Journal of Alzheimer's Disease - Volume 43, issue 3

Authors: Pachana, Nancy A. | Liddle, Jacki | Peel, Nancye M. | Beattie, Elizabeth | Juang, Christine | Knight, Bob G.

Article Type: Review Article

Abstract: The goal of this study was to describe researchers' experiences in submitting ethical proposals focused on older adult populations, including studies with persons with dementia, to ethical review boards. Ethical approval was granted for an online survey. Researchers were recruited via listservs and snowballing techniques. Participants included 157 persons (73% female) from Australia and the United States, with a mean age of 46 (±13). Six main issues were encountered by researchers who participated in this survey. In descending order, these included questions regarding: informed consent and information requirements (61.1%), participants' vulnerability, particularly for those with cognitive impairments (58.6%), participant burden …(44.6%), data access (29.3%), adverse effects of data collection/intervention (26.8%), and study methodology (25.5%). An inductive content analysis of responses revealed a range of encounters with ethical review panels spanning positive, negative, and neutral experiences. Concerns voiced about ethical review boards included committees being overly focused on legal risk, as well as not always hearing the voice of older research participants, both potential and actual. Respondents noted inability to move forward on studies, as well as loss of researchers and participant groups from gerontological and clinical research as a result of negative interactions with ethics committees. Positive interactions with the committees reinforced researchers' need to carefully construct their research approaches with persons with dementia in particular. Suggested guidelines for committees when dealing with ethics applications involving older adults include self-reflecting on potential biases and stereotypes, and seeking further clarification and information from gerontological researchers before arriving at decisions. Show more

Keywords: Aging, ethics committees, frail older adults, healthcare research, research ethics

DOI: 10.3233/JAD-141956

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 701-707, 2015

Authors: Lingler, Jennifer H.

Article Type: Review Article

DOI: 10.3233/JAD-142577

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 709-710, 2015

Authors: Lucke-Wold, Brandon P. | Turner, Ryan C. | Logsdon, Aric F. | Simpkins, James W. | Alkon, Daniel L. | Smith, Kelly E. | Chen, Yi-Wen | Tan, Zhenjun | Huber, Jason D. | Rosen, Charles L.

Article Type: Review Article

Abstract: Ischemic stroke and Alzheimer's disease (AD), despite being distinct disease entities, share numerous pathophysiological mechanisms such as those mediated by inflammation, immune exhaustion, and neurovascular unit compromise. An important shared mechanistic link is acute and chronic changes in protein kinase C (PKC) activity. PKC isoforms have widespread functions important for memory, blood-brain barrier maintenance, and injury repair that change as the body ages. Disease states accelerate PKC functional modifications. Mutated forms of PKC can contribute to neurodegeneration and cognitive decline. In some cases the PKC isoforms are still functional but are not successfully translocated to appropriate locations within the cell. …The deficits in proper PKC translocation worsen stroke outcome and amyloid-β toxicity. Cross talk between the innate immune system and PKC pathways contribute to the vascular status within the aging brain. Unfortunately, comorbidities such as diabetes, obesity, and hypertension disrupt normal communication between the two systems. The focus of this review is to highlight what is known about PKC function, how isoforms of PKC change with age, and what additional alterations are consequences of stroke and AD. The goal is to highlight future therapeutic targets that can be applied to both the treatment and prevention of neurologic disease. Although the pathology of ischemic stroke and AD are different, the similarity in PKC responses warrants further investigation, especially as PKC-dependent events may serve as an important connection linking age-related brain injury. Show more

Keywords: Alzheimer's disease, blood-brain barrier, immune exhaustion, innate immunity, ischemic stroke, protein kinase C

DOI: 10.3233/JAD-141422

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 711-724, 2015

Authors: Shoemark, Deborah K. | Allen, Shelley J.

Article Type: Review Article

Abstract: This review, gathered from diverse sources, shows how our microbiome influences health and ultimately how well we age. Evidence linking oral bacteria to Alzheimer's disease (AD) is discussed in the context of aging, drawing together data from epidemiological, experimental, genetic, and environmental studies. Immunosenescence results in increased bacterial load as cell-mediated and humoral immune responses wane. The innate immune system gradually takes over; contributing to the rise in circulating proinflammatory cytokines such as TNFα. Maintaining the integrity of the blood-brain barrier (BBB) against a backdrop of increasing bacterial load is important. Aging may favor the proliferation of anaerobes in the …mouth eliciting a robust TNFα response from the oral epithelium. Prolonged exposure to high levels of circulating TNFα compromises the integrity of the BBB. Sensitive techniques now detect the “asymptomatic” presence of bacteria in areas previously thought to be sterile, providing new insights into the wider distribution of components of the microbiome. These “immune-tolerated” bacteria may slowly multiply elsewhere until they elicit a chronic inflammatory response; some are now considered causal in instances of atherosclerosis and back pain. Inflammatory processes have long been associated with AD. We propose for a subset of AD patients, aging favors the overgrowth of oral anaerobes established earlier in life provoking a pro-inflammatory innate response that weakens the BBB allowing bacteria to spread and quietly influence the pathogenesis of AD. Finally, we suggest that human polymorphisms considered alongside components of the microbiome may provide new avenues of research for the prevention and treatment of disease. Show more

Keywords: Alzheimer's disease, blood-brain barrier, environmental, epidemiological, immune-tolerated, innate, microbiome, oral, polymorphism

DOI: 10.3233/JAD-141170

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 725-738, 2015

Authors: Emmerzaal, Tim L. | Kiliaan, Amanda J. | Gustafson, Deborah R.

