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

Authors: Wang, Xiaonan | Li, Fengjie | Gao, Qi | Jiang, Zhen | Abudusaimaiti, Xiayidanmu | Yao, Jiangyue | Zhu, Huiping

Article Type: Research Article

Abstract: Background: Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) are neuropsychological tests commonly used by physicians for screening cognitive dysfunction of Alzheimer’s disease (AD). Due to different imperfect reference standards, the performance of MoCA and MMSE do not reach consensus. It is necessary to evaluate the consistence and differentiation of MoCA and MMSE in the absence of a gold standard for AD. Objective: We aimed to assess the accuracy of MoCA and MMSE in screening AD without a gold standard reference test. Methods: Studies were identified from PubMed, Web of Science, CNKI, Chinese Wanfang Database, …China Science and Technology Journal Database, and Cochrane Library. Our search was limited to studies published in English and Chinese before August 2021. A hierarchical Bayesian latent class model was performed in meta-analysis when the gold standard was absent. Results: A total of 67 studies comprising 5,554 individuals evaluated for MoCA and 76,862 for MMSE were included in this meta-analysis. The pooled sensitivity was 0.934 (95% CI 0.905 to 0.954) for MoCA and 0.883 (95% CI 0.859 to 0.903) for MMSE, while the pooled specificity was 0.899 (95% CI 0.859 to 0.928) for MoCA and 0.903 (95% CI 0.879 to 0.923) for MMSE. MoCA was useful to rule out dementia associated with AD with lower negative likelihood ratio (LR-) (0.074, 95% CI 0.051 to 0.108). MoCA showed better performance with higher diagnostic odds ratio (DOR) (124.903, 95% CI 67.459 to 231.260). Conclusion: MoCA had better performance than MMSE in screening dementia associated with AD from patients with mild cognitive impairment or healthy controls. Show more

Keywords: Alzheimer’s disease, meta-analysis, Mini-Mental State Examination, Montreal Cognitive Assessment, sensitivity, specificity

DOI: 10.3233/JAD-215394

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 285-304, 2022

Authors: Ashford, J. Wesson | Schmitt, Frederick A. | Bergeron, Michael F. | Bayley, Peter J. | Clifford, James O. | Xu, Qun | Liu, Xiaolei | Zhou, Xianbo | Kumar, Vinod | Buschke, Herman | Dean, Margaret | Finkel, Sanford I. | Hyer, Lee | Perry, George

Article Type: Article Commentary

Abstract: Wang et al. analyze Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment accuracy as screening tests for detecting dementia associated with Alzheimer’s disease (AD). Such tests are at the center of controversy regarding recognition and treatment of AD. The continued widespread use of tools such as MMSE (1975) underscores the failure of advancing cognitive screening and assessment, which has hampered the development and evaluation of AD treatments. It is time to employ readily available, efficient computerized measures for population/mass screening, clinical assessment of dementia progression, and accurate determination of approaches for prevention and treatment of AD and related conditions.

Keywords: Alzheimer’s disease, cognition assessment, computerized testing, MemTrax, Mini-Mental State Examination, Montreal Cognitive Assessment, neuroplasticity

DOI: 10.3233/JAD-220211

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 305-315, 2022

Authors: Luppi, Janne J. | Schoonhoven, Deborah N. | van Nifterick, Anne M. | Gouw, Alida A. | Hillebrand, Arjan | Scheltens, Philip | Stam, Cornelis J. | de Haan, Willem

