Journal of Alzheimer's Disease - Volume 73, issue 2

Authors: Hamilton, Rachel K.B. | Phelan, Cynthia H. | Chin, Nathaniel A. | Wyman, Mary F. | Lambrou, Nickolas | Cobb, Nichelle | Kind, Amy J.H. | Blazel, Hanna | Asthana, Sanjay | Gleason, Carey E.

Article Type: Review Article

Abstract: With increased longevity and growth in the number of older adults comes rising rates of individuals with cognitive impairment and dementia. The expansion of this population has important implications for research on aging and dementia syndromes, namely increased enrollment of older individuals in clinical research. Ethical prerogatives, as well as historical underrepresentation of persons with dementia in research studies due to the perceived burden of traditional decisional capacity evaluations, necessitates the development of pragmatic approaches to ascertain decisional abilities in research settings. We outline a protocol used in the Wisconsin Alzheimer’s Disease Research Center (ADRC) that adopts a stepped approach …to the evaluation of decisional capacity meant to maximize study visit efficiency while preserving participant safety and autonomy. The protocol specifies the structure of the consent process and incorporates a brief semi-structured interview based on Appelbaum & Grisso’s theoretical model for evaluating a patient’s decisional capacity to provide informed consent to participate in research. This protocol is easily implemented in a research study visit and is designed to minimize participant burden and ensure reliable assessment of decisional capacity in older adults across a wide range of research protocols. The protocol emphasizes capacity optimization, using memory aids and other compensatory strategies to preserve participant autonomy while protecting welfare. Show more

Keywords: Clinical research protocol, dementia, informed consent, mental competence

DOI: 10.3233/JAD-190457

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 431-442, 2020

Authors: Rogers, Nicole K. | Romero, Cesar | SanMartín, Carol D. | Ponce, Daniela P. | Salech, Felipe | López, Mercedes N. | Gleisner, Alejandra | Tempio, Fabián | Behrens, María I.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the adult population. There is evidence of an inverse epidemiological relationship between AD and cancer, another prevalent age-related disease. This has led to hypothesize that there could be a common biological mechanism, deregulated in opposite directions that might explain the phenomenon of mutual protection. The immunological system and its regulatory checkpoints are good candidates to explain why having survived a cancer could protect from developing AD. During cancerous growth, the neoplastic cells induce immune tolerance to block the host’s immunity system that would prevent tumor growth. This has led to …the development of drugs that block distinct immune checkpoints, such as Programmed Death 1 (PD-1) and its major ligand PD-L1, that have shown great promise in treating diverse types of cancer. We propose that in those individuals who survived a cancer, the immune system is left in a state of diminished tolerance or proinflammatory systemic milieu, after its successful attempt to fight the cancer, that protects them from developing AD. Show more

Keywords: Alzheimer’s disease, cancer, immune checkpoint, inflammation

DOI: 10.3233/JAD-190839

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 443-454, 2020

Authors: Fuller-Thomson, Esme | Deng, ZhiDi

Article Type: Research Article

Abstract: Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) is a disease in which the clinical presentation mimics that of Alzheimer’s disease. TDP-43 proteinopathy associated with LATE has been identified in more than 20% of autopsies of community-dwelling adults over the age of 80. It is believed to contribute significantly toward tau-negative dementia. Heavy metals such as lead has also been linked to TDP-43 proteinopathy. In particular, lead triggers TDP-43 accumulation and disrupts TDP-43 homeostasis. However, the specific relationship between LATE and lead remains unknown. Before leaded gasoline was phased out during the 1970s and 1980s, average blood lead levels were 15 times what …they are today. Thus, each successive birth cohort entering old age has had less cumulative lifeime exposure to lead. Lifetime exposure can be tracked in the tibia bone, where the half-life of lead is many decades. We hypothesize that lead plays a role in the development of LATE. There are two ways to explore the validity of this hypothesis. Generational differences in lead exposure should result in a steady decline in the prevalence of LATE among older adults. We propose the use of tibia bone lead levels be examined in conjunction with brain autopsies from different birth cohorts to examine the link between lead exposure and LATE prevalence, holding age constant. Furthermore, individuals with genetic polymorphisms that confer a greater lead absorption phenotype should display a higher degree of TDP-43 accumulation in autopsies. The results of such studies could provide insight into gene by environment interactions relevant to the development of LATE. Show more