Article Type: Review Article

Abstract: The occurrence of obesity, commonly estimated using body mass index (BMI), and the most common late-onset dementia, Alzheimer's disease (AD), are increasing globally. The year 2013 marked a decade of epidemiologic observational reports on the association between BMI and late-onset dementias. In this review, we highlight epidemiological studies that measured both mid- and late-life BMI in association with dementia. Studies investigating the association between midlife BMI and risk for dementia demonstrated generally an increased risk among overweight and obese adults. When measured in late-life, elevated BMI has been associated with lower risk. In addition, being underweight and/or having a decrease …in BMI in late-life are associated with higher dementia risk compared to BMI in the normal range or stable BMI. In this review, a decade (2003–2013) of epidemiologic observational studies on associations between BMI and AD is highlighted. These observations provide a strong base for addressing biological mechanisms underlying this complex association. Show more

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

DOI: 10.3233/JAD-141086

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 739-755, 2015

Authors: Serpente, Maria | Fenoglio, Chiara | Clerici, Francesca | Bonsi, Rossana | Arosio, Beatrice | Cioffi, Sara M.G. | Rotondo, Emanuela | Franceschi, Massimo | Boneschi, Filippo Martinelli | Mari, Daniela | Mariani, Claudio | Scarpini, Elio | Galimberti, Daniela

Article Type: Short Communication

Abstract: We carried out an association study of transmembrane protein 106B gene (TMEM106B) rs1020004 A/G, rs6966915C/T, and rs1990622 A/G in a population of 656 patients with Alzheimer's disease (AD) and 619 controls, and tested whether the rs1990622 influences plasma progranulin levels. No differences in allele and genotype distribution were observed between cases and controls, even stratifying according to APOE status (p > 0.05). No differences in progranulin plasma levels were found between carriers of the rs1990622 and non-carriers. TMEM106b variability does not influence AD risk or plasma levels. Replication, preferably in a population with pathological confirmation, is required to confirm these …results. Show more

Keywords: Alzheimer's disease, progranulin, TDP-43, TMEM106b

DOI: 10.3233/JAD-141167

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 757-761, 2015

Authors: Sotiropoulos, Ioannis | Silva, Joana | Kimura, Tetsuya | Rodrigues, Ana Joao | Costa, Patricio | Almeida, Osborne F.X. | Sousa, Nuno | Takashima, Akihiko

Article Type: Research Article

Abstract: Tau-mediated neurodegeneration is a central event in Alzheimer's disease (AD) and other tauopathies. Consistent with suggestions that lifetime stress may be a clinically-relevant precipitant of AD pathology, we previously showed that stress triggers Tau hyperphosphorylation and accumulation; however, little is known about the etiopathogenic interaction of chronic stress with other AD risk factors, such as sex and aging. This study focused on how these various factors converge on the cellular mechanisms underlying Tau aggregation in the hippocampus of chronically stressed male and female (middle-aged and old) mice expressing the most commonly found disease-associated Tau mutation in humans, P301L-Tau. We report …that environmental stress triggers memory impairments in female, but not male, P301L-Tau transgenic mice. Furthermore, stress elevates levels of caspase-3-truncated Tau and insoluble Tau aggregates exclusively in the female hippocampus while it also alters the expression of the molecular chaperones Hsp90, Hsp70, and Hsp105, thus favoring accumulation of Tau aggregates. Our findings provide new insights into the molecular mechanisms through which clinically-relevant precipitating factors contribute to the pathophysiology of AD. Our data point to the exquisite sensitivity of the female hippocampus to stress-triggered Tau pathology. Show more

Keywords: Chaperones, hippocampus, memory, mice, stress, tau aggregates

DOI: 10.3233/JAD-140693

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 763-774, 2015

Authors: Du, Lai-Ling | Chai, Da-Min | Zhao, Li-Na | Li, Xiao-Hong | Zhang, Fu-Chi | Zhang, Hai-Bo | Liu, Lv-Bin | Wu, Kang | Liu, Rong | Wang, Jian-Zhi | Zhou, Xin-Wen