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease (AD), oscillatory activity of the human brain slows down. However, oscillatory slowing varies between individuals, particularly in prodromal AD. Cortical oscillatory changes have shown suboptimal accuracy as diagnostic markers. We speculated that focusing on the hippocampus might prove more successful, particularly using magnetoencephalography (MEG) for capturing subcortical oscillatory activity. Objective: We explored MEG-based detection of hippocampal oscillatory abnormalities in prodromal AD patients. Methods: We acquired resting-state MEG data of 18 AD dementia patients, 18 amyloid-β-positive amnestic mild cognitive impairment (MCI, prodromal AD) patients, and 18 amyloid-β-negative persons with subjective cognitive decline (SCD). …Oscillatory activity in 78 cortical regions and both hippocampi was reconstructed using beamforming. Between-group and hippocampal-cortical differences in spectral power were assessed. Classification accuracy was explored using ROC curves. Results: The MCI group showed intermediate power values between SCD and AD, except for the alpha range, where it was higher than both (p  < 0.05 and p  < 0.001). The largest differences between MCI and SCD were in the theta band, with higher power in MCI (p  < 0.01). The hippocampi showed several unique group differences, such as higher power in the higher alpha band in MCI compared to SCD (p  < 0.05). Classification accuracy (MCI versus SCD) was best for absolute theta band power in the right hippocampus (AUC = 0.87). Conclusion: In this MEG study, we detected oscillatory abnormalities of the hippocampi in prodromal AD patients. Moreover, hippocampus-based classification performed better than cortex-based classification. We conclude that a focus on hippocampal MEG may improve early detection of AD-related neuronal dysfunction. Show more

Keywords: Alzheimer’s disease, dementia, hippocampus, magnetoencephalography, mild cognitive impairment, spectral analysis

DOI: 10.3233/JAD-215464

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 317-333, 2022

Authors: Cao, Min | Liu, Jing | Zhang, Xiaomin | Yang, Tingting | Wang, Yaqi | Hou, Yuli | Song, Qiao | Cui, Yuting | Wang, Yifei | Wang, Peichang

Article Type: Research Article

Abstract: Background: The Abi3 gene has been suggested to be an important regulator of microglia during Alzheimer’s disease (AD), but the diagnostic power of ABI3 in neurodegenerative disease has rarely been reported. Objective: The aim of this study was to evaluate the diagnostic value of ABI3 in AD patients. Methods: ELISAs were used to measure the ABI3 level in the serum and cerebrospinal fluid (CSF) of AD patients as well as in the serum of APP/PS1 mice. RT-PCR and western blot were further performed to detect the expression levels of ABI3 in peripheral blood mononuclear …cells (PBMCs) of AD subjects as well as in the hippocampus and cortical tissue of APP/PS1 mice. The correlation of cognitive ability with ABI3 level was estimated by linear regression analysis. Moreover, the diagnostic value of ABI3 for AD was assessed with ROC analysis. Results: The ABI3 levels all decreased significantly in the serum, CSF, and PBMCs of AD patients and showed a good diagnostic performance. In addition, the ABI3 levels were observed to decrease markedly in the hippocampus from 5-month-old mice, but the dramatic change only appeared in the cortical tissue in the 9-month-old APP/PS1 mice. The ABI3 levels in serum and in the hippocampus of APP/PS1 mice were significantly correlated with cognitive capacity. Conclusion: These results demonstrated that ABI3 in serum, CSF, and PBMCs could be a novel early diagnostic biomarker of AD. Moreover, ABI3 had potential to be a novel tracer marker in hippocampus of early AD. Show more

Keywords: ABI3, Alzheimer’s disease, biomarker, dementia of Alzheimer type, mild cognitive impairment

DOI: 10.3233/JAD-215635

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 335-344, 2022

Authors: Smith, Patrick J. | Sherwood, Andrew | Hinderliter, Alan L. | Mabe, Stephanie | Tyson, Crystal | Avorgbedor, Forgive | Watkins, Lana L. | Lin, Pao-Hwa | Kraus, William E. | Blumenthal, James A.

