Journal of Alzheimer's Disease - Volume 58, issue 4

Authors: Dougherty, Ryan J. | Schultz, Stephanie A. | Kirby, Taylor K. | Boots, Elizabeth A. | Oh, Jennifer M. | Edwards, Dorothy | Gallagher, Catherine L. | Carlsson, Cynthia M. | Bendlin, Barbara B. | Asthana, Sanjay | Sager, Mark A. | Hermann, Bruce P. | Christian, Bradley T. | Johnson, Sterling C. | Cook, Dane B. | Okonkwo, Ozioma C.

Article Type: Research Article

Abstract: The objective of this study was to investigate the relationship between accelerometer-measured physical activity (PA) and glucose metabolism in asymptomatic late-middle-aged adults. Ninety-three cognitively healthy late-middle-aged adults from the Wisconsin Registry for Alzheimer’s Prevention participated in this cross-sectional study. They underwent 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging and wore an accelerometer (ActiGraph GT3X+) to measure free-living PA. Accelerometer data yielded measures of light (LPA), moderate (MPA), and vigorous (VPA) intensity PA. FDG-PET images were scaled to the cerebellum and pons, and cerebral glucose metabolic rate was extracted from specific regions of interest (ROIs) known to be hypometabolic in AD, …i.e., hippocampus, posterior cingulate, inferior temporal cortex, and angular gyrus. Regression analyses were utilized to examine the association between PA and glucose metabolism, while adjusting for potential confounds. There were associations between MPA and glucose metabolism in all ROIs examined. In contrast, LPA was not associated with glucose uptake in any ROI and VPA was only associated with hippocampal FDG uptake. Secondary analyses did not reveal associations between sedentary time and glucose metabolism in any of the ROIs. Exploratory voxel-wise analysis identified additional regions where MPA was significantly associated with glucose metabolism including the precuneus, supramarginal gyrus, amygdala, and middle frontal gyrus. These findings suggest that the intensity of PA is an important contributor to neuronal function in a late-middle-aged cohort, with MPA being the most salient. Prospective studies are necessary for fully elucidating the link between midlife engagement in PA and later life development of AD. Show more

Keywords: Exercise, motor activity, neuroimaging, risk factor

DOI: 10.3233/JAD-161067

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1089-1097, 2017

Authors: Cañabate, Pilar | Martínez, Gabriel | Rosende-Roca, Maitée | Moreno, Mariola | Preckler, Silvia | Valero, Sergi | Sotolongo, Oscar | Hernández, Isabel | Alegret, Montserrat | Ortega, Gemma | Espinosa, Ana | Mauleón, Ana | Vargas, Liliana | Rodríguez, Octavio | Abdelnour, Carla | Sánchez, Domingo | Martín, Elvira | Ruiz, Agustín | Tárraga, Lluís | Boada, Mercè

Article Type: Research Article

Abstract: Background: Different interpretations of cognitive impairment and dementia due to differences in health structures, such as cultural differences could affect the diagnosis and treatment of the condition. it is reasonable to expect that the social and family impact of the disease and coping strategies will differ among societies. Objective: The general aim of this study is to understand the social representations of dementia, its associated practices, and the effects they imply. Methods: People diagnosed with clinical dementia and their families were assessed from 2005 to 2015 in the memory clinic of the Fundació ACE, Institut …Català de Neurociències Aplicades in Barcelona, Spain. Results: 9,898 people were examined and 5,792 were diagnosed with dementia. For those with a caregiver (71%), the decision-making fell on the person with dementia in 16.2% of the cases; and for those without a caregiver, in 26.4% of the cases the family did not perceive the deficits as a disease, which led to multiple risk situations (74.6%). Conclusions: The recognition of dementia as part of aging is common among families. Consequently, risk situations may arise and diagnosis and access to treatment may be delayed. The incorporation of a social appraisal to the diagnostic process is a necessity to evaluate these situations. Show more

Keywords: Alzheimer’s disease, beliefs, caregiver, dementia, social perception, social representation, social-cultural

DOI: 10.3233/JAD-161119

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1099-1108, 2017

Authors: Tripathi, Ajai K. | Karmakar, Shilpita | Asthana, Abhishek | Ashok, Ajay | Desai, Vilok | Baksi, Shounak | Singh, Neena

