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

Authors: López-Higes, Ramón | Rodríguez-Rojo, Inmaculada C. | Prados, José M. | Montejo, Pedro | Del-Río, David | Delgado-Losada, María Luisa | Montenegro, Mercedes | López-Sanz, David | Barabash, Ana

Article Type: Research Article

Abstract: Background: Most research points to the ɛ 4 allele of the apolipoprotein E (APOE ) gene as the most recognizable genetic risk factor associated with Alzheimer’s disease pathogenesis. It has been also suggested that the APOE ɛ 4 allele has a negative influence on cognitive functioning, which begins long before cognitive impairment becomes manifest. However, still, little is known about the APOE ɛ 4 interaction with cognitive intervention programs. Objective: The main goal of this study was to explore whether there was a differential APOE genotype modulation effect after cognitive training in different domains, …such as language comprehension, executive functions, and memory. Contrary to other studies, hippocampal volume was controlled for. Methods: Fifty older adults (65+ years; 30 women and 20 men) participated in a multi-domain cognitive training that involved 30 sessions taking place over 12 weeks. Half of the participants were APOE ɛ 4 carriers. The control group was matched in age, gender, normalized hippocampal volume, cognitive reserve, Mini-Mental State Examination score, and Geriatric Depression Scale-Short Version. Results: The study revealed that there were consistent treatment benefits in complex sentence comprehension (noncanonical sentences and sentences with two propositions), a domain that was not directly trained, but only in the A POE ɛ 4 noncarrier group. Conclusion: Genetic profile modulates training outcomes in sentence comprehension. Show more

Keywords: Apolipoprotein E, cognitive training, elderly, neuropsychology

DOI: 10.3233/JAD-161014

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1201-1215, 2017

Authors: Nave, Stephane | Doody, Rachelle S. | Boada, Mercè | Grimmer, Timo | Savola, Juha-Matti | Delmar, Paul | Pauly-Evers, Meike | Nikolcheva, Tania | Czech, Christian | Borroni, Edilio | Ricci, Benedicte | Dukart, Juergen | Mannino, Marie | Carey, Tracie | Moran, Emma | Gilaberte, Inma | Muelhardt, Nicoletta Milani | Gerlach, Irene | Santarelli, Luca | Ostrowitzki, Susanne | Fontoura, Paulo

Article Type: Research Article

Abstract: Background: Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer’s disease (AD). Objective: To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD. Methods: In this Phase II study (NCT01677754), 542 patients with moderate dementia (MMSE 13–20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1 mg, 5 mg, or placebo once daily orally for 52 weeks. Results: No differences between treated groups and placebo in adverse events or in study completion. The primary endpoint, change from baseline in ADAS-Cog11, …was not met. At Week 52, the difference between sembragiline and placebo in ADAS-Cog11 change from baseline was – 0.15 (p  = 0.865) and 0.90 (p  = 0.312) for 1 and 5 mg groups, respectively. Relative to placebo at Week 52 (but not at prior assessment times), the 1 mg and 5 mg sembragiline groups showed differences in ADCS-ADL of 2.64 (p  = 0.051) and 1.89 (p  = 0.160), respectively. A treatment effect in neuropsychiatric symptoms (as assessed by the difference between sembragiline and placebo on BEHAVE-AD-FW) was also seen at Week 52 only: – 2.80 (p  = 0.014; 1 mg) and – 2.64 (p  = 0.019; 5 mg), respectively. A post hoc subgroup analysis revealed greater treatment effects on behavior and functioning in patients with more severe baseline behavioral symptoms (above the median). Conclusions: This study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline. Show more

Keywords: Alzheimer’s disease, dementia, monoamine oxidase B, Phase II clinical trial

DOI: 10.3233/JAD-161309

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1217-1228, 2017

Authors: Ochoa, John Fredy | Alonso, Joan Francesc | Duque, Jon Edinson | Tobón, Carlos Andrés | Baena, Ana | Lopera, Francisco | Mañanas, Miguel Angel | Hernández, Alher Mauricio