Article Type: Research Article

Abstract: Background: Impaired cerebrovascular reactivity (CVR) and blunted cerebral hemodynamic recruitment are thought to be important mechanisms linking hypertension to cerebrovascular and cognitive outcomes. Few studies have examined cardiovascular or dietary correlates of CVR among hypertensives. Objective: To delineate associations between cardiometabolic risk, diet, and cerebrovascular functioning among individuals with resistant hypertension from the TRIUMPH trial (n  = 140). Methods: CVR was assessed by examining changes in tissue oxygenation (tissue oxygenation index [TOI] and oxygenated hemoglobin [HBO2 ]) using functional near-infrared spectroscopy (fNIRS) during a breath holding test, a standardized CVR assessment to elicit a hypercapnic response. Participants …also underwent fNIRS during three cognitive challenge tasks. Vascular function was assessed by measurement of brachial artery flow-mediated dilation and hyperemic flow response. Cardiometabolic fitness was assessed from peak VO2 on an exercise treadmill test and body mass index. Dietary patterns were quantified using the DASH eating score. Cognitive function was assessed using a 45-minute test battery assessing Executive Function, Processing Speed, and Memory. Results: Greater levels fitness (B  = 0.30, p  = 0.011), DASH compliance (B  = 0.19, p  = 0.045), and lower obesity (B  = –0.30, p  = 0.004), associated with greater changes in TOI, whereas greater flow-mediated dilation (B  = 0.19, p  = 0.031) and lower stroke risk (B  = –0.19, p  = 0.049) associated with greater HBO2 . Similar associations were found for cerebral hemodynamic recruitment, and associations between CVR and cognition were moderated by duration of hypertension. Conclusion: Impaired CVR elevated cardiometabolic risk, obesity, vascular function, and fitness among hypertensives. Show more

Keywords: Cerebrovascular reactivity, cognitive function, resistant hypertension, vascular endothelial function

DOI: 10.3233/JAD-215522

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 345-357, 2022

Authors: de Oliveira, Fabricio Ferreira | Bertolucci, Paulo Henrique Ferreira | Chen, Elizabeth Suchi | Smith, Marilia Cardoso

Article Type: Research Article

Abstract: Background: Pharmacogenetic effects of statins on clinical changes in Alzheimer’s disease (AD) could be mediated by epistatic interactions among relevant genetic variants involved in cholesterol metabolism. Objective: To investigate associations of HMGCR (rs3846662), NR1H2 (rs2695121), or CETP (rs5882&rs708272) with cognitive and functional changes in AD, with stratification according to APOE ɛ 4 carrier status and lipid-lowering treatment with lipophilic statins. Methods: Consecutive outpatients with late-onset AD were screened with cognitive tests, while caregivers scored functionality and global ratings, with prospective neurotranslational associations documented for one year. Results: Considering n  = 190:142 …had hypercholesterolemia, 139 used lipophilic statins; minor allele frequencies were 0.379 (rs2695121-T:46.3% heterozygotes), 0.368 (rs5882-G:49.5% heterozygotes), and 0.371 (rs708272-A:53.2% heterozygotes), all in Hardy-Weinberg equilibrium. For APOE ɛ 4 carriers: rs5882-GG protected from cognitive decline; rs5882-AA caused faster cognitive decline; carriers of rs2695121-CC or rs5882-AA were more susceptible to harmful cognitive effects of lipophilic statins; carriers of rs5882-GG or rs708272-AG had functional benefits when using lipophilic statins. APOE ɛ 4 non-carriers resisted any cognitive or functional effects of lipophilic statins, while invariability of rs3846662 (all AA) prevented the assessment of HMGCR effects. When assessing CETP haplotypes only: rs5882-GG protected from cognitive and functional decline, regardless of lipophilic statin therapy; lipophilic statins usually caused cognitive and functional harm to carriers of rs5882-A and/or rs708272-A; lipophilic statins benefitted cognition and functionality of carriers of rs5882-G and/or rs708272-G. Conclusion: Reportedly protective variants of CETP and NR1H2 also slowed cognitive and functional decline particularly for APOE ɛ 4 carriers, and regardless of cholesterol variations, while therapy with lipophilic statins might affect carriers of specific genetic variants. Show more

Keywords: Alzheimer’s disease, dementia, drug therapy, hydroxymethylglutaryl-CoA reductase inhibitors, neuropsychiatry, pharmacogenetics

DOI: 10.3233/JAD-215735

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 359-372, 2022

Authors: Dharmaraj, Gowdame Lakshmanan | Arigo, Fraulein Denise | Young, Kimberly A. | Martins, Ralph | Mancera, Ricardo L. | Bharadwaj, Prashant