Keywords: Alzheimer’s disease, dementia with TDP-43 pathology, lead poisoning, nervous system, TDP-43 proteinopathies, tetraethyl lead

DOI: 10.3233/JAD-190943

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 455-459, 2020

Authors: Koulousakis, Philippos | van den Hove, Daniel | Visser-Vandewalle, Veerle | Sesia, Thibaut

Article Type: Short Communication

Abstract: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has been shown to exert promising therapeutical effects in a pilot study with patients suffering from Alzheimer’s disease (AD). We aimed at comparing the cognitive effects of intermittent and continuous NBM stimulation paradigms in an animal model for AD. In this exploratory study, aged Tgf344-AD rats were behaviorally tested pre-, and post implantation, while being stimulated with unilateral- or bilateral-intermittent and bilateral-continuous patterns. Bilateral-intermittent NBM DBS lead to supernormal performance in a spatial memory task. These findings suggest that NBM DBS could be further refined, thereby improving patient care.

Keywords: Alzheimer’s disease, deep brain stimulation, intermittent stimulation, nucleus basalis of Meynert

DOI: 10.3233/JAD-190919

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 461-466, 2020

Authors: Bouji, Marc | Lecomte, Anthony | Gamez, Christelle | Blazy, Kelly | Villégier, Anne-Sophie

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common type of neurodegenerative disease leading to dementia. Several studies suggested that mobile phone radiofrequency electromagnetic field (RF-EMF) exposures modified AD memory deficits in rodent models. Objective: Here we aimed to test the hypothesis that RF-EMF exposure may modify memory through corticosterone and oxidative stress in the Samaritan rat model of AD. Methods: Long-Evans male rats received intracerebroventricular infusion with ferrous sulphate, amyloid-beta 1-42 peptide, and buthionine-sufloximine (AD rats) or with vehicle (control rats). To mimic cell phone use, RF-EMF were exposed to the head for 1 month (5 …days/week, in restraint). To look for hazard thresholds, high brain averaged specific absorption rates (BASAR) were tested: 1.5 W/Kg (15 min), 6 W/Kg (15 min), and 6 W/Kg (45 min). The sham group was in restraint for 45 min. Endpoints were spatial memory in the radial maze, plasmatic corticosterone, heme oxygenase-1 (HO1), and amyloid plaques. Results: Results indicated similar corticosterone levels but impaired memory performances and increased cerebral staining of thioflavine and of HO1 in the sham AD rats compared to the controls. A correlative increase of cortical HO1 staining was the only effect of RF-EMF in control rats. In AD rats, RF-EMF exposures induced a correlative increase of hippocampal HO1 staining and reduced corticosterone. Discussion: According to our data, neither AD nor control rats showed modified memory after RF-EMF exposures. Unlike control rats, AD rats showed higher hippocampal oxidative stress and reduced corticosterone with the higher BASAR. This data suggests more fragility related to neurodegenerative disease toward RF-EMF exposures. Show more

Keywords: Alzheimer’s disease, corticosterone, memory, mobile phone, oxidative stress, radiofrequency

DOI: 10.3233/JAD-190593

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 467-476, 2020

Authors: Brown, Monique J. | Patterson, Robert

Article Type: Research Article

Abstract:  The risk of dementia and mild cognitive impairment between older adults in same-sex relationships and those in opposite-sex relationships have been found to be statistically not different. However, studies examining subjective cognitive decline (SCD) among sexual and gender minority populations (SGM) are lacking. The primary objective was to determine if SGM report greater SCD compared to non-SGM populations in a U.S. population-based sample of non-institutionalized adults aged 45 and older. The secondary objective was to assess the association between gender and SCD. Cross-sectional data were obtained from the 2016 Behavioral Risk Factor Surveillance System (n  = 36,734). There were 1,094 SGM …adults in the sample. Descriptive statistics examined sociodemographic characteristics and their distribution by SCD and SGM status. Crude and multivariable logistic regression models were used to determine the association between SGM status, gender, and SCD. Adjusted models controlled for age, race/ethnicity, income, education, employment, marital status, depression, and diabetes. Statistically significant differences in SGM status and SCD existed by age, race/ethnicity, education, employment, marital status, and depression. Differences in SCD also existed by income and diabetes status. There was no statistically significant association between SGM status and SCD (OR: 0.88; 95% CI: 0.63–1.24). However, men had 64% higher odds (OR: 1.64; 95% CI: 1.44–1.88) of reporting SCD compared to women. Future studies examining the potential reasons for this null association, including resilience and/or premature aging are warranted. Future research assessing potential reasons for gender differences in SCD, whether physiological or environmental, is also needed. Show more

