Journal of Alzheimer's Disease - Volume 49, issue 1

Authors: Schreurs, Bernard G. | Sparks, D. Larry

Article Type: Research Article

Abstract: Background: Cholesterol-fed rabbits have been documented to show increased amyloid-β (Aβ) deposits in the brain that can be exacerbated by the quality of drinking water especially if rabbits drink tap water or distilled water containing copper. One mechanism of cholesterol and Aβ clearance may be through the ATP-binding cassette transporter A1 (ABCA1). Objective and Methods: Using an ABCA1 antibody, we determined the number of ABCA1-immunopositive neurons in three areas of rabbit brain as a function of feeding 2% cholesterol and providing tap water, distilled water, or distilled water to which aluminum, copper, or zinc was added. …Results: The number of neurons with ABCA1 immunoreactivity was increased significantly as a result of dietary cholesterol in the rabbit hippocampus and inferior and superior temporal cortex. The number of neurons with ABCA1 immunoreactivity was further increased in all three areas as a result of cholesterol-fed rabbits drinking tap water or distilled water with copper. Finally, cholesterol-fed rabbits that drank distilled water with aluminum also showed an increased number of ABCA1-immunopositive neurons in inferior and superior temporal cortex. Conclusions: These data suggest that ABCA1 levels increase in parallel with previously documented increases in Aβ levels as a result of high dietary cholesterol and copper in the drinking water. Addition of aluminum to distilled water may have a similar effect in the temporal cortex. ABCA1 has been proposed as a means of clearing Aβ from the brain and manipulations that increase Aβ also result in an increase of clearance machinery. Show more

Keywords: Aluminum, ATP-binding cassette transporter A1, cholesterol-fed rabbit, copper, zinc

DOI: 10.3233/JAD-150601

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 201-209, 2016

Authors: Nørgaard, Ane | Jensen-Dahm, Christina | Gasse, Christiane | Hansen, Hanne Vibe | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: Antipsychotics are often used to treat neuropsychiatric symptoms in dementia, but the evidence for effect is limited. Antipsychotics have been associated with increased risk of adverse events and mortality in patients with dementia, leading to safety regulations worldwide. Objective: To investigate time trends in use of antipsychotics and other psychotropic drugs in dementia care. Methods: The study included longitudinal data on all Danish residents ≥65 years. The study population was defined on January 1 of each year from 2000–2012. Data included prescriptions, discharge diagnoses, and somatic and psychiatric comorbidities. Multivariate time trend analyses of psychotropic …drug use in patients with dementia within 4-year age bands were performed. Results: Overall, among patients with dementia the prevalence of antipsychotic drug use decreased from 31.3% in 2000 to 20.4% in 2012. The decreasing use of antipsychotics was accompanied by decreasing use of anxiolytics and hypnotics/sedatives, but an increase in the use of antidepressants from 43.3% in 2000 to 53.8% in 2012. These changes were significant across almost all age groups. Treatment intensity among patients using antipsychotics increased as the annual median number of defined daily doses (DDD) increased from 33.3 to 42.0 DDD. Conclusions: The changing patterns of psychotropic drug use may be caused by warnings against use of antipsychotics. Further research is needed to explore the implications for patient safety. Show more

Keywords: Antidepressant drugs, antipsychotic drugs, dementia, neuropsychiatric symptoms, time trend

DOI: 10.3233/JAD-150481

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 211-220, 2016

Authors: Edwards, Melissa | Hall, James | Williams, Benjamin | Johnson, Leigh | O’Bryant, Sid

Article Type: Research Article

Abstract: Background: Mexican Americans face a significant health disparity when it comes to Alzheimer’s disease (AD) as they present with higher rates of the disease and develop AD at an earlier age compared to other ethnic groups. Recent work identified a proteomic profile of AD among this population; however, no work to date has sought to examine the biological profile of pre-AD among Mexican Americans. Objective: This study aims to identify an amnestic mild cognitive impairment (aMCI) proteomic profile among Mexican Americans. Methods: Data were analyzed from 284 Mexican American participants (aMCI, n  = 73; normal controls, n … = 211) from the Health & Aging Brain among Latino Elders study. Fasting serum samples were analyzed using a multi-plex biomarker assay platform. A biomarker profile was generated using random forest analyses. Results: Among aMCI cases, the biomarker profile was found to be largely inflammatory with the top three markers shown to include TNFα , IL10, and TARC. The overall diagnostic accuracy of the biomarkers in detecting aMCI was 96% (sensitivity = 0.82; specificity = 0.97). Inclusion of clinical variables with the selected biomarkers did not impact the overall detection accuracy (area under the curve = 0.96) but led to a slight improvement in specificity (specificity = 0.99) and decrease in sensitivity (sensitivity = 0.74). Conclusion: The biomarker profile of aMCI was shown to be different from our previously generated AD profile among Mexican Americans, which was largely metabolic in nature. The findings implicate a possible interplay between inflammatory and metabolic processes and additional work is needed to further examine this. Show more

Keywords: Amnestic, biomarker, Mexican American, mild cognitive impairment

DOI: 10.3233/JAD-150553

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 221-228, 2016

Authors: Agostini, Simone | Mancuso, Roberta | Baglio, Francesca | Cabinio, Monia | Hernis, Ambra | Guerini, Franca Rosa | Calabrese, Elena | Nemni, Raffaello | Clerici, Mario

