Journal of Alzheimer's Disease - Volume 80, issue 1

Authors: Zhuang, Qi-Shuai | Meng, Lei | Wang, Zhe | Shen, Liang | Ji, Hong-Fang

Article Type: Research Article

Abstract: Background: Identifying modifiable risk factors, such as obesity, to lower the prevalence of Alzheimer’s disease (AD) has gained much interest. However, whether the association is causal remains to be evaluated. Objective: The present study was designed: 1) to make a quantitative assessment of the association between obesity and AD; 2) to validate whether there was a causal association between them; and 3) to provide genetic clues for the association through a network-based analysis. Methods: Two-sample Mendelian randomization (2SMR) analysis, meta-analysis, and protein-protein interaction (PPI) network analysis, were employed. Results: Firstly, the meta-analysis based on …9 studies comprising 6,986,436 subjects indicated that midlife obesity had 33%higher AD odds than controls (OR = 1.33, 95%CI = [1.03, 1.62]), while late-life obesity were inversely associated with AD risk (OR = 0.57, 95%CI = [0.47, 0.68]). Secondly, 2SMR analysis indicated that there was no causal association between them. Thirdly, CARTPT was identified to be shared by the anti-obesity drug targets and AD susceptibility genes. Further PPI network analysis found that CARTPT interacted with CD33, a strong genetic locus linked to AD. Finally, 2SMR analysis showed that CNR1 could be a protective factor for AD. Conclusion: Multiple bioinformatic analyses indicated that midlife obesity might increase the risk of AD, while current evidence indicated that there was no causal association between them. Further, CARTPT might be an important factor linking the two disease conditions. It could help to better understand the mechanisms underlying the associations between obesity and AD. Show more

Keywords: Alzheimer’s disease, drug targets, Mendelian randomization, meta-analysis, obesity, susceptibility genes.

DOI: 10.3233/JAD-201235

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 271-281, 2021

Authors: Hartmann, Julia | Roßmeier, Carola | Riedl, Lina | Dorn, Bianca | Fischer, Julia | Slawik, Till | Fleischhaker, Mareike | Hartmann, Florentine | Egert-Schwender, Silvia | Kehl, Victoria | Haller, Bernhard | Schneider-Schelte, Helga | Dinkel, Andreas | Jox, Ralf J. | Diehl-Schmid, Janine

Article Type: Research Article

Abstract: Background: Advanced stages of dementia are characterized by severe cognitive and physical impairment. It has not yet been investigated whether persons with young onset dementia (YOD) and late onset dementia (LOD) differ in advanced disease stages. Objectives: To compare quality of life (QoL) between persons with advanced YOD and LOD; to explore the determinants of QoL; to investigate whether YOD and LOD differ with regard to symptoms and care. Methods: The study was performed in the context of EPYLOGE (IssuEs in Palliative care for persons in advanced and terminal stages of YOD and LOD in Germany). …Persons with advanced dementia (PWAD) were assessed and caregivers were interviewed. QoL was measured with the proxy rating Quality of Life in Late Stage Dementia (QUALID) scale. Results: 93 persons with YOD and 98 with LOD were included. No significant differences in QoL were detected. Determinants of QoL were similar in YOD and LOD. Behavioral and psychological symptoms of dementia (BPSD), suffering and other distressing symptoms were associated with a lower QoL. In YOD but not in LOD antipsychotic treatment was associated with low QoL. The group of persons who were younger than 65 years at the time of the study visit experienced significantly more distressing symptoms than older PWAD. Conclusion: Overall, persons with advanced YOD do not appear to be disadvantaged compared to old and oldest PWAD. Special attention, however, must be paid to the group of the very young persons who seem to be particularly vulnerable. Show more

Keywords: Antipsychotics, caregivers, dementia, home care, late onset dementia, long term care, quality of life, young onset dementia

DOI: 10.3233/JAD-201302

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 283-297, 2021

Authors: Guo, Mingyan | Peng, Jun | Huang, Xiaoyan | Xiao, Lingjun | Huang, Fenyan | Zuo, Zhiyi

