Journal of Alzheimer's Disease - Volume 66, issue 2

Authors: Kim, Si Eun | Woo, Sookyoung | Kim, Seon Woo | Chin, Juhee | Kim, Hee Jin | Lee, Byung In | Park, Jinse | Park, Kyung Won | Kang, Do-Young | Noh, Young | Ye, Byoung Seok | Yoo, Han Soo | Lee, Jin San | Kim, Yeshin | Kim, Seung Joo | Cho, Soo Hyun | Na, Duk L. | Lockhart, Samuel N. | Jang, Hyemin | Seo, Sang Won

Article Type: Research Article

Abstract: Background: Most clinical trials focus on amyloid-β positive (Aβ+) amnestic mild cognitive impairment (aMCI), but screening failures are high because only a half of patients with aMCI are positive on Aβ PET. Therefore, it becomes necessary for clinicians to predict which patients will have Aβ biomarker. Objective: We aimed to compare clinical factors, neuropsychological (NP) profiles, and apolipoprotein E (APOE ) genotype between Aβ+ aMCI and Aβ–aMCI and to develop a clinically useful prediction model of Aβ positivity on PET (PET-Aβ+) in aMCI using a nomogram. Methods: We recruited 523 aMCI patients who underwent Aβ PET …imaging in a nation-wide multicenter cohort. The results of NP measures were divided into following subgroups: 1) Stage (Early and Late-stage), 2) Modality (Visual, Verbal, and Both), 3) Recognition failure, and 4) Multiplicity (Single and Multiple). A nomogram for PET-Aβ+ in aMCI patients was constructed using a logistic regression model. Results: PET-Aβ+ had significant associations with NP profiles for several items, including high Clinical Dementia Rating Scale Sum of Boxes score (OR 1.47, p = 0.013) and impaired memory modality (impaired both visual and verbal memories compared with visual only, OR 3.25, p = 0.001). Also, presence of APOE ɛ 4 (OR 4.14, p < 0.001) was associated with PET-Aβ+. These predictors were applied to develop the nomogram, which showed good prediction performance (C-statistics = 0.79). Its prediction performances were 0.77/0.74 in internal/external validation. Conclusions: The nomogram consisting of NP profiles, especially memory domain, and APOE ɛ 4 genotype may provide a useful predictive model of PET-Aβ+ in patients with aMCI. Show more

Keywords: Amnestic mild cognitive impairment, amyloid PET positivity, neuropsychological tests, nomogram, prediction

DOI: 10.3233/JAD-180048

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 681-691, 2018

Authors: Baird, Amee | Brancatisano, Olivia | Gelding, Rebecca | Thompson, William Forde

Article Type: Research Article

Abstract: Background: Music evoked autobiographical memories (MEAMs) have been documented in people with Alzheimer’s disease (AD), but it is unclear whether music is more effective than other familiar stimuli at evoking memories. Objective: To explore the frequency and specificity of memories in response to famous songs compared with photographs of famous events (photograph evoked autobiographical memories, PEAMs), and whether stimuli from the period of the reminiscence bump (10–30 years of age) were more likely to elicit memories. Methods: 10 participants with AD and 10 aged-matched healthy elderly people reported memories following exposure to 2 songs (longest time …at number one in Australian music charts) and 2 photographs (of prominent famous events) from each decade from 1930 to 2010. Results: PEAMs were more frequent than MEAMs in healthy elderly (p < 0.05), but no such differences were observed among people with AD. There was no difference in the frequency of MEAMs between groups, but people with AD showed a significant decline in the frequency of PEAMs. In both groups, MEAMs were typically less specific than PEAMs and comprised semantic knowledge or repeated/extended events. Stimuli from when participants were aged 10–30 years triggered more frequent memories compared with stimuli from later decades, but this was only statistically significant for MEAMs. Conclusion: Our findings indicate a preserved mnemonic effect of music relative to pictures in this patient population, corroborating suggestions that MEAMs represent an island of preservation during the progression of AD. Show more