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), the most common form of dementia worldwide, is associated with impairment in the mechanisms of the clearing of amyloid-β within a scenario of neuroinflammation. The etiopathogenesis of the AD is unclear, but a role for viral infection is suspected to play a role in initiating the disease. We recently described a positive correlation between high titers of HSV-1-specific antibodies (Ab) and the volumes of brain regions typically affected in disease. Objective: The exploration of a possible role for Herpesviridae in AD was extended by analyzing HHV-6-specific humoral immunity in individuals with AD or …a diagnosis of amnestic mild cognitive impairment (aMCI), a condition that is often prodromic of the development of AD. Methods: 59 AD, 60 aMCI, and 61 age-matched healthy controls were enrolled in the study. Serum HHV-6 IgG antibody titers and avidity index were tested by ELISA. Two randomly selected subgroups of AD and aMCI in whom HHV-6 serum antibodies were detected underwent brain magnetic resonance imaging (MRI) by 1.5 T scanner. Results: HHV-6 seroprevalence, antibody titers, and avidity were similar in the three groups. No correlation was found between Ab titers or avidity and brain volumes, either overall or in the regions typically affected by disease. Conclusions: The lack of any relation between humoral immune response against HHV-6 and AD and aMCI seems to rule out a role for this virus in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, HHV-6, humoral immunity, magnetic resonance imaging

DOI: 10.3233/JAD-150464

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 229-235, 2016

Authors: Leh, Sandra E. | Kälin, Andrea M. | Schroeder, Clemens | Park, Min Tae M. | Chakravarty, M. Mallar | Freund, Patrick | Gietl, Anton F. | Riese, Florian | Kollias, Spyros | Hock, Christoph | Michels, Lars

Article Type: Research Article

Abstract: Alterations in brain structures, including progressive neurodegeneration, are a hallmark in patients with Alzheimer’s disease (AD). However, pathological mechanisms, such as the accumulation of amyloid and the proliferation of tau, are thought to begin years, even decades, before the initial clinical manifestations of AD. In this study, we compare the brain anatomy of amnestic mild cognitive impairment patients (aMCI, n  = 16) to healthy subjects (CS, n  = 22) using cortical thickness, subcortical volume, and shape analysis, which we believe to be complimentary to volumetric measures. We were able to replicate “classical” cortical thickness alterations in aMCI in the hippocampus, amygdala, putamen, …insula, and inferior temporal regions. Additionally, aMCI showed significant thalamic and striatal shape differences. We observed higher global amyloid deposition in aMCI, a significant correlation between striatal displacement and global amyloid, and an inverse correlation between executive function and right-hemispheric thalamic displacement. In contrast, no volumetric differences were detected in thalamic, striatal, and hippocampal regions. Our results provide new evidence for early subcortical neuroanatomical changes in patients with aMCI, which are linked to cognitive abilities and amyloid deposition. Hence, shape analysis may aid in the identification of structural biomarkers for identifying individuals at highest risk of conversion to AD. Show more

Keywords: Alzheimer’s disease, cortical thickness, hippocampus, mild cognitive impairment, shape analysis, striatum, thalamus, volumetry

DOI: 10.3233/JAD-150080

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 237-249, 2016

Authors: Nafar, Firoozeh | Williams, J. Bradley | Mearow, Karen M.

Article Type: Research Article

Abstract: Although heat shock proteins are thought to function primarily as intracellular chaperones, the release and potential extracellular functions of heat shock proteins have been the focus of an increasing number of studies. Our particular interest is HspB1 (Hsp25/27) and as astrocytes are an in vivo source of HspB1 it is a reasonable possibility they could release HspB1 in response to local stresses. Using primary cultures of rat cortical astrocytes, we investigated the extracellular release of HspB1 with exposure to amyloid-β (Aβ). In order to assess potential mechanisms of release, we cotreated the cells with compounds that can modulate protein …secretion including Brefeldin A, Methyl β-cyclodextrin, and MAP kinase inhibitors. Exposure to Aβ (0.1, 1.0, 2.0 μM) for 24–48 h resulted in a selective release of HspB1 that was insensitive to BFA treatment; none of the other inhibitors had any detectable influence. Protease protection assays indicated that some of the released HspB1 was associated with a membrane bound fraction, and analysis of exosomal preparations indicated the presence of HspB1 in exosomes. Finally, immunoprecipitation experiments demonstrated that the extracellular HspB1 was able to interact with extracellular Aβ. In summary, Aβ can stimulate release of HspB1 from astrocytes, this release is insensitive to Golgi or lipid raft disruption, and HspB1 can be found either free in the medium or associated with exosomes. This release suggests that there is a potential for extracellular HspB1 to be able to bind and sequester extracellular Aβ. Show more

Keywords: Amyloid, astrocytes, extracellular heat shock protein B1 (Hsp27)

DOI: 10.3233/JAD-150317

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 251-263, 2016

Authors: Tsvetkov, Philipp O. | Cheglakov, Ivan B. | Ovsepyan, Armen A. | Mediannikov, Oleg Y. | Morozov, Alexander O. | Telegin, Georgy B. | Kozin, Sergey A.

Article Type: Other

DOI: 10.3233/JAD-159005

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 265-265, 2016

Article Type: Other

DOI: 10.3233/JAD-150781

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 267-270, 2016