Journal of Alzheimer's Disease - Volume 87, issue 1

Authors: Nicsanu, Roland | Cervellati, Carlo | Benussi, Luisa | Squitti, Rosanna | Zanardini, Roberta | Rosta, Valentina | Trentini, Alessandro | Ferrari, Clarissa | Saraceno, Claudia | Longobardi, Antonio | Bellini, Sonia | Binetti, Giuliano | Zanetti, Orazio | Zuliani, Giovanni | Ghidoni, Roberta

Article Type: Research Article

Abstract: Background: Beta-site APP cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid-β (Aβ) plaques formation. BACE1 activity is increased in brains of patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) and plasma levels of BACE1 appears to reflect those in the brains. Objective: In this work, we investigated the role of serum BACE1 activity as biomarker for AD, estimating the diagnostic accuracy of the assay and assessing the correlation of BACE1 activity with levels of Aβ1 - 40 , Aβ1 - 42 , and Aβ40/42 ratio in serum, known biomarkers of brain amyloidosis. Methods: Serum BACE1 …activity and levels of Aβ1 - 40 , Aβ1 - 42 , were assessed in 31 AD, 28 MCI, diagnosed as AD at follow-up (MCI-AD), and 30 controls. The BACE1 analysis was performed with a luciferase assay, where interpolation of relative fluorescence units with a standard curve of concentration reveals BACE1 activity. Serum levels of Aβ1 - 40 , Aβ1 - 42 were measured with the ultrasensitive Single Molecule Array technology. Results: BACE1 was increased (higher than 60%) in AD and MCI-AD: a cut-off of 11.04 kU/L discriminated patients with high sensitivity (98.31%) and specificity (100%). Diagnostic accuracy was higher for BACE1 than Aβ40/42 ratio. High BACE1 levels were associated with worse cognitive performance and earlier disease onset, which was anticipated by 8 years in patients with BACE1 values above the median value (> 16.67 kU/L). Conclusion: Our results provide new evidence supporting serum/plasma BACE1 activity as an early biomarker of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, BACE1, mild cognitive impairment

DOI: 10.3233/JAD-215542

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 433-441, 2022

Authors: Ternák, Gábor | Németh, Márton | Rozanovic, Martin | Bogár, Lajos

Article Type: Research Article

Abstract: Background: Several putative factors are identified in the literature as causative agents or risk factors for the development of Alzheimer’s disease (AD). The amyloid cascade hypothesis has been the main hypothesis about the pathophysiology of AD for decades, but recent studies raised the possible role of dysbiosis in the development of AD, which prevents memory loss. Objective: Finding possible associations between antibiotic consumption patterns and the prevalence of AD in European countries. Methods: Antibiotic consumption (European Centre for Disease Prevention and Control, ECDC) for 1997–2007, 2008–2018, and as the whole 1997–2018 period, has been compared to …the AD prevalence for 2018 expressed in percentage of the population and statistically analyzed by Pearson calculation. Results: A significant positive correlation has been found between the AD prevalence (2018) and the average quinolone consumption for the years 1997–2007 (r : 0.37, p : 0.044). A similar association was not observed for the entire 22 years (1997–2018) of the average quinolone consumption, and the years 2008–2018, indicating 10–20 years of time-lapse between the antibiotic exposure and the development of AD. The ratio of broad-spectrum and narrow-spectrum antibiotics (B/N) estimated in the ECDC database for the years of 2008–2018 showed a strong positive association with AD prevalence (2018) (r : 0.406, p : 0.026) and a positive correlation tendency for the entire 22 years 1997–2018 (r : 0.344, p : 0.063), but none for the years 1997–2007 (r : 0.256, p : 0.241). Conclusion: Our study indicated the possible sequential role of certain classes of antibiotics in the development of dysbiosis leading to amyloid deposits of AD, which strengthen the possible role of different mediator molecules (short-chain fatty acids, lipopolysaccharides, etc.) produced by the altered microbiome in the development of AD. Show more

Keywords: Alzheimer’s disease, antibiotic consumption, dementia, dysbiosis, gut-brain axis, gut flora, mediator molecules

DOI: 10.3233/JAD-220018

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 443-451, 2022

Authors: Meysami, Somayeh | Raji, Cyrus A. | Mendez, Mario F.