Article Type: Research Article

Abstract: Background: Presenilin-1 (PSEN1) mutations are the most common cause of familial early onset Alzheimer’s disease (AD). The PSEN1 E280A (E280A) mutation has an autosomal dominant inheritance and is involved in the production of amyloid-β. The largest family group of carriers with E280A mutation is found in Antioquia, Colombia. The study of mutation carriers provides a unique opportunity to identify brain changes in stages previous to AD. Electroencephalography (EEG) is a low cost and minimally invasiveness technique that enables the following of brain changes in AD. Objective: To examine how previous reported differences in EEG for Theta and …Alpha-2 rhythms in E280A subjects are related to specific regions in cortex and could be tracked across different ages. Methods: EEG signals were acquired during resting state from non-carriers and carriers, asymptomatic and symptomatic subjects from E280A kindred from Antioquia, Colombia. Independent component analysis (ICA) and inverse solution methods were used to locate brain regions related to differences in Theta and Alpha-2 bands. Results: ICA identified two components, mainly related to the Precuneus, where the differences in Theta and Alpha-2 exist simultaneously at asymptomatic and symptomatic stages. When the ratio between Theta and Alpha-2 is used, significant correlations exist with age and a composite cognitive scale. Conclusion: Theta and Alpha-2 rhythms are altered in E280A subjects. The alterations are possible to track at Precuneus regions using EEG, ICA, and inverse solution methods. Show more

Keywords: Alzheimer’s disease, autosomal-dominant, independent component analysis, inverse solution methods, presenilin-1, quantitative electroencephalography

DOI: 10.3233/JAD-161291

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1229-1244, 2017

Authors: Deters, Kacie D. | Risacher, Shannon L. | Kim, Sungeun | Nho, Kwangsik | West, John D. | Blennow, Kaj | Zetterberg, Henrik | Shaw, Leslie M. | Trojanowski, John Q. | Weiner, Michael W. | Saykin, Andrew J. | for the Alzheimer Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Peripheral (plasma) and central (cerebrospinal fluid, CSF) measures of tau are higher in Alzheimer’s disease (AD) relative to prodromal stages and controls. While elevated CSF tau concentrations have been shown to be associated with lower grey matter density (GMD) in AD-specific regions, this correlation has yet to be examined for plasma in a large study. Objective: Determine the neuroanatomical correlates of plasma tau using voxel-based analysis. Methods: Cross-sectional data for 508 ADNI participants were collected for clinical, plasma total-tau (t-tau), CSF amyloid (Aβ42 ) and tau, and MRI variables. The relationship between plasma tau …and GMD and between CSF t-tau and GMD were assessed on a voxel-by-voxel basis using regression models. Age, sex, APOE ɛ 4 status, diagnosis, and total intracranial volume were used as covariates where appropriate. Participants were defined as amyloid positive (Aβ+) if CSF Aβ42 was <192 pg/mL. Results: Plasma tau was negatively correlated with GMD in the medial temporal lobe (MTL), precuneus, thalamus, and striatum. The associations with thalamus and striatum were independent of diagnosis. A negative correlation also existed between plasma tau and GMD in Aβ+ participants in the MTL, precuneus, and frontal lobe. When compared to CSF t-tau, plasma tau showed a notably different associated brain atrophy pattern, with only small overlapping regions in the fusiform gyrus. Conclusion: Plasma tau may serve as a non-specific marker for neurodegeneration but is still relevant to AD considering low GMD was associated with plasma tau in Aβ+ participants and not Aβ–participants. Show more

Keywords: Alzheimer disease, magnetic resonance imaging, mild cognitive impairment, plasma, tau protein

DOI: 10.3233/JAD-161114

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1245-1254, 2017

Authors: Moon, Byungseung | Kim, Seongheon | Park, Young Ho | Lim, Jae-Sung | Youn, Young Chul | Kim, SangYun | Jang, Jae-Won | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Depressive symptoms are prevalent in patients with mild cognitive impairment (MCI) and are considered to be a risk factor for progression to dementia. Objective: The purpose of this study was to evaluate whether depressive symptoms in MCI promote disease progression in a manner related to amyloid status, and to determine the relationship between depressive symptoms and longitudinal cerebral structural changes. Methods: Baseline data for 336 patients with MCI (75 with depression and 261 without) from the Alzheimer’s Disease Neuroimaging Initiative study were analyzed. All participants underwent comprehensive cognitive testing, volumetric magnetic resonance imaging (MRI), …and [18 F]AV45 positron emission tomography amyloid imaging. Depressive symptoms were measured using the Neuropsychiatric Inventory Questionnaire. A voxel-based morphometric analysis using volumetric brain MRI data was used to compare longitudinal structural changes related to depressive symptoms. Results: The conversion rate to dementia was different between patients with and without depression in amyloid-positive MCI (40.8% versus 19.7%, respectively; p  = 0.006). Patients who were amyloid-positive at baseline also exhibited a greater degree of 2-year cognitive decline. Depression in amyloid-positive MCI was associated with longitudinal cortical atrophy in the left cingulate gyrus. Conclusion: Our study indicates that the presence of depressive symptoms in patients with amyloid-positive MCI is associated with higher progression to dementia and longitudinal cortical atrophy. Show more