Article Type: Research Article

Abstract: Background: Patients with Alzheimer’s disease (AD) have gut microbiome alterations compared with healthy controls. However, previous studies often assess AD patients who have been on medications or other interventions for the disease. Also, simultaneous determination of gut microbiome in patients with mild cognitive impairment (MCI) or AD in a study is rare. Objective: To determine whether there was a gut microbiome alteration in patients newly diagnosed with AD or MCI and whether the degree of gut microbiome alteration was more severe in patients with AD than patients with MCI. Methods: Fecal samples of 18 patients with …AD, 20 patients with MCI, and 18 age-matched healthy controls were collected in the morning for 16S ribosomal RNA sequencing. No patient had medications or interventions for AD or MCI before the samples were collected. Results: Although there was no difference in the microbial α -diversity among the three groups, patients with AD or MCI had increased β-diversity compared with healthy controls. Patients with AD had decreased Bacteroides, Lachnospira , and Ruminiclostridium_9 and increased Prevotella at the genus level compared with healthy controls. The changing direction of these genera in patients with MCI was the same as patients with AD. However, Lachnospira was the only genus whose abundance in patients with MCI was statistically significantly lower than healthy controls. Bacteroides, Lachnospira , and Ruminiclostridium_9 were positively associated with better cognitive functions whereas Prevotella was on the contrary when subjects of all three groups were considered. The negative correlation of Prevotella with cognitive functions remained among patients with MCI. Conclusion: Patients newly diagnosed with AD or MCI have gut dysbiosis that includes the decrease of potentially protective microbiome, such as Bacteroides , and the increase of microbiome that can promote inflammation, such as Prevotella . Our results support a novel idea that the degree of gut dysbiosis is worsened with the disease stage from MCI to AD. Show more

Keywords: Alzheimer’s disease, Chinese, gut microbiome, mild cognitive impairment

DOI: 10.3233/JAD-201040

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 299-310, 2021

Authors: Llano, Daniel A. | Devanarayan, Viswanath | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: There is intense interest in the development of blood-based biomarkers, not only that can differentiate Alzheimer’s disease (AD) from controls, but that can also predict conversion from mild cognitive impairment (MCI) to AD. Serum biomarkers carry the potential advantage over imaging or spinal fluid markers both in terms of cost and invasiveness. Objective: Our objective was to measure the potential for serum lipid markers to differentiate AD from age-matched healthy controls as well as to predict conversion from MCI to AD. Methods: Using a publicly-available dataset, we examined the relationship between baseline serum levels of …349 known lipids from 16 classes of lipids to differentiate disease state as well as to predict the conversion from MCI to AD. Results: We observed that several classes of lipids (cholesteroyl ester, phosphatidylethanolamine, lysophosphatidylethanolamine, and acylcarnitine) differentiated AD from normal controls. Among these, only two classes, phosphatidylethanolamine (PE) and lysophosphatidylethanolamine (lyso-PE), predicted time to conversion from MCI to AD. Low levels of PE and high levels of lyso-PE result in two-fold faster median time to progression from MCI to AD, with hazard ratios 0.62 and 1.34, respectively. Conclusion: These data suggest that serum PE and lyso-PE may be useful biomarkers for predicting MCI to AD conversion. In addition, since PE is converted to lyso-PE by phospholipase A2, an important inflammatory mediator that is dysregulated in AD, these data suggest that the disrupted serum lipid profile here may be related to an abnormal inflammatory response early in the AD pathologic cascade. Show more

Keywords: Alzheimer’s disease, biomarker, lipids, lysophosphatidylethanolamine, mild cognitive impairment, phosphatidylethanolamine