Keywords: Alzheimer’s disease, autobiographical memory, music, reminiscence bump

DOI: 10.3233/JAD-180627

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 693-706, 2018

Authors: Kustra, Rafal | Awh, Carl C. | Rojas-Fernandez, Carlos | Zanke, Brent

Article Type: Research Article

Abstract: Background: An interaction between genetic variants in complement factor H (CFH ) and age-related maculopathy susceptibility 2 (ARMS2 ) and high-dose zinc supplementation on progression to advanced age-related macular degeneration (AMD) exists. Because cognitive impairment (CI) is associated with AMD, we used data from the Women’s Health Initiative (WHI) to search for a zinc/genetics interaction. Objective: To study the interaction of chronic zinc supplementation with genetic variants in CFH and ARMS2 on the development of CI. Background: Zinc dietary supplements, CFH and ARMS2 genotypes, and serial mental status was analyzed in …participants with available genetic data (n = 7,483). Cognition was assessed using the Modified Mini-Mental State Examination. The development of CI over 5 years was analyzed by genotype and zinc intake using a repeated measures logistic regression model. Results: Zinc supplementation of approximately 15 mg/day was associated with decreased development of CI in women with 1 or 2 CFH and no ARMS2 risk alleles (OR = 0.46: 1 CFH risk allele; 0.20: 2 CFH risk alleles; p = 0.002). Conclusion: Low-dose zinc (approximately 15 mg) is associated with reduced CI in women with 2 CFH and 0 ARMS2 AMD risk alleles. This interaction is opposite in direction to that observed in AMD, where patients with 2 CFH and 0 ARMS2 risk alleles had increased progression to neovascular AMD if treated with 80 mg/day of zinc. This may be due to a zinc dose-response or to a fundamental difference in the role of zinc in the progression of early CI versus advanced AMD. Show more

Keywords: Cognitive dysfunction, complement factor H, gene-environment interaction, genotype, macular degeneration, zinc

DOI: 10.3233/JAD-180673

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 707-715, 2018

Authors: Nguyen, Trung P. | Schaffert, Jeff | LoBue, Christian | Womack, Kyle B. | Hart, John | Cullum, C. Munro

Article Type: Research Article

Abstract: Background: Traumatic brain injury (TBI) with loss of consciousness (LOC) has been associated with earlier onset of mild cognitive impairment, frontotemporal dementia, Parkinson’s disease, and Alzheimer’s disease (AD), but has not been examined as a risk factor for earlier onset of dementia with Lewy bodies (DLB). Objective: The purpose of this study was to assess the association between a history of TBI and the age of onset of DLB. Method: Data from 576 subjects with a clinical diagnosis of DLB were obtained from the National Alzheimer’s Coordinating Center (NACC). Analyses of Covariance examined whether self-reported history …of remote TBI with LOC (i.e., >1 year prior to the first Alzheimer’s Disease Center visit) was associated with earlier DLB symptom onset. Results: Controlling for sex, those with a history of remote TBI had an approximately 1.5-year earlier clinician-estimated age of onset (F = 0.87, p = 0.35) and 0.75-years earlier age of diagnosis (F = 0.14, p = 0.71) of DLB compared to those without a history of TBI, though the differences did not reach statistical significance. Analysis of subjects with autopsy-confirmed diagnoses was underpowered due to the low number of TBI+ subjects. Conclusions: Remote TBI with LOC was not significantly associated with DLB onset, despite being a significant risk factor for cognitive decline and earlier age of onset in other neurodegenerative conditions. Replication of these results using a larger cohort of DLB subjects with and without a TBI history who have undergone autopsy is indicated, as our TBI+ subjects did show a slightly earlier onset of about 1.5 years. Further investigations into other potential DLB risk factors are also warranted. Show more

Keywords: Age of onset, dementia, dementia with Lewy bodies, traumatic brain injury