Keywords: Alzheimer’s disease, depression, mild cognitive impairment

DOI: 10.3233/JAD-170225

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1255-1264, 2017

Authors: Cermakova, Pavla | Nelson, Maja | Secnik, Juraj | Garcia-Ptacek, Sara | Johnell, Kristina | Fastbom, Johan | Kilander, Lena | Winblad, Bengt | Eriksdotter, Maria | Religa, Dorota

Article Type: Research Article

Abstract: Background: Many people with Alzheimer’s disease (AD) live alone in their own homes. There is a lack of knowledge about whether these individuals receive the same quality of diagnostics and treatment for AD as patients who are cohabiting. Objectives: To investigate the diagnostic work-up and treatment of community-dwelling AD patients who live alone. Methods: We performed a cross-sectional cohort study based on data from the Swedish Dementia Registry (SveDem). We studied patients diagnosed with AD between 2007 and 2015 (n  = 26,163). Information about drugs and comorbidities was acquired from the Swedish Prescribed Drug Register and …the Swedish Patient Register. Results: 11,878 (46%) patients lived alone, primarily older women. After adjusting for confounders, living alone was inversely associated with receiving computed tomography (OR 0.90; 95% CI 0.82–0.99), magnetic resonance imaging (OR 0.91; 95% CI 0.83–0.99), and lumbar puncture (OR 0.86; 95% CI 0.80–0.92). Living alone was also negatively associated with the use of cholinesterase inhibitors (OR 0.81; 95% CI 0.76; 0.87), memantine (OR 0.77; 95% CI 0.72; 0.83), and cardiovascular medication (OR 0.92; 0.86; 0.99). On the other hand, living alone was positively associated with the use of antidepressants (OR 1.15; 95% CI 1.08; 1.22), antipsychotics (OR 1.41; 95% CI 1.25; 1.58), and hypnotics and sedatives (OR 1.09; 95% CI 1.02; 1.17). Conclusions: Solitary living AD patients do not receive the same extent of care as those who are cohabiting. Show more

Keywords: Alzheimer’s disease, dementia, diagnostics, solitary living, treatment

DOI: 10.3233/JAD-170102

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1265-1272, 2017

Authors: Pink, Anna | Przybelski, Scott A. | Krell-Roesch, Janina | Stokin, Gorazd B. | Roberts, Rosebud O. | Mielke, Michelle M. | Knopman, David S. | Jack Jr., Clifford R. | Petersen, Ronald C. | Geda, Yonas E.

Article Type: Research Article

Abstract: Altered cortical thickness has been observed in aging and various neurodegenerative disorders. Furthermore, reduced hippocampal volume has been reported in late-life depression. Even mild depressive symptoms are common in the elderly. However, little is known about the structural MRI measures of depressive symptoms in normal cognitive aging. Thus we sought to examine the association between depressive symptoms with cortical thickness and hippocampal volume as measured by brain MRI among community-dwelling participants. We conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging, involving cognitively normal participants (N  = 1,507) aged≥70 years. We observed that depressive symptoms were …associated with lower global cortical thickness and lower thickness in specific prefrontal and temporal cortical regions, labeled by FreeSurfer software, version 5.3. As expected, the strength of correlation was very small, given that participants were community-dwelling with only mild depressive symptoms. We did not observe associations between hippocampal volume and depressive symptoms. These findings may provide insight into the structural correlates of mild depressive symptoms in elderly participants. Show more

Keywords: Aging, cortical thickness, depression, depressive symptoms, magnetic resonance imaging