Article Type: Research Article

Abstract: A direct correlation between brain iron and Alzheimer’s disease (AD) raises questions regarding the transport of non-transferrin-bound iron (NTBI), a toxic but less researched pool of circulating iron that is likely to increase due to pathological and/or iatrogenic systemic iron overload. Here, we compared the distribution of radiolabeled-NTBI (59 Fe-NTBI) and transferrin-bound iron (59 Fe-Tf) in mouse models of iron overload in the absence or presence of inflammation. Following a short pulse, most of the 59 Fe-NTBI was taken up by the liver, followed by the kidney, pancreas, and heart. Notably, a strong signal of 59 Fe-NTBI was detected in …the brain ventricular system after 2 h, and the brain parenchyma after 24 h. 59 Fe-Tf accumulated mainly in the femur and spleen, and was transported to the brain at a much slower rate than 59 Fe-NTBI. In the kidney, 59 Fe-NTBI was detected in the cortex after 2 h, and outer medulla after 24 hours. Most of the 59 Fe-NTBI and 59 Fe-Tf from the kidney was reabsorbed; negligible amount was excreted in the urine. Acute inflammation increased the uptake of 59 Fe-NTBI by the kidney and brain from 2–24 hours. Chronic inflammation, on the other hand, resulted in sequestration of iron in the liver and kidney, reducing its transport to the brain. These observations provide direct evidence for the transport of NTBI to the brain, and reveal a complex interplay between inflammation and brain iron homeostasis. Further studies are necessary to determine whether transient increase in NTBI due to systemic iron overload is a risk factor for AD. Show more

Keywords: Alzheimer’s disease, brain, kidney, inflammation, non-transferrin-bound iron

DOI: 10.3233/JAD-170097

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1109-1119, 2017

Authors: Liu, Guiyou | Sun, Jing-yi | Xu, Meiling | Yang, Xiao-yi | Sun, Bao-liang

Article Type: Research Article

Abstract: A recent study sequenced the full coding region of SORL1 in 1,255 early-onset Alzheimer’s disease (EOAD) cases and 1,938 control individuals, and investigated the contribution of genetic variability in SORL1 to EOAD risk in a European cohort. This study identified six common variants and five low frequency variants in the SORL1 coding sequence. However, none of these 11 variants was significantly associated with EOAD risk after adjusting for multiple testing. We consider whether these 11 SORL1 variants identified in European EOAD contribute to late-onset Alzheimer’s disease (LOAD) risk in individuals of European ancestry. Here, we investigated these 11 SORL1 variants …identified in European EOAD and LOAD risk in individuals of European ancestry using a large-scale LOAD GWAS. Our results indicate that three genetic variants rs2070045, rs2276412, and rs17125548 as well as their tagged genetic variants contribute to LOAD risk in European population. We further investigate whether these variants could affect SORL1 expression using multiple expression quantitative trait loci (eQTLs) datasets. Our findings suggest that three genetic variants rs2070045, rs1699102, and rs3824968 could significantly regulate SORL1 expression in human brain tissues. We believe that our findings further provide important supplementary information about the involvement of the SORL1 variants in LOAD risk. Show more

Keywords: Alzheimer’s disease, genome-wide association studies, SORL1

DOI: 10.3233/JAD-170005

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1121-1128, 2017

Authors: Morris, Jill K. | Uy, Roxanne Adeline Z. | Vidoni, Eric D. | Wilkins, Heather M. | Archer, Ashley E. | Thyfault, John P. | Miles, John M. | Burns, Jeffrey M.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) may have heterogeneous pathophysiological underpinnings, with risk factors including apolipoprotein rmvarep4 (APOE4) genotype and insulin resistance. We hypothesized that distinct phenotypes exist within AD. We examined APOE4 and metabolic biomarkers in 338 subjects (n  = 213 nondemented (ND), n  = 125 AD). We further characterized steady state free fatty acid (FFA) levels in a subset of 45 participants who had also participated in a hyperinsulinemic-euglycemic clamp. Insulin resistance (HOMA-IR) was elevated in AD versus ND (p  = 0.04) and in APOE4 noncarriers versus carriers (p  < 0.01). This was driven by increased fasting insulin in AD versus ND (p  < 0.01) and …in APOE4 non-carriers versus carriers (p  = 0.01). Fasting glucose was not different. In subjects who underwent a clamp, there was a group x genotype interaction on FFA levels during hyperinsulinemia (p  = 0.03). APOE4 non-carriers with AD had higher FFA levels, while APOE4 carriers with AD exhibited lower FFA levels. Metabolic dysfunction is overrepresented in individuals with AD dementia who do not carry the APOE4 allele. This suggests that important subsets of AD phenotypes may exist that diverge metabolically. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, hyperinsulinemia, insulin, insulin resistance