Keywords: Cognitive dysfunction, GLBT persons, health status disparities, men, women

DOI: 10.3233/JAD-190869

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 477-487, 2020

Authors: Tarumi, Takashi | Thomas, Binu P. | Tseng, Benjamin Y. | Wang, Ciwen | Womack, Kyle B. | Hynan, Linda | Lu, Hanzhang | Cullum, C. Munro | Zhang, Rong

Article Type: Research Article

Abstract: Cerebral white matter (WM) represents the structural substrate of neuronal communications which is damaged by Alzheimer’s disease (AD). Aerobic exercise training (AET) may improve WM integrity in cognitively normal older adults, but its efficacy remains unknown in patients with amnestic mild cognitive impairment (MCI), a prodromal phase of AD dementia. Therefore, we conducted a proof-of-concept study that randomized 70 amnestic MCI patients to a 1-year program of AET or a non-aerobic stretching and toning (SAT), active control group. Thirty-six patients completed both baseline and follow-up MRI scans, and cerebral WM integrity was measured by WM lesion volume and diffusion characteristics …using fluid-attenuated-inversion-recovery and diffusion tensor imaging respectively. Peak oxygen uptake (VO2peak ) and neuropsychological function were also measured. At baseline and 1-year follow-up, WM lesion volume and diffusion characteristics were similar between the AET and SAT groups, although VO2peak significantly improved after AET. The AET group showed slight improvement in neuropsychological performance. When analyzing individual data, tract-based spatial statistics demonstrated that VO2peak improvements are associated with attenuated elevations in mean and axial diffusivities, particularly the anterior WM fiber tracts (e.g., genu of corpus callosum). In patients with amnestic MCI, we found that although AET intervention did not improve WM integrity at group level analysis, individual cardiorespiratory fitness gains were associated with improved WM tract integrity of the prefrontal cortex. Show more

Keywords: Aerobic exercise, cardiorespiratory fitness, diffusion tensor imaging, mild cognitive impairment, white matter integrity

DOI: 10.3233/JAD-190875

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 489-501, 2020

Authors: Yin, Ping | Wang, Shuang | Wei, Yafen | Wang, Xu | Zhang, Jingdian | Yin, Xiang | Feng, Jiachun | Zhu, Mingqin

Article Type: Research Article

Abstract: Inflammation resolution is regulated by specialized pro-resolving lipid mediators (SPMs) and the levels of SPMs are found decreased in Alzheimer’s disease (AD) brain. We have previously found that one of the SPMs, Maresin1 (MaR1), improved neuronal survival and increase microglial phagocytosis of amyloid-β 1-42 (Aβ42 ); however, the mechanisms underlying the protective mechanism remain further investigation. We aim to investigate the effects of MaR1 on microglial chemotaxis and activation in this study. Both indirect and direct primary neuron and microglia co-culture system was used in this study. Our results showed MaR1 downregulated the increased microglial chemotaxis induced by Aβ42 . …The microglial inactivation marker CD200R was downregulated by Aβ42 and upregulated by MaR1. Pro-inflammatory cytokines secretion such as tumor necrosis factor (TNF)-α were increased by Aβ42 and these changes were revised by MaR1 treatment. In addition, the levels of chemokine monocyte chemoattractant protein (MCP)-1 were increased while the levels of anti-inflammatory factor IL-10 secretion were decreased by Aβ42 , and these changes were abolished by MaR1 treatment. Moreover, by proteomics analysis, we identified cell signaling pathways affected by MaR1 were not only limited to inflammation-related pathways such as P38, but also in pathways involved in cell survival, autophagy, axon formation, and apoptosis, including PI3K/AKT, mTOR, ERK, caspase3, Cdc42, and p75NTR. In conclusion, MaR1 promoted inflammation resolution by inhibiting chemotaxis and regulating activation of microglia. MaR1 played a neuroprotective role by affecting cell signaling pathways involving inflammation, cell survival, autophagy, axon formation, and apoptosis inhibition. Show more