DOI: 10.3233/JAD-201420

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 311-319, 2021

Authors: Yu, Guang-Xiang | Zhang, Ting | Hou, Xiao-He | Ou, Ya-Nan | Hu, Hao | Wang, Zuo-Teng | Guo, Yu | Xu, Wei | Tan, Lin | Yu, Jin-Tai | Tan, Lan | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Increasing evidence supports an important role of vascular risk in cognitive decline and dementia. Objective: This study aimed to examine whether vascular risk was associated with cognitive decline, cerebral hypometabolism, and clinical progression in cognitively intact elders. Methods: Vascular risk was assessed by the Framingham Heart Study general Cardiovascular disease (FHS-CVD) risk score. The cross-sectional and longitudinal associations of FHS-CVD risk score with cognition and brain glucose metabolism were explored using multivariate linear regression and linear mixed effects models, respectively. The risk of clinical progression conversion was assessed using Kaplan-Meier survival curves and multivariate Cox …proportional hazard models. Results: A total of 491 cognitively intact elders were included from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Participants with high FHS-CVD risk scores had lower baseline Mini-Mental State Examination (MMSE) (p  = 0.009), executive function (EF) (p  < 0.001), memory function (MEM) (p  < 0.001) scores, and F18-fluorodeoxyglucose positron emission tomography (FDG-PET) uptake (p  < 0.001) than those with low FHS-CVD risk scores. In longitudinal analyses, individuals with higher FHS-CVD risk scores had greater longitudinal declines in MMSE (p  = 0.043), EF (p  = 0.029) scores, and FDG-PET uptake (p  = 0.035). Besides, individuals with a higher vascular risk had an increased risk of clinical progression (p  = 0.004). Conclusion: These findings indicated effects of vascular risk on cognitive decline, cerebral hypometabolism, and clinical progression. Early detection and management of vascular risk factors might be useful in the prevention of dementia. Show more

Keywords: Clinical progression, cognition, dementia, FDG-PET, vascular risk

DOI: 10.3233/JAD-201117

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 321-330, 2021

Authors: Takemoto, Mami | Yamashita, Toru | Ohta, Yasuyuki | Tadokoro, Koh | Omote, Yoshio | Morihara, Ryuta | Abe, Koji

Article Type: Research Article

Abstract: Background: Cerebral microbleeds (CMBs) in patients with Parkinson’s disease (PD) or dementia with Lewy bodies (DLB) have not been adequately studied. Objective: This study aims to find a difference in the total number, prevalence, and common locations of CMBs between PD and DLB and evaluate 99 m Tc-ECD SPECT subtraction images of these two diseases. Methods: We examined 112 patients with PD (53 males and 59 females; age: 77.4±3.6 years) and 28 age-matched patients with DLB (15 males and 13 females; age: 77.1±6.7 years) using brain magnetic resonance imaging (MRI) and 99 m Tc-ECD SPECT subtraction imaging. …Results: The total number of CMBs was higher in patients with DLB (41.2%) than in those with PD (11.5%), and the prevalence was significantly higher in the former (0.7±1.1) than the latter (0.2±0.5, p  < 0.05). The odds ratio was 5.4 (95% confidence interval [CI]: 1.7–17.4). Furthermore, CMBs were commonly located in the basal ganglia of patients with PD (6 out of 87 patients) but in the occipital lobe of patients with DLB (8 out of 17 patients). 99 m Tc-ECD SPECT subtraction imaging indicated lower cerebral blood flow in the posterior cingulate gyrus among the patients with CMB-positive DLB than among those with CMB-positive PD; additionally, the cerebral blood flow was lower in the bilateral basal ganglia and midbrain among patients with CMB-positive DLB compared to those with CMB-negative DLB. Conclusion: A reduction in occipital glucose metabolism may be related to CMBs in the occipital lobe of patients with DLB. Show more

Keywords: Brain magnetic resonance imaging, cerebral microbleeds, dementia with Lewy bodies, Parkinson’s disease, 99 mTc-ECD SPECT subtraction imaging

DOI: 10.3233/JAD-201495

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 331-335, 2021

Authors: Shiekh, Suhail Ismail | Cadogan, Sharon Louise | Lin, Liang-Yu | Mathur, Rohini | Smeeth, Liam | Warren-Gash, Charlotte