Article Type: Research Article

Abstract: Background: Type 2 diabetes related human islet amyloid polypeptide (hIAPP) plays a dual role in Alzheimer’s disease (AD). hIAPP has neuroprotective effects in AD mouse models whereas, high hIAPP concentrations can promote co-aggregation with amyloid-β (Aβ) to promote neurodegeneration. In fact, both low and high plasma hIAPP concentration has been associated with AD. Therefore, non-aggregating hIAPP analogues have garnered interest as a treatment for AD. The aromatic amino acids F23 and I26 in hIAPP have been identified as the key residues involved in self-aggregation and Aβ cross-seeding. Objective: Three novel IAPP analogues with single and double alanine mutations …(A1 = F23, A2 = I26, and A3 = F23 + I26) were assessed for their ability to aggregate, modulate Aβ oligomer formation, and alter neurotoxicity. Methods: A range of biophysical methods including Thioflavin-T, gel electrophoresis, photo-crosslinking, circular dichroism combined with cell viability assays were utilized to assess protein aggregation and toxicity. Results: All IAPP analogues showed significantly less self-aggregation than hIAPP. Co-aggregated Aβ42 -A2 and A3 also showed reduced aggregation compared to Aβ42 -hIAPP mixtures. Self- and co-oligomerized A1, A2, and A3 exhibited random coil conformations with reduced beta sheet content compared to hIAPP and Aβ42 -hIAPP aggregates. A1 was toxic at high concentrations compared to A2 and A3. However, co-aggregated Aβ42 -A1, A2, or A3 showed reduced neurotoxicity compared to Aβ42 , hIAPP, and Aβ42 -hIAPP aggregates. Conclusion: These findings confirm that hIAPP analogues with non-aromatic residues at positions 23 and 26 have reduced self-aggregation and the ability to neutralize Aβ42 toxicity. This warrants further characterization of their protective effects in pre-clinical AD models. Show more

Keywords: Aggregation, Alzheimer’s disease, amylin analogue, amyloid-beta, human islet amyloid polypeptide (hIAPP)

DOI: 10.3233/JAD-215339

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 373-390, 2022

Authors: Shim, YongSoo | Han, Hyun Jeong | Park, Kyung Won | Kim, Byeong C. | Park, Kee Hyung | Park, Mee Young | Kim, Hee-Jin | Moon, So Young | Choi, Seong Hye | Park, Kun Woo | Yang, Dong Won | Yoon, Soo Jin | Kim, Sang Yun | Youn, Young Chul | Choi, Hojin | Yoon, Koung Eun | Cho, Hyun Ju | Han, Seol-Heui

Article Type: Research Article

Abstract: Background: Preclinical studies in transgenic models of Alzheimer’s disease (AD) suggest that DHP1401 has neuroprotective and memory-enhancing effects. Objective: To evaluate the efficacy and safety of DHP1401 in AD patients treated with donepezil Methods: Methods: In a double-blind study, patients with mild-to-moderate AD were randomized (1:1:1) to receive a twice daily total dose of 500 mg or 1000 mg DHP1401 or placebo for 24 weeks. Tolerability and safety were monitored at baseline and weeks 12 and 24. Results: total of 180 patients were randomized to Active 1 (500 mg: n  = 62), Active 2 (1000 …mg: n  = 53), and control groups (n  = 65) in 16 sites in Korea. There was no significant difference in the Alzheimer’s Disease Assessment Scale (ADAS-cog) score, the primary efficacy endpoint, from baseline. However, in the subgroup with mild AD patients (MMSE, 20–26) who received the high dose of DHP1401 and the group that received donepezil 5 mg, the ADAS-cog scores improved. MMSE and K-TMT-e type B were significant in both active groups at week 24. The most frequently observed symptom was dizziness (2.78%), and the most commonly observed reactions were related to metabolism and nutrition disorders (5.00%). No remarkable adverse events were observed for 24 weeks. Conclusion: Although the effectiveness of DHP1401 was not proved to be superior as the primary efficacy endpoint, the secondary endpoints, MMSE and K-TMT-e type B, showed significant beneficial effects. Also, the subgroups showed that ADAS-cog scores significantly were improved. DHP1401 could be proven beneficial for the AD treatment by further clinical trials. Show more