Article Type: Research Article

Abstract: Background: The differentiation of behavioral variant frontotemporal dementia (bvFTD) from early-onset Alzheimer’s disease (EOAD) by clinical criteria can be inaccurate. The volumetric quantification of clinically available magnetic resonance (MR) brain scans may facilitate early diagnosis of these neurodegenerative dementias. Objective: To determine if volumetric quantification of brain MR imaging can identify persons with bvFTD from EOAD. Methods: 3D T1 MR brain scans of 20 persons with bvFTD and 45 with EOAD were compared using Neuroreader to measure subcortical, and lobar volumes, and Volbrain for hippocampal subfields. Analyses included: 1) discriminant analysis with leave one out cross-validation; …2) input of predicted probabilities from this process into a receiver operator characteristic (ROC) analysis; and 3) Automated linear regression to identify predictive regions. Results: Both groups were comparable in age and sex with no statistically significant differences in symptom duration. bvFTD had lower volume percentiles in frontal lobes, thalamus, and putamen. EOAD had lower parietal lobe volumes. ROC analyses showed 99.3% accuracy with Neuroreader percentiles and 80.2% with subfields. The parietal lobe was the most predictive percentile. Although there were differences in hippocampal (particularly left CA2-CA3) subfields, it did not add to the discriminant analysis. Conclusion: Percentiles from an MR based volumetric quantification can help differentiate between bvFTD from EOAD in routine clinical care. Use of hippocampal subfield volumes does not enhance the diagnostic separation of these two early-onset dementias. Show more

Keywords: Behavioral variant frontal temporal dementia, early-onset Alzheimer’s disease, volumetric MRI

DOI: 10.3233/JAD-215667

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 453-461, 2022

Authors: Huang, Shu-Yi | Yang, Yu-Xiang | Zhang, Ya-Ru | Kuo, Kevin | Li, Hong-Qi | Shen, Xue-Ning | Chen, Shi-Dong | Chen, Ke-Liang | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Metabolomics is a promising approach that can be used to understand pathophysiological pathways of Alzheimer’s disease (AD). However, the causal relationships between metabolism and AD are poorly understood. Objective: We aimed to investigate the causal association between circulating metabolites and risk of AD through two-sample Mendelian randomization (MR) approach. Methods: Genetic associations with 123 circulating metabolic traits were utilized as exposures. Summary statistics data from International Genomics of Alzheimer’s Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was performed using family history of AD data from UK Biobank (27,696 …cases of maternal AD, 14,338 cases of paternal AD, and 272,244 controls). We utilized inverse-variance weighted method as primary method. Results: We found significantly increased risks of developing AD per standard deviation increase in the levels of circulating ApoB (odd ratio[OR] = 3.18; 95% confidence interval[CI]: 1.52–6.66, p  = 0.0022), glycoprotein acetyls (OR = 1.21; 95% CI: 1.05–1.39, p  = 0.0093), total cholesterol (OR = 2.73; 95% CI: 1.41–5.30, p  = 0.0030), and low-density lipoprotein (LDL) cholesterol (OR = 2.34; 95% CI: 1.53–3.57, p  = 0.0001). Whereas glutamine (OR = 0.81; 95% CI: 0.71–0.92, p  = 0.0011) were significantly associated with lower risk of AD. We also detected causal effects of several different composition of LDL fractions on increased AD risk, which has been verified in validation. However, we found no association between circulating high-density lipoprotein cholesterol and AD. Conclusion: Our findings suggest causal effects of circulating glycoprotein acetyls, ApoB, LDL cholesterol, and serum total cholesterol on higher risk of AD, whereas glutamine showed the protective effect. Show more