Article Type: Research Article

Abstract: Collecting evidence has shown that type 2 diabetes mellitus is a high risk factor of late-onset Alzheimer's disease (AD); the energy metabolic dysfunction is thought to be a convergent point of the two diseases. However, the underlying mechanisms of diabetes-associated AD are still unclear. In the current study, we investigated the roles of AMPK in diabetes-related AD-like pathologic features in models of intracerebroventricular-streptozotocin (ICV-STZ) animals. Rats infused with STZ (3 mg/kg, once) were followed by injection of AICAR (AMPK activator) or vehicle via ICV. We found that the level of p-AMPK (active type of AMPK) and SIRT1 activity were decreased …and the level of phosphorylated tau was increased at Ser396 and Thr231 sites in ICV-STZ rats when compared with control rats. Mitochondria from ICV-STZ rats displayed a significant decrease in mitochondrial membrane potential, complex I activity, ATP level, and superoxide dismutase activity as well as an increase of reactive oxygen species production when compared with that from control rats. Meanwhile the number of apoptotic cell confirmed by cleaved caspase-3 (active type of caspase-3) staining was also stronger in ICV-STZ rats than control rats. All pathological changes including biochemistry and cognitive function could be mitigated through rescuing AMPK activity with its specific activator (AICAR) in ICV-STZ rats. Taken together, these results suggested that AMPK activation improves AD-like pathological changes via repairing mitochondrial functions in ICV-STZ rats. Show more

Keywords: Alzheimer's disease, AMPK, diabetes mellitus, mitochondria, tau

DOI: 10.3233/JAD-140564

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 775-784, 2015

Authors: McNeely, Alicia A. | Ramirez, Joel | Nestor, Sean M. | Zhao, Jiali | Gao, Fuqiang | Kiss, Alex | Stuss, Donald T. | Black, Sandra E.

Article Type: Research Article

Abstract: Background: Subcortical hyperintensities within the cholinergic fiber projections (chSH) on MRI are believed to reflect cerebral small vessel disease (SVD) which may adversely impact cognition. Additionally, hippocampal atrophy represents a commonly used biomarker to support the diagnosis of Alzheimer's disease (AD). Objective: To examine potential differences in neuropsychological test performance between AD patients (n = 234) with high and low chSH volumes and whether these differences corresponded to hippocampal atrophy. Methods: A modified version of Lesion Explorer was used to volumetrically quantify chSH severity. The Sunnybrook Hippocampal Volumetry Tool was applied to obtain hippocampal volumes. Composite …z-scores to assess executive, memory, and visuospatial functioning were generated from standardized neuropsychological test performance scores. Results: Inter-method technique validation demonstrated a high degree of correspondence with the Cholinergic Pathways Hyperintensities Scale (n = 40, ρ = 0.84, p < 0.001). After adjusting for brain atrophy, disease severity, global SH volumes, and demographic variables, multivariate analyses revealed a significant group difference, with the high chSH group demonstrating poorer memory function compared to the low chSH group (p = 0.03). A significant difference was found between low and high chSH groups in total (p < 0.05) and left (p < 0.01) hippocampal volume. Conclusion: These results suggest degradation of the cholinergic projections due to strategic SVD may independently contribute to memory dysfunction and hippocampal atrophy. Future studies examining subcortical vasculopathy in the cholinergic pathways may have implications on the development of therapeutic strategies for dementia and SVD. Show more

Keywords: Alzheimer's disease, cholinergic pathway, hippocampus, magnetic resonance imaging, memory, small vessel disease, subcortical hyperintensity

DOI: 10.3233/JAD-140588

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 785-796, 2015

Authors: Song, Hyundong | Chang, Yu Jin | Moon, Minho | Park, Sarah Kyua | Tran, Phuong-Thao | Hoang, Van-Hai | Lee, Jeewoo | Mook-Jung, Inhee

Article Type: Review Article

Abstract: Alzheimer's disease is the most prevalent neurodegenerative disorder, characterized by neurofibrillary tangles, senile plaques, and neuron loss. Amyloid-β peptides (Aβ) are generated from amyloid-β precursor protein by consecutive catalysis by β- and γ-secretases. Diversely modified forms of Aβ have been discovered, including pyroglutamate Aβ (N3pE-42 Aβ). N3pE-42 Aβ has received considerable attention as one of the major constituents of the senile plaques of AD brains due to its higher aggregation velocity, stability, and hydrophobicity compared to the full-length Aβ. A previous study suggested that N3pE-42 Aβ formation is catalyzed by glutaminyl cyclase (QC) following limited proteolysis of Aβ at the …N-terminus. Here, we reveal that decreasing the QC activity via application of a QC inhibitor modulates γ-secretase activity, resulting in diminished plaque formation as well as reduced N3pE-42 Aβ aggregates in the subiculum of the 5XFAD mouse model of AD. This study suggests a possible novel mechanism by which QC regulates Aβ formation, namely modulation of γ-secretase activity. Show more

Keywords: Alzheimer's disease, γ-secretase, glutaminyl cyclase, pyroglutamate amyloid-β, 5XFAD

DOI: 10.3233/JAD-141356

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 797-807, 2015