Keywords: Alzheimer’s disease, DHP1401, mild to moderate AD, randomized placebo-controlled clinical trial

DOI: 10.3233/JAD-215277

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 391-403, 2022

Authors: Verdelho, Ana | Correia, Manuel | Ferro, José Manuel | Madureira, Sofia | Vilela, Pedro | Rodrigues, Mário | Borges, Mariana | Oliveira, Vanessa | Santos, Ana Catarina | Gonçalves-Pereira, Manuel | Santa-Clara, Helena

Article Type: Research Article

Abstract: Background: The World Health Organization (WHO) recommends a minimum of 150 minutes of moderate physical activity per week. Adherence to these recommendations is difficult to assess. Objective: We aimed to evaluate the validity of self-reported physical activity in mild vascular cognitive impairment (mVCI) and whether physical activity was associated with cognitive status, by using baseline data from a randomized controlled trial. Methods: A hundred and four subjects with mVCI were included (mean age 72 years; 51% women). Subjects underwent neurological, physical, and comprehensive neuropsychological assessments. Adherence to WHO physical activity recommendations was evaluated using both self-reported …information and objective measures (accelerometry). Results: There was poor agreement (kappa = 0.106) between self-report of following WHO recommendations and actually fulfilling them according to accelerometry. Only 16.6% of participants reported following WHO recommendations and displayed compatible values according to the accelerometer. Participants whose accelerometry values confirmed adherence to WHO recommendations had better performance in a global measure of cognition, attention, and mental speed processing. In multiple regression analyses, education and accelerometry values in accordance with WHO recommendations were independently associated with the global measure of cognition, attention, and processing speed, controlling for sex, age, and depressive symptoms. Accelerometry results were not associated with memory and executive functions. Conclusion: In this sample of mVCI subjects, self-reported physical activity displayed poor agreement with accelerometry values, suggesting that objective measures of physical activity are preferable. Physical activity (performed, at least, according to WHO recommendations) was associated with better cognitive performance overall. Show more

Keywords: Accelerometry, cognition, dementia, prevention

DOI: 10.3233/JAD-215381

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 405-414, 2022

Authors: Du, Xianglin L. | Song, Lulu | Schulz, Paul E. | Xu, Hua | Chan, Wenyaw

Article Type: Research Article

Abstract: Background: No study on the long-term incidence of Alzheimer’s disease (AD) and related dementias (ADRD) has been reported in women with breast cancer by vascular diseases. Objective: To determine the risk of ADRD in association with cardiovascular diseases (CVD), stroke, hypertension, and diabetes in women with breast cancer. Methods: Study identified 246,686 women diagnosed with breast cancer at age≥65 years in 1991–2015 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Women were free of ADRD at the time of cancer diagnosis and followed from 1991 to 2016. Results: Cumulative incidence of AD …over 26 years of follow-up varied from 10.7% to 13.6% by CVD, stroke, hypertension, and diabetes. Cumulative incidence of ADRD was higher in those with CVD (40.75%) versus no-CVD (31.32%), stroke (40.24%) versus no-stroke (31.34%), hypertension (33.06%) versus no-hypertension (30.47%), and diabetes (33.38%) versus no-diabetes (31.77%). After adjusting for confounders, those with CVD (hazard ratio:1.30, 95% CI: 1.27–1.33), stroke (1.50,1.47–1.54), hypertension (1.08,1.06–1.09), and diabetes (1.26,1.24–1.29) had significantly higher risks of developing ADRD. Women aged 80–84, and≥85 had 5- and 7-fold higher risks of AD than those aged 65–69. As compared to white women, black women had a significantly higher risk of AD (1.21, 1.16–1.27), whereas Asians/Pacific-Islanders had a significantly lower risk of AD (0.77, 0.71–0.83). Conclusion: In women with breast cancer, CVD, stroke, hypertension, and diabetes were associated with a significantly higher risk of developing any ADRD combined. The risk of ADRD was higher in black women and lower in Asian/Pacific-Islanders than white women. Show more

Keywords: Alzheimer’s disease, breast cancer, dementias, medicare, vascular diseases

DOI: 10.3233/JAD-215657

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 415-432, 2022

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