DOI: 10.3233/JAD-170148

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1129-1135, 2017

Authors: Pinner, Elhanan | Gruper, Yaron | Ben Zimra, Micha | Kristt, Don | Laudon, Moshe | Naor, David | Zisapel, Nava

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, deposition of amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles, and neuronal cell death. Neuroinflammation is commonly believed to participate in AD pathogenesis. CD44 is an inflammation-related gene encoding a widely-distributed family of alternatively spliced cell surface glycoproteins that have been implicated in inflammation, metastases, and inflammation-linked neuronal injuries. Here we investigated the expression patterns of CD44S (which does not contain any alternative exon) and CD44 splice variants in postmortem hippocampal samples from AD patients and matched non-AD controls. The expression of CD44S and CD44 splice variants CD44V3, CD44V6, and …CD44V10 was significantly higher in AD patients compared to non-AD controls. Immunohistochemistry of human hippocampal sections revealed that CD44S differentially localized to neuritic plaques and astrocytes, whereas CD44V3, CD44V6, and CD44V10 expression was mostly neuronal. Consistent with these findings, we found that the expression of CD44V6 and CD44V10 was induced by Aβ peptide in neuroblastoma cells and primary neurons. Furthermore, in loss of function studies we found that both CD44V10-specific siRNA and CD44V10 antibody protected neuronal cells from Aβ-induced toxicity, suggesting a causal relationship between CD44V10 and neuronal cell death. These data indicate that certain CD44 splice variants contribute to AD pathology and that CD44V10 inhibition may serve as a new neuroprotective treatment strategy for this disease. Show more

Keywords: Amyloid, apoptosis, dementia, expression, neurodegeneration, neuroinflammation, siRNA, splice variants, viability

DOI: 10.3233/JAD-161245

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1137-1149, 2017

Authors: Nakamura, Norimichi | Ohyagi, Yasumasa | Imamura, Tomohiro | Yanagihara, Yuki T. | Iinuma, Kyoko M. | Soejima, Naoko | Murai, Hiroyuki | Yamasaki, Ryo | Kira, Jun-ichi

Article Type: Research Article

Abstract: Apomorphine (APO) promotes intraneuronal amyloid-β (Aβ) degradation and improves memory function in an Alzheimer’s disease (AD) model, 3xTg-AD mice. Since insulin resistance is increased in AD neurons, we investigated the effects of APO on brain insulin resistance in 3xTg-AD mice at early and late stages. After 1-month subcutaneous injection of Apokyn® to 3xTg-AD mice at 6 or 12 months of age, memory function was significantly improved in both age groups. Protein levels of insulin-degrading enzyme (IDE), which is linked to insulin signaling and degrades Aβ, significantly increased in the 3xTg-AD mice brain compared with non-transgenic mice, and were further …increased by APO. Protein levels of two types of serine-phosphorylated insulin receptor substrate-1 (IRS-1), pS616 and pS636/639 , significantly decreased following APO treatment in the 13-month-old 3xTg-AD mice brain, suggesting improved brain insulin resistance. Immunostaining of the IDE, pS616 and pS636/639 IRS-1 demonstrated similar changes due to APO treatment. Thus, brain insulin resistance is considered an important therapeutic target in AD, and APO may provide improved neuronal insulin resistance. Show more

Keywords: 3xTg-AD, apomorphine, insulin-degrading enzyme, insulin receptor substrate-1, insulin resistance, memory

DOI: 10.3233/JAD-160344

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1151-1161, 2017

Authors: Tian, Sai | Han, Jing | Huang, Rong | Sun, Jie | Cai, Rongrong | Shen, Yanjue | Wang, Shaohua

Article Type: Research Article

Abstract: Background: Homocysteine (Hcy) is involved in the pathogenesis of type 2 diabetes mellitus (T2DM) and Alzheimer’s disease. Objective: We aimed to investigate the role of Hcy in T2DM patients with mild cognitive impairment (MCI), and to determine whether methylene tetrahydrofolate reductase (MTHFR) C677T or cystathionine beta-synthase (CBS) 844ins68 polymorphism is related to T2DM-associated MCI. Methods: We recruited 285 T2DM patients and divided them into two groups, 140 patients with MCI, and 145 healthy-cognition controls, on the basis of Montreal Cognitive Assessment (MoCA) scores. Demographic characteristics, clinical parameters, and neuropsychological tests were assessed. MTHFR C677T and …CBS 844ins68 polymorphisms were analyzed. Results: The MCI group exhibited significantly higher plasma total Hcy (tHcy) levels than control group (p  < 0.001). Plasma tHcy level was negatively correlated with MoCA scores (p  = 0.002), but positively associated with Trail Making Test A and B scores (p  = 0.044; p  = 0.005, respectively). Multivariable logistic regression model showed that high tHcy level was an independent factor for MCI in T2DM patients. No significant difference was observed in the genotype or allele distributions of MTHFR and CBS between MCI and control groups. We did not find significant MCI risks in MTHFR T allele compared with C allele, and in CBS I allele compared with D allele (OR = 1.361, p  = 0.067; OR = 1.048, p  = 0.909, respectively). Conclusion: Increased plasma tHcy level was significantly related to T2DM-associated MCI, especially executive dysfunction. Further investigation with a large population size should be conducted to confirm these findings. Show more

