are also needed to determine. Show more

Keywords: Alzheimer's disease, anti-inflammatory drug, aspirin, meta-analysis, NSAIDs, prevention, systematic review

DOI: 10.3233/JAD-141506

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 385-396, 2015

Authors: Stothart, George | Kazanina, Nina | Näätänen, Risto | Haworth, Judy | Tales, Andrea

Article Type: Research Article

Abstract: Background: Cortical visual association areas are highly vulnerable to Alzheimer's disease (AD) microscopic pathology. Visual evoked potentials (VEPs) provide the tools to examine the functional integrity of these areas and may provide useful indicators of early disease progression. Objective: To assess the functional integrity of visual association area processing in AD and amnestic mild cognitive impairment (aMCI) using VEPs. Methods: We investigated the visual processing of healthy older adults (n = 26), AD (n = 20), and aMCI (n = 25) patients in a visual oddball paradigm designed to elicit the visual P1, N1, and visual …mismatch negativity (vMMN). Results: AD patients showed a significant reduction of P1 and N1 VEP amplitudes and aMCI patients showed a reduction in N1 amplitude compared to healthy older adults. P1 amplitude in response to deviant stimuli and vMMN amplitude were found to be associated with the degree of cognitive impairment as measured by the Mini-Mental State Examination. Conclusions: Changes in VEPs in AD may be a consequence of the microscopic AD pathology typically found in the extrastriate cortex. Neural measures of visual processing may help to better characterize subgroups of aMCI patients likely to develop AD. Additionally, VEPs and vMMN may provide objective markers of cognitive decline. Show more

Keywords: Alzheimer's disease, electroencephalography, mild cognitive impairment, mismatch negativity, visual evoked potentials

DOI: 10.3233/JAD-140930

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 397-408, 2015

Authors: Matsumura, Akihiro | Suzuki, Syuuichirou | Iwahara, Naotoshi | Hisahara, Shin | Kawamata, Jun | Suzuki, Hiromi | Yamauchi, Ayano | Takata, Kazuyuki | Kitamura, Yoshihisa | Shimohama, Shun

Article Type: Research Article

Abstract: We previously reported that activated microglia are involved in amyloid-β (Aβ) clearance and that stimulation of α7 nicotinic acetylcholine receptors (nAChR) in microglia enhances Aβ clearance. Nevertheless, how microglia and α7 nAChR in microglia are affected in Alzheimer's disease (AD) remains unknown. The present study aimed to collect fundamental data for considering whether microglia are potential targets for AD treatment and the appropriate timing of therapeutic intervention, by evaluating the temporal changes of Aβ, microglia, neurons, presynapses, and α7 nAChR by immunohistochemical studies in mouse models of AD. In an Aβ-injected AD mouse model, we observed early accumulation of CD68-positive …microglia at Aβ deposition sites and gradual reduction of Aβ. Microglia were closely associated with Aβ deposits, and were confirmed to participate in clearing Aβ. In a transgenic mouse model of AD, we observed an increase in Aβ deposition from 6 months of age, followed by a gradual increase in microglial accumulation at Aβ deposit sites. Activated microglia in APdE9 mice showed two-step transition: a CD68-negative activated form at 6–9 months and a CD68-positive form from 12 months of age. In addition, α7 nAChR in microglia increased markedly at 6 months of age when activated microglia appeared for the first time, and decreased gradually coinciding with the increase of Aβ deposition. These findings suggest that early microglial activation is associated with α7 nAChR upregulation in microglia in APdE9 mice. These novel findings are important for the development of new therapeutic strategy for AD. Show more

Keywords: α7 nAChR, Alzheimer's disease, amyloid-β, CD68, hippocampus, injections, microglia, phagocytosis, temporal, transgenic

DOI: 10.3233/JAD-141572

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 409-423, 2015

Authors: Charles, Jocelyn | Naglie, Gary | Lee, Jacques | Moineddin, Rahim | Jaglal, Susan | Tierney, Mary C.