Article Type: Research Article

Abstract: Background: Globally around 50 million people have dementia. Risk factors for dementia such as hypertension and diabetes are more common in Black, Asian, and other ethnic minorities. There are also marked ethnic inequalities in care seeking, likelihood of diagnosis, and uptake of treatments for dementia. Nevertheless, ethnic differences in dementia incidence and prevalence remain under-explored. Objective: To examine published peer-reviewed observational studies comparing age-specific or age-adjusted incidence or prevalence rates of dementia between at least two ethnic groups. Methods: We searched seven databases on 1 September 2019 using search terms for ethnicity, dementia, and incidence or …prevalence. We included population-based studies comparing incidence or prevalence of dementia after accounting for age of at least two ethnic groups in adults aged 18 or more. Meta-analysis was conducted for eligible ethnic comparisons. Results: We included 12 cohort studies and seven cross-sectional studies. Thirteen were from the US, and two studies each from the UK, Singapore, and Xinjiang Uyghur Autonomous Region in China. The pooled risk ratio for dementia incidence obtained from four studies comparing Black and White ethnic groups was 1.33 (95% CI 1.07–1.65; I-squared = 58.0%). The pooled risk ratio for dementia incidence comparing the Asian and White ethnic groups was 0.86 (95% CI 0.728–1.01; I-squared = 43.9%). There was no difference in the incidence of dementia for Latino ethnic group compared to the White ethnic group. Conclusion: Evidence to date suggest there are ethnic differences in risk of dementia. Better understanding of the drivers of these differences may inform efforts to prevent or treat dementia. Show more

Keywords: Alzheimer’s disease, dementia, ethnic groups, incidence, prevalence

DOI: 10.3233/JAD-201209

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 337-355, 2021

Authors: Rühlmann, Claire | Dannehl, David | Brodtrück, Marcus | Adams, Andrew C. | Stenzel, Jan | Lindner, Tobias | Krause, Bernd J. | Vollmar, Brigitte | Kuhla, Angela

Article Type: Research Article

Abstract: Background: To date, there are no effective treatments for Alzheimer’s disease (AD). Thus, a significant need for research of therapies remains. Objective: One promising pharmacological target is the hormone fibroblast growth factor 21 (FGF21), which is thought to be neuroprotective. A clinical candidate for medical use could be the FGF21 analogue LY2405319 (LY), which has a specificity and potency comparable to FGF21. Methods: The present study investigated the potential neuroprotective effect of LY via PPARγ /apoE/abca1 pathway, which is known to degrade amyloid-β (Aβ) plaques by using primary glial cells and hippocampal organotypic brain slice cultures …(OBSCs) from 30- and 50-week-old transgenic APPswe/PS1dE9 (tg) mice. By LY treatment of 52-week-old tg mice with advanced Aβ deposition, we further aimed to elaborate the effect of LY on AD pathology in vivo . Results: LY application to primary glial cells caused an upregulation of ppar γ , apoE , and abca1 mRNA expression and significantly decreased number and area of Aβ plaques in OBSCs. LY treatment in tg mice increased cerebral [18 F] FDG uptake and N-acetylaspartate/creatine ratio indicating enhanced neuronal activity and integrity. Although LY did not reduce the number of Aβ plaques in tg mice, the number of iba1-positive cells was significantly decreased indicating reduced microgliosis. Conclusion: These data identified LY in vitro as an activator of Aβ degrading genes leading to cerebral Aβ load amelioration in early and late AD pathology. Although Aβ plaque reduction by LY failed in vivo , LY may be used as therapeutic agent to treat AD-related neuroinflammation and impaired neuronal integrity. Show more

Keywords: Alzheimer’s disease, amyloid-β plaques, APPswe/PS1dE9 mouse model, [18F] FDG, LY2405319, MR spectroscopy, positron emission tomography