DOI: 10.3233/JAD-180586

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 717-723, 2018

Authors: Bohlken, Jens | Jacob, Louis | Kostev, Karel

Article Type: Research Article

Abstract: Background: There is a conflicting literature on the association between the use of antihyperglycemic drugs and dementia risk. Objective: The goal of this case-control study was to analyze the association between the use of antihyperglycemic drugs and dementia risk in patients followed in general practices in Germany. Methods: This study included patients with type 2 diabetes mellitus who had received a first dementia diagnosis in 972 general practices in Germany between January 2013 and December 2017 (index date). Controls without dementia were matched (1:1) to cases by age, gender, index year, and physician. …Two multivariate regression models were used to study the association between the use of antihyperglycemic drugs and dementia risk. Model 1 included all antihyperglycemic drugs prescribed to patients regardless of the prescription duration, whereas Model 2 only included the longest therapy prescribed to each patient. Results: There were 8,276 diabetes patients with dementia and 8,276 diabetes patients without dementia included in this study. In Model 1, glitazones were associated with a decreased dementia risk (odds ratio [OR] = 0.80), whereas insulin was associated with an increased risk of developing the condition (OR = 1.34). In Model 2, metformin, prescribed as monotherapy (OR = 0.71) or as dual therapy with sulfonylureas (OR = 0.90), was associated with a decrease in the likelihood of subsequently being diagnosed with dementia. By contrast, the combination of basal insulin and bolus insulin (OR = 1.47) and premix insulin (OR = 1.33) were risk factors for dementia. Conclusion: Metformin and glitazones were negatively associated with dementia, while insulin was positively associated with dementia. Show more

Keywords: Antihyperglycemic drugs, case-control study, dementia, Germany

DOI: 10.3233/JAD-180808

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 725-732, 2018

Authors: Elias, Alby | Cummins, Tia | Tyrrell, Regan | Lamb, Fiona | Dore, Vincent | Williams, Robert | Rosenfeld, J.V. | Hopwood, Malcolm | Villemagne, Victor L. | Rowe, Christopher C.

Article Type: Research Article

Abstract: Background: An association between obstructive sleep apnea (OSA) and Alzheimer’s disease has been suggested but little is known about amyloid-β and tau deposition in this syndrome. Objective: To determine amyloid and tau burden and cognitive function in OSA in comparison with those without a diagnosis of OSA. Methods: The status of OSA was determined by asking participants about history of polysomnographic diagnosis of OSA and the use of Continuous Positive Airway Pressure (CPAP). A comprehensive neuropsychological battery measured cognitive function. Positron emission tomography (PET) was used to measure standardized uptake value ratio (SUVR) …of 18 F-florbetaben and 18 F-AV1451, to quantify amyloid and tau burden. Results: 119 male Vietnam veterans completed assessment. Impairment in visual attention and processing speed and increased body mass index (BMI) were seen in subjects with OSA compared with those without a diagnosis OSA. The cortical uptake of 18 F-florbetaben was higher in the OSA group than in the control group (SUVR: 1.35±0.21 versus 1.27±0.16, p  = 0.04). There were more apolipoprotein E ɛ 4 allele (APOE ɛ 4) carriers in the OSA group than in the control group. In multilinear regression analysis, the significance of OSA in predicting 18 F-florbetaben uptake remained independent of age and vascular risk factors but not when BMI or APOE ɛ 4 was adjusted. The reported use of CPAP (n  = 14) had no effect on cognitive or amyloid PET findings. There was no significant difference in 18 F-AV1451 uptake between the two groups. Conclusions: Obstructive sleep apnea is associated with Alzheimer’s disease pathology, but this relationship is moderated by APOE ɛ 4 and BMI. Show more

Keywords: Alzheimer’s disease, amyloid PET, dementia, obstructive sleep apnea, tau PET

DOI: 10.3233/JAD-180640

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 733-741, 2018

Authors: Katisko, Kasper | Kokkonen, Nina | Krüger, Johanna | Hartikainen, Päivi | Koivisto, Anne M. | Helisalmi, Seppo | Korhonen, Ville E. | Kokki, Merja | Tuusa, Jussi | Herukka, Sanna-Kaisa | Solje, Eino | Haapasalo, Annakaisa | Tasanen, Kaisa | Remes, Anne M.