DOI: 10.3233/JAD-170041

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1273-1281, 2017

Authors: Gu, Lihua | Zhang, Zhijun

Article Type: Research Article

Abstract: Background: Early diagnosis and effective management are pivotal steps in preventing the transition from mild cognitive impairment (MCI) to Alzheimer’s disease. Previous investigations indicated that some event-related potential (ERP) components in MCI are sensitive to cognitive decline. However, several comparative analyses of these components in MCI and healthy controls (HC) yielded inconsistent results. Objective: The aim was to perform a systematic review and meta-analysis of ERP studies on MCI patients. Methods: We systematically searched on PubMed and Web of Science for MCI-related ERP studies published from April 1986 to August 2016. Standard mean difference estimates …of all components were compared between MCI and HC. Results: Our study showed increased P50 amplitude at the Cz site; reduced N2pc amplitude and delayed P200 latency at the Cz site; N200 latency at the Cz and Pz sites, and P300 latency at the Cz and Pz sites in MCI patients compared to HC. Conclusions: In summary, our study indicated that some ERP components, such as P50 and N2pc amplitude, P200, N200, and P300 latency might be potential electrophysiological biomarkers for MCI diagnosis. Show more

Keywords: Event-related potential, meta-analysis, mild cognitive impairment

DOI: 10.3233/JAD-161286

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1283-1292, 2017

Authors: Lim, Yen Ying | Williamson, Robert | Laws, Simon M. | Villemagne, Victor L. | Bourgeat, Pierrick | Fowler, Christopher | Rainey-Smith, Stephanie | Salvado, Olivier | Martins, Ralph N. | Rowe, Christopher C. | Masters, Colin L. | Maruff, Paul | for the AIBL Research Group

Article Type: Research Article

Abstract: Background: The association between the apolipoprotein E (APOE ) ɛ 4 allele and high risk of developing Alzheimer’s disease (AD) dementia before the age of 80 has been recognized for over 30 years. However, the timing and mode of action of APOE is not understood, nor has there been a detailed analysis of the effect of APOE genotype on memory, hippocampal volume, and amyloid-β (Aβ) levels in cognitively normal adults. Objective: Examine the effect of APOE allelic genotype on the relationship between Aβ levels, hippocampal volume, and memory in cognitively normal adults. Methods: …This is a cross-sectional study of 989 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, all of whom underwent APOE genotyping and memory assessment. A subset of this group underwent PET neuroimaging for Aβ (n  = 585) and MRI for hippocampal volume (n  = 303). Results: APOE ɛ 4 homozygotes (ɛ 4/ɛ 4) showed significantly worse episodic memory and higher Aβ levels than ɛ 4 heterozygotes. The relationship between increasing Aβ levels and worse episodic memory was significant for ɛ 3 homozygotes (ɛ 3/ɛ 3), ɛ 4 heterozygotes, and strongest for ɛ 4 homozygotes. There were no differences in hippocampal volume between APOE groups; the relationship between smaller hippocampal volume and worse episodic memory was significant only for ɛ 4 homozygotes. Conclusion: APOE acts in a co-dominant fashion on Aβ levels, episodic memory, and hippocampal volume in cognitively normal older adults. APOE ɛ 4 is central to the events that lead to AD in cognitively normal older adults, likely through a quantitative role in the disruption of Aβ clearance. Show more

Keywords: Alzheimer’s disease, amyloid, apolipoprotein E, hippocampal volume, memory, mild cognitive impairment

DOI: 10.3233/JAD-170072

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1293-1302, 2017

Authors: Busse, Mandy | Michler, Enrico | von Hoff, Franz | Dobrowolny, Henrik | Hartig, Roland | Frodl, Thomas | Busse, Stefan

Article Type: Research Article

Abstract: Alterations in the immune response that result in inflammation might play a role in the pathology of dementias. In order to analyze changes of the peripheral immune system associated with different types of dementias, we determined several innate and adaptive cell populations in whole blood using flow cytometry. We included patients with Alzheimer’s disease (AD; n  = 60), vascular dementia (VaD; n  = 20), and frontotemporal dementia (FTD; n  = 12) at the time point of diagnosis and 24 age-matched neuropsychiatric healthy persons. Monocytes and NK cells were diminished in VaD, but not in AD and FTD. B cell and T cell numbers …were decreased in all investigated forms of dementia. Changes in the contribution of naïve/memory T cells were only present in AD. Correlation and regression analyses revealed associations between altered immune cell populations and Q Albumin as marker for the integrity of the blood-cerebrospinal fluid-barrier, Mini-Mental State Examination values, and age. The peripheral immune system is altered in AD, VaD, and FTD. However, each disorder presents unique changes in the investigated cell types indicating different mechanisms underlying the pathology. Show more

Keywords: Alzheimer’s disease, B cells, frontotemporal dementia, monocytes, NK cells, T cells, vascular dementia

DOI: 10.3233/JAD-161304

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1303-1313, 2017

Article Type: Other

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1315-1328, 2017