Keywords: Alzheimer’s disease, chemotaxis, Maresin1, microglia, proteomics, resolution of inflammation

DOI: 10.3233/JAD-190682

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 503-515, 2020

Authors: Feng, Maoxiao | Cui, Donghai | Li, Yi | Shi, Jian | Xiang, Lan | Bian, Hong | Ma, Zhiyong | Xia, Wen | Wei, Guangwei

Article Type: Research Article

Abstract: The cell surface level of apolipoprotein E receptor 2 (ApoER2) increases by cyclic transport of ApoER2 and then activates Reelin signaling pathway to exert neuroprotective function in AD. ApoER2 ligand Apolipoprotein E4 (ApoE4) inhibits the recycling of ApoER2 to the cell surface rendering neurons unresponsive to Reelin. Carnosic acid (CA) is proven to possess neuroprotective and neurotrophic functions in Alzheimer’s disease (AD) mouse model. However, there are few reports about how ApoE4 impairs the recycling of ApoER2 and if CA can affect the cyclic transport of ApoER2. In this study, we demonstrated that ApoE4 attenuates the binding of sorting nexin …17 (SNX17) to ApoER2 and inhibits the recycling of ApoER2, resulting in decreased cell surface level of ApoER2. Further, we found that CA enhances the binding of SNX17 to ApoER2, counteracts the negative effects of ApoE4 on the cell surface level of ApoER2 to reverse the ApoE4-induced reduction in Reelin signaling activation by increasing the phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) and cAMP-response element-binding protein (CREB) and the expression of Gria2. Thus, CA promotes neurite growth inhibited by ApoE4. Our work suggests that CA may be a potential approach to attenuate the risk of ApoE4-associated AD. Show more

Keywords: Apolipoprotein E receptor 2, Apolipoprotein E4, carnosic acid, Reelin signaling pathway, sorting nexin 17

DOI: 10.3233/JAD-190914

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 517-528, 2020

Authors: Agca, Cansu | Klakotskaia, Diana | Stopa, Edward G. | Schachtman, Todd R. | Agca, Yuksel

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is one of the most devastating and costly diseases, and prevalence of AD increases with age. Furthermore, females are twice as likely to suffer from AD compared to males. The cessation of reproductive steroid hormone production during menopause is hypothesized to cause this difference. Two rodent AD models, APP21 and APP+PS1, and wild type (WT) rats underwent an ovariectomy or sham surgery. Changes in learning and memory, brain histology, amyloid-β (Aβ) deposition, levels of mRNAs involved in Aβ production and clearance, and synaptic and cognitive function were determined. Barnes maze results showed that regardless of ovariectomy status, …APP+PS1 rats learned slower and had poor memory retention. Ovariectomy caused learning impairment only in the APP21 rats. High levels of Aβ42 and very low levels of Aβ40 were observed in the brain cortices of APP+PS1 rats indicating limited endogenous PS1. The APP+PS1 rats had 43-fold greater formic acid soluble Aβ42 than Aβ40 at 17 months. Furthermore, levels of formic acid soluble Aβ42 increased 57-fold in ovariectomized APP+PS1 rats between 12 and 17 months of age. The mRNA encoding Grin1 significantly decreased due to ovariectomy whereas levels of Bace1, Chat, and Prkcb all decreased with age. The expression levels of mRNAs involved in Aβ degradation and AβPP cleavage (Neprilysin, Ide, Adam9, and Psenen) were found to be highly correlated with each other as well as hippocampal Aβ deposition. Taken together, these results indicate that both ovariectomy and genotype influence AD markers in a complex manner. Show more

Keywords: Alzheimer’s disease, amyloid-β , estrogen, gene expression, ovarian hormones, ovariectomy, progesterone, rat, transgenic

DOI: 10.3233/JAD-190935

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 529-541, 2020