Article Type: Research Article

Abstract: Background: Primary care physicians (PCPs) increasingly must identify which of their cognitively impaired patients who live alone are at greatest risk of harm due to self-neglect. Objectives: To determine whether brief patient self-report measures could accurately do this. Methods: Participants were ≥65 years, lived alone, and recruited from PCPs' practices, community agencies, a hospital emergency department, and acute care medical units. All had cognitive impairment (≤130 on the Dementia Rating Scale) and all had a PCP. Baseline self-report measures included: Geriatric Depression Scale (GDS), a social resources scale, a single item health rating scale, and the …Quality of Life-Alzheimer's Disease Scale. We adjusted for baseline demographic, health, and mental status differences. We prospectively captured incidents of harm involving self-neglect or disorientation, resulting in physical injury, property loss, or damage, and requiring emergency services. These were obtained over a one-year longitudinal period, at 3-month intervals, from PCPs and caregivers. Emergency service records were obtained and reviewed for each incident. Proportional hazards modeling estimated how well the self-report measures predicted time to the first incident harm. Results: 190 women and 34 men were followed. Based on the agreement of three medical raters, 23 participants (10%) experienced harmful outcomes. Being depressed on the GDS and rating one's health as fair or poor were the only two measures that significantly shortened time to first harmful outcome. Conclusion: GDS and self-rated health are simple measures to administer in the primary care setting and may be useful to PCPs in the earlier identification of those at greatest risk of harm in this vulnerable group of patients. Show more

Keywords: Cognition disorders, dementia, depression, self report

DOI: 10.3233/JAD-141671

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 425-430, 2015

Authors: Mohamed, Nur-Ezan | Lee, Jasinda H. | Francis, Paul T. | Esiri, Margaret M. | Chen, Christopher P. | Lai, Mitchell K.P.

Article Type: Research Article

Abstract: Background: Glutamatergic deficits are well-established neurochemical findings in Alzheimer's disease (AD) and are thought to underlie both cognitive and behavioral symptoms of the disease. However, it is unclear whether subcortical ischemic vascular dementia (SIVD) and mixed SIVD/AD (MixD) manifest similar changes in the glutamatergic system. Objective: To measure the immunoreactivities of NMDA receptor GluN1, GluN2A, and GluN2B subunits in SIVD and MixD. Methods: Postmortem neocortical tissues from a cohort of well-characterized, longitudinally followed-up patients with SIVD and MixD, together with age-matched controls, were processed for immunoblotting with GluN subunit-specific antibodies. Results: There was a …significant reduction of GluN1 only in MixD, while significant increases of GluN2A and GluN2B were found only in SIVD. Furthermore, GluN1 loss and GluN2A/2B upregulation was associated respectively with higher Braak stages and lacunar infarct scores. Conclusions: Our data suggest that the differential alterations of GluN subunits in SIVD and MixD may result from separate, interacting disease processes, and point to the potential utility of glutamatergic approaches for pharmacotherapy. Show more

Keywords: Alzheimer's disease, GluN receptors, mixed dementia, neurochemistry, subcortical ischemic vascular dementia

DOI: 10.3233/JAD-141764

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 431-437, 2015

Authors: Berger, Christoph | Erbe, Anna-Katharina | Ehlers, Inga | Marx, Ivo | Hauenstein, Karlheinz | Teipel, Stefan

Article Type: Research Article

Abstract: Background: Research suggests generally impaired cognitive control functions in working memory (WM) processes in amnestic mild cognitive impairment (MCI) and incipient Alzheimer's disease (AD). Little is known how emotional salience of task-irrelevant stimuli may modulate cognitive control of WM performance and neurofunctional activation in MCI and AD individuals. Objective: We investigated the impact of emotional task-irrelevant visual stimuli on cortical activation during verbal WM. Methods: Twelve AD/MCI individuals and 12 age-matched healthy individuals performed a verbal WM (nback-) task with task-irrelevant emotionally neutral and emotionally negative background pictures during fMRI measurement. Results: AD/MCI individuals …showed decreased WM performance compared with controls; both AD/MCI and control groups reacted slower during presentation of negative pictures, regardless of WM difficulty. The AD/MCI group showed increased activation in the left hemispheric prefrontal network, higher amygdala and less cerebellar activation with increasing WM task difficulty compared to healthy controls. Correlation analysis between neurofunctional activation and WM performance revealed a negative correlation between task sensitivity and activation in the dorsal anterior cingulum for the healthy controls but not for the AD/MCI group. Conclusion: Our data suggest compensatory activation in prefrontal cortex and amygdala, but also dysfunctional inhibition of distracting information in the AD/MCI group during higher WM task difficulty. Additionally, attentional processes affecting the correlation between WM performance and neurofunctional activation seem to be different between incipient AD and healthy aging. Show more

Keywords: Alzheimer's disease, amygdala, cognitive control, emotional interference, verbal n-back task, working memory

DOI: 10.3233/JAD-141848

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 439-453, 2015