Keywords: Homocysteine, mild cognitive impairment, polymorphism, type 2 diabetes mellitus

DOI: 10.3233/JAD-170162

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1163-1173, 2017

Authors: Li, Yuxia | Jing, Bin | Liu, Han | Li, Yifan | Gao, Xuan | Li, Yongqiu | Mu, Bin | Yu, Haikuo | Cheng, Jinbo | Barker, Peter B. | Wang, Hongxing | Han, Ying

Article Type: Research Article

Abstract: Background: Depression is a potential marker of preclinical Alzheimer’s disease (AD). However, little is known about the abnormal characteristics revealed by resting-state functional magnetic resonance imaging (rs-fMRI) in mild cognitive impairment (MCI) subjects with depressive symptoms (MCI-d). Objective: The study was to examine whether abnormalities in amplitudes of low-frequency oscillation occurred in MCI-d and tried to find the possible spectrum showed higher recognition ability to the diagnosis by utilizing functional MRI (fMRI). Methods: The amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) within full frequency (0.01–0.1 Hz), slow-5 (0.01–0.027 Hz), and slow-4 (0.027–0.073 Hz) were computed using …resting-state fMRI data of 27 MCI without depressive symptoms, 19 MCI-d, and 32 well-matched healthy controls (HC). Analysis of covariance was performed on ALFF and fALFF among MCI, MCI-d, and HC groups. Results: Several brain regions showed significant differences in ALFF and fALFF within full frequency, slow-5, and slow-4 bands among three groups. Importantly, receiver operating characteristic analysis revealed that the ALFF values in the full frequency band in the left parahippocampal gyrus and the left precuneus, Slow 5 value in ALFF in the left inferior frontal gyrus, and Slow 4 value in ALFF in the left precuneus could effectively differentiate MCI-d from MCI patients. Conclusion: In this study, we found that several changes in special brain regions are associated with MCI and MCI-d patients. And the differences depend on the studied frequency bands of rs-fMRI data. The affective network and the default-mode network might be damaged simultaneously in MCI-d patients. Show more

Keywords: Alzheimer’s disease, depression, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-161282

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1175-1187, 2017

Authors: Amen, Daniel G. | Harris, William S. | Kidd, Parris M. | Meysami, Somayeh | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: The interrelationships between omega-3 fatty acids status, brain perfusion, and cognition are not well understood. Objective: To evaluate if SPECT brain imaging of cerebral perfusion and cognition varies as a function of omega-3 fatty acid levels. Methods: A random sample of 166 study participants was drawn from a psychiatric referral clinical for which erythrocyte quantification of omega-3 eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) (the Omega-3 Index) was available. Quantitative brain SPECT was done on 128 regions based on a standard anatomical Atlas. Persons with erythrocyte EPA+DHA concentrations were dichotomized based on membership in …top 50th percentile versus bottom 50th percentile categories. Two-sample t -tests were done to identify statistically significant differences in perfusion between the percentile groups. Partial correlations were modeled between EPA+DHA concentration and SPECT regions. Neurocognitive status was assessed using computerized testing (WebNeuro) and was separately correlated to cerebral perfusion on brain SPECT imaging and omega-3 EPA+DHA levels. Results: Partial correlation analyses showed statistically significant relationships between higher omega-3 levels and cerebral perfusion were in the right parahippocampal gyrus (r  = 0.20, p  = 0.03), right precuneus (r  = 0.20, p  = 0.03), and vermis subregion 6 (p  = 0.21, p  = 0.03). Omega-3 Index levels separately correlated to the feeling subsection of the WebNeuro (r  = 0.25, p  = 0.01). Conclusion: Quantitative omega-3 EPA+DHA erythrocyte concentrations are independently correlated with brain perfusion on SPECT imaging and neurocognitive tests. These results have implications for the role of omega-3 fatty acids toward contributing to cognitive reserve. Show more

Keywords: Brain SPECT, cognitive, omega-3

DOI: 10.3233/JAD-170281

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1189-1199, 2017