Keywords: Alzheimer’s disease, cholesterol, mendelian randomization, metabolite

DOI: 10.3233/JAD-220050

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 463-477, 2022

Authors: Soo, See Ann | Zailan, Fatin Zahra | Tan, Jayne Yi | Sandhu, Gurveen Kaur | Wong, Benjamin Yi Xin | Wang, Brian Zhiyang | Ng, Adeline Su Lyn | Chiew, Hui Jin | Ng, Kok Pin | Kandiah, Nagaendran

Article Type: Research Article

Abstract: Background: Young-onset cognitive disorders (YOCD) often manifests with complex and atypical presentations due to underlying heterogenous pathologies. Therefore, a biomarker-based evaluation will allow for timely diagnosis and definitive management. Objective: Here, we evaluated the safety and usefulness of cerebrospinal fluid (CSF) sampling through lumbar puncture (LP) in YOCD patients in a tertiary clinical setting. Methods: Patients with mild cognitive impairment (MCI) and mild dementia with age of onset between 45-64 years were evaluated. Patients underwent magnetic resonance imaging and their medial temporal lobe atrophy (MTA) was rated. LP side-effects and the impact of the CSF findings …on diagnosis and management were analyzed. Results: 142 patients (53 (37.32%) MCI, 51 (35.92%) dementia of the Alzheimer’s disease [DAT] type, and 38 (26.76%) non-AD type dementia) who underwent LP between 2015 to 2021 were analyzed. Using post-LP results and MTA ratings, 74 (52.11%) patients met the AT(N) criteria for AD. 56 (39.44%) patients (28 out of 53 (50.0%) MCI, 12 out of 51 (21.43%) DAT, and 16 out of 38 (28.57%) non-AD dementia) had a change in diagnosis following LP. 13 (9.15%) patients developed side-effects post-LP (11 (84.62%) patients had headache, 1 (7.69%) patient had backache, and 1 (7.69%) patient had headache and backache). 32 (22.54%) patients had a change in management post-LP, 24 (75.0%) had medication changes, 10 (31.30%) had referrals to other specialists, and 3 (9.40%) was referred for clinical trial with disease modifying interventions. Conclusion: LP is well-tolerated in YOCD and can bring about relevant clinical decisions with regards to the diagnosis and management of this complex clinical condition. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, dementia, lumbar puncture, mild cognitive impairment, post-LP complications, young-onset cognitive disorders

DOI: 10.3233/JAD-215453

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 479-488, 2022

Authors: Murchison, Charles F. | Jaeger, Byron C. | Szychowski, Jeff M. | Cutter, Gary R. | Roberson, Erik D. | Kennedy, Richard E.

Article Type: Research Article

Abstract: Background: Accurate longitudinal modelling of cognitive decline is a major goal of Alzheimer’s disease and related dementia (ADRD) research. However, the impact of subject-specific effects is not well characterized and may have implications for data generation and prediction. Objective: This study seeks to address the impact of subject-specific effects, which are a less well-characterized aspect of ADRD cognitive decline, as measured by the Alzheimer’s Disease Assessment Scale’s Cognitive Subscale (ADAS-Cog). Methods: Prediction errors and biases for the ADAS-Cog subscale were evaluated when using only population-level effects, robust imputation of subject-specific effects using model covariances, and directly …known individual-level effects fit during modelling as a natural control. Evaluated models included pre-specified parameterizations for clinical trial simulation, analogous mixed-effects regression models parameterized directly, and random forest ensemble models. Assessment used a meta-database of Alzheimer’s disease studies with validation in simulated synthetic cohorts. Results: All models observed increases in variance under imputation leading to increased prediction error. Bias decreased with imputation except under the pre-specified parameterization, which increased in the meta-database, but was attenuated under simulation. Known fitted subject effects gave the best prediction results. Conclusion: Subject-specific effects were found to have a profound impact on predicting ADAS-Cog. Reductions in bias suggest imputing random effects assists in calculating results on average, as when simulating clinical trials. However, reduction in error emphasizes population-level effects when attempting to predict outcomes for individuals. Forecasting future observations greatly benefits from using known subject-specific effects. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, forecasting, mental status and dementia tests, statistical models

DOI: 10.3233/JAD-215553

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 489-501, 2022