DOI: 10.3233/JAD-200837

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 357-369, 2021

Authors: Li, Xudong | Shen, Miaoxin | Jin, Yi | Jia, Shuhong | Zhou, Zhi | Han, Ziling | Zhang, Xiangfei | Tong, Xiaopeng | Jiao, Jinsong

Article Type: Research Article

Abstract: Background: Alzheimer’s disease dementia (ADD) is an important health problem in the world. Objective: The present study investigated the validity and reliability of a new version of the Frontal Assessment Battery (FAB) named the FAB-phonemic (FAB-P). Methods: A total of 76 patients with ADD, 107 patients with amnestic mild cognitive impairment (aMCI), 37 patients with non-amnestic MCI (naMCI), and 123 healthy controls were included in this study. All participants were evaluated with the FAB-P and the cognitive assessments according to a standard procedure. Results: The global FAB-P scores in patients with ADD were lower …than those of patients with aMCI, patients with naMCI, and healthy controls (p  < 0.001). Patients with aMCI performed worse than healthy controls (p  < 0.001). The interrater reliability, test-retest reliability, and Cronbach’s alpha coefficient for the FAB-P were 0.997, 0.819, and 0.736, respectively. The test could distinguish the patients with mild ADD, aMCI, and naMCI from healthy controls with classification accuracy of 89.4%, 70.9%, and 61.6%, respectively. It could also discriminate between the patients with ADD and aMCI, between those with ADD and naMCI, and between those with aMCI and naMCI with classification accuracy of 73.8%, 83.9%, and 58.0%, respectively. The regression analysis revealed that the Montreal Cognitive Assessment and the Stroop Color Word Test Part C had the greatest contribution to FAB-P score variance. Conclusion: The FAB-P is a valid and reliable tool for evaluating frontal lobe function and can effectively discriminate ADD, aMCI, and naMCI. Show more

Keywords: Alzheimer’s disease dementia, Frontal Assessment Battery, mild cognitive impairment, phonetics

DOI: 10.3233/JAD-201028

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 371-381, 2021

Authors: Peira, Enrico | Grazzini, Matteo | Bauckneht, Matteo | Sensi, Francesco | Bosco, Paolo | Arnaldi, Dario | Morbelli, Silvia | Chincarini, Andrea | Pardini, Matteo | Nobili, Flavio

Article Type: Research Article

Abstract: Background: In clinical practice, the amy-PET is globally inspected to provide a binary outcome, but the role of a regional assessment has not been fully investigated yet. Objective: To deepen the role of regional amyloid burden and its implication on clinical-neuropsychological features. Materials: Amy-PET and a complete neuropsychological assessment (Trail Making Test, Rey Auditory Verbal Learning Test, semantic verbal fluency, Symbol Digit, Stroop, visuoconstruction) were available in 109 patients with clinical suspicion of Alzheimer’s disease. By averaging the standardized uptake value ratio and ELBA, a regional quantification was calculated for each scan. Patients were grouped according …to their overall amyloid load: correlation maps, based on regional quantification, were calculated and compared. A regression analysis between neuropsychological assessment and the regional amyloid-β (Aβ) load was carried out. Results: Significant differences were observed between the correlation maps of patients at increasing levels of Aβ and the overall dataset. The Aβ uptake of the subcortical gray matter resulted not related to other brain regions independently of the global Aβ level. A significant association of semantic verbal fluency was observed with ratios of cortical and subcortical distribution of Aβ which represent a coarse measure of differences in regional distribution of Aβ. Conclusion: Our observations confirmed the different susceptibility to Aβ accumulation among brain regions. The association between cognition and Aβ distribution deserves further investigations: it is possibly due to a direct local effect or it represents a proxy marker of a more aggressive disease subtype. Regional Aβ assessment represents an available resource on amy-PET scan with possibly clinical and prognostic implications. Show more

Keywords: Amyloid PET, ELBA, regional amyloid, semi-quantification, standardized uptake value ratio

DOI: 10.3233/JAD-201156

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 383-396, 2021