Article Type: Research Article

Abstract: Recent studies have shown an epidemiological and immunological association between bullous pemphigoid (BP) and several neurological or psychiatric diseases. Here, our aim was for the first time to specify whether an association exists between BP and frontotemporal lobar degeneration (FTLD). Medical histories of FTLD patients (N = 196) were screened for clinical comorbidity, and BP180 and BP230 autoantibodies were analyzed in the sera of FTLD patients (N = 70, including 24 C9orf72 repeat expansion carriers) by BP180-NC16A-ELISA and BP230-ELISA. One FTLD patient (C9orf72 repeat expansion carrier) had a comorbid diagnosis of BP. Increased levels of serum BP180 autoantibodies …(cutoff value >9 U/ml) were detected more often in FTLD patients (10.0%) than in controls (4.9%). Moreover, elevated levels of both BP180 and BP230 autoantibodies were found more often in C9orf72 repeat expansion-carrying FTLD than non-carrying patients or controls. However, none of these differences reached a statistical significance likely due to our limited cohort size. In conclusion, our findings suggest that subset of FTLD patients especially with the C9orf72 repeat expansion may have an immunological association with BP. Show more

Keywords: Autoantibody, bullous pemphigoid, C9orf72 , comorbidity, dementia, frontotemporal dementia, immunology

DOI: 10.3233/JAD-180624

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 743-750, 2018

Authors: Chen, Mei | Song, Hailong | Cui, Jiankun | Johnson, Catherine E. | Hubler, Graham K. | DePalma, Ralph G. | Gu, Zezong | Xia, Weiming

Article Type: Research Article

Abstract: Alzheimer’s disease (AD), the most prevalent form of dementia, is characterized by two pathological hallmarks: Tau-containing neurofibrillary tangles and amyloid-β protein (Aβ )-containing neuritic plaques. The goal of this study is to understand mild traumatic brain injury (mTBI)-related brain proteomic changes and tau-related biochemical adaptations that may contribute to AD-like neurodegeneration. We found that both phosphorylated tau (p-tau) and the ratio of p-tau/tau were significantly increased in brains of mice collected at 3 and 24 h after exposure to 82-kPa low-intensity open-field blast. Neurological deficits were observed in animals at 24 h and 7 days after the blast using …Simple Neuroassessment of Asymmetric imPairment (SNAP) test, and axon/dendrite degeneration was revealed at 7 days by silver staining. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to analyze brain tissue labeled with isobaric mass tags for relative protein quantification. The results from the proteomics and bioinformatic analysis illustrated the alterations of axonal and synaptic proteins in related pathways, including but not being limited to substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis, suggesting a potential axonal damage caused by blast-induced mTBI. Among altered proteins found in brains suffering blast, microtubule-associated protein 1B, stathmin, neurofilaments, actin binding proteins, myelin basic protein, calcium/calmodulin-dependent protein kinase, and synaptotagmin I were representative ones involved in altered pathways elicited by mTBI. Therefore, TBI induces elevated phospho-tau, a pathological feature found in brains of AD, and altered a number of neurophysiological processes, supporting the notion that blast-induced mTBI as a risk factor contributes to AD pathogenesis. LC/MS-based profiling has presented candidate target/pathways that could be explored for future therapeutic development. Show more

DOI: 10.3233/JAD-180726

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 751-773, 2018

Authors: Weng, Yi-Ching | Hsiao, Ing-Tsung | Huang, Chu-Yun | Huang, Kuo-Lun | Liu, Chi-Hung | Chang, Ting-Yu | Yen, Tzu-Chen | Lin, Kun-Ju | Huang, Chin-Chang

Article Type: Research Article

Abstract: Background: The amyloid AV-45 (florbetapir) positron emission tomography (PET) has been used in the study of the familial Alzheimer’s disease (FAD) with the D678H amyloid precursor protein (APP) mutation. In addition, the progress of the disease remains unknown. Objective: We aim to investigate the progression rate of amyloid accumulation in FAD patients with this mutation by neuroimages analysis. Methods: The clinical course, changes in cognitive function, brain magnetic resonance imaging (MRI) and 18 F-AV-45 PET scan were investigated in FAD patients and sporadic AD (sAD) patients. We compared the amyloid deposition pattern in …serial brain 18 F-AV-45 PET scan among the FAD, familial mild cognitive impairment (FMCI), and sMCI and sAD patients. Results: Seven familial patients received a follow-up survey. The follow up duration for brain AV-45 PET was from 1.54 to 3.61 years. In 4 FMCI patients, an increased regional SUVR was noted, and the annual change rates were increased from 1.03% to 18.82%. However, a decreased regional SUVR was noted in 3 FAD patients and the annual change rates were from –2.62% to –16.03%. As compared with the sAD and sMCI patients, the annual change rate is statistically significant in FAD and FMCI patients respectively. Conclusions: The data indicate a biphasic course with an initial increase and then a decrease of SUVR in brain amyloid PET scan in familial APP mutation patients. The data also reveal that the novel Taiwan APP (D678H) mutation has a more amyloid burden than the sAD patients, particularly in an MCI stage. Show more

Keywords: Amyloid, angiopathy, annual change rate, brain AV-45 PET, familial Alzheimer’s disease, Taiwan D678H APP mutation

DOI: 10.3233/JAD-180824

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 775-787, 2018

Authors: Zuo, Li-jun | Guo, Peng | Liu, Li | Yu, Shu-yang | Lian, Teng-hong | Yu, Qiu-jin | Hu, Yang | Jin, Zhao | Wang, Rui-dan | Piao, Ying-shan | Li, Li-xia | Wang, Ya-jie | Wang, Xiao-min | Zhang, Wei

Article Type: Research Article

Abstract: Background: OD is common in patients with Alzheimer’s disease (AD). However, the relationship between OD and clinical symptoms and the potential mechanisms of OD in AD patients are still unknown. Objective: To explore the relationship between OD and clinical symptoms and the potential mechanisms of OD in AD patients. Methods: We evaluated OD using the Hyposmia Rating Scale (HRS), classified patients into AD with OD (AD-OD) and AD with no OD (AD-NOD) groups, and detected the levels of free radicals and inflammatory factors, including hydroxyl radical (•OH), hydrogen peroxide (H2 O2 ), nitric oxide, interleukin-1β , …interleukin-6, tumor necrosis factor-α , and prostaglandin E2 in serum from AD patients. Results: It was shown that the scores of the Mini-Mental State Examination, Animal Fluency Test, Boston Naming Test (BNT), and Auditory Verbal Learning Test-delayed recall were all significantly lower and the score of overall activity of daily living (ADL) and instrumental ADL were significantly higher in AD-OD group than those in AD-NOD group. Compared with AD-NOD group, •OH level in serum was prominently elevated, and H2 O2 level was dramatically declined in AD-OD group. In the correlation analysis, HRS score was significantly and positively correlated with the score of BNT, and negatively correlated with •OH level in serum. Conclusions: AD-OD patients suffered from severe cognitive impairment in the domain of language. Oxidative stress might be correlated with AD-OD featured by the drastically increased •OH level in serum. Show more

Keywords: Alzheimer’s disease, language, •OH , olfactory dysfunction, oxidative stress

DOI: 10.3233/JAD-180425

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 789-799, 2018