Journal of Alzheimer's Disease - Volume 88, issue 2

Authors: Hannonen, Sanna | Andberg, Sami | Kärkkäinen, Virve | Rusanen, Minna | Lehtola, Juha-Matti | Saari, Toni | Korhonen, Ville | Hokkanen, Laura | Hallikainen, Merja | Hänninen, Tuomo | Leinonen, Ville | Kaarniranta, Kai | Bednarik, Roman | Koivisto, Anne M.

Article Type: Research Article

Abstract: Background: Wide-ranging functional defects in eye movements have been reported in Alzheimer’s disease (AD) dementia. The detection of abnormal eye movements and reading problems may identify persons at risk of AD when clear clinical symptoms are lacking. Objective: To examine whether computer-based eye-tracking (ET) analysis of King-Devick (KD) test results differentiates cognitively healthy persons from persons with minor problems in cognitive testing or diagnosed mild AD. Methods: We recruited 78 participants (57 non-demented, 21 with mild AD) who underwent neurological examination, the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological test battery (CERAD-NB), and a …Clinical Dementia Rating (CDR) interview. The non-demented participants were further divided into control (normal CERAD subtests, mean MMSE = 28) and objective mild cognitive impairment (MCI; decline in at least one CERAD memory score, mean MMSE = 27) groups. The KD reading test was performed using computer-based ET. The total time used for the reading test, errors made, fixation and saccade durations, and saccade amplitudes were analyzed. Results: We found significant differences between the control, objective MCI, and AD groups in regard to the mean saccade amplitude (3.58, 3.33, and 3.21 ms, respectively, p  < 0.03) and duration (27.1, 25.3, and 24.8 ms, respectively, p  < 0.05). The KD error scores in the AD group differed significantly (p  < 0.01) from the other groups. Conclusion: Computed ET analysis of the KD test may help detect persons with objective MCI early when clear clinical symptoms are lacking. The portable device for ET is easy to use in primary health care memory clinics. Show more

Keywords: Alzheimer’s disease, biomarker, CERAD, eye tracking, King-Devick, mild cognitive impairment, saccadic eye movements

DOI: 10.3233/JAD-215551

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 609-618, 2022

Authors: Huda, Taha I. | Diaz, Michael J. | Gozlan, Etienne C. | Chobrutskiy, Andrea | Chobrutskiy, Boris I. | Blanck, George

Article Type: Research Article

Abstract: Background: Despite the fact that only modest adaptive immune system related approaches to treating Alzheimer’s disease (AD) are available, an immunogenomics approach to the study of AD has not yet substantially advanced. Objective: Thus, we sought to better understand adaptive immune receptor chemical features in the AD setting. Methods: We characterized T-cell receptor alpha (TRA) complementarity determining region-3 (CDR3) physicochemical features and identified TRA CDR3 homology groups, represented by TRA recombination reads extracted from 2,665 AD-related, blood- and brain-derived exome files. Results: We found that a higher isoelectric value for the brain TRA CDR3s …was associated with a higher (clinically worse) Braak stage and that a number of TRA CDR3 chemical homology groups, in particular representing bloodborne TRA CDR3s, were associated with higher or lower Braak stages. Lastly, greater chemical complementarity of both blood- and brain-derived TRA CDR3s and tau, based on a recently described CDR3-candidate antigen chemical complementarity scoring process (https://adaptivematch.com ), was associated with higher Braak stages. Conclusion: Overall, the data reported here raise the questions of (a) whether progression of AD is facilitated by the adaptive immune response to tau; and (b) whether assessment of such an anti-tau immune response could potentially serve as a basis for adaptive immune receptor related, AD risk stratification? Show more

Keywords: Alzheimer’s Disease Sequencing Project (ADSP), Braak stages, blood and brain sample exomes, CDR3-tau chemical complementarity, T-cell receptor recombination reads

DOI: 10.3233/JAD-220119

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 619-629, 2022

Authors: Jacob, Louis | Smith, Lee | Koyanagi, Ai | Konrad, Marcel | Haro, Josep Maria | Shin, Jae Il | Kostev, Karel

Article Type: Research Article

Abstract: Background: Little is known about the sex differences in the association between body mass index (BMI) and dementia in late life. Objective: Therefore, this retrospective cohort study aimed to analyze associations between BMI and dementia in older women and men separately in general practices in Germany. Methods: This study included patients followed in one of 832 general practices in Germany between 2006 and 2019 (index date: first visit date). Study variables included dementia (dependent variable), BMI (independent variable), age, sex, and comorbidities (control variables). Kaplan-Meier curves and adjusted Cox regression analyses were conducted to analyze associations …between BMI and the 10-year incidence of dementia in women and men, separately. Results: There were 296,767 patients included in this study (mean [standard deviation] age 70.2 [5.9] years; 54.3% women). The proportion of underweight, normal weight, overweight, and obesity was 0.9%, 25.5%, 41.5%, and 32.1%, respectively. The 10-year incidence of dementia significantly decreased with increasing BMI, from 11.5% in women with underweight to 9.1% in those with obesity (log-rank p  < 0.001). Respective figures in men were 12.0% and 8.2% (log-rank p  < 0.001). In women, only overweight (versus normal weight) was significantly associated with dementia (HR = 0.93, 95% CI = 0.88–0.97). In contrast, in men, the only BMI category significantly associated with the incidence of dementia was underweight (HR = 1.58, 95% CI = 1.11–2.25). Conclusion: In this study conducted in Germany, overweight was negatively associated with dementia in women, whereas there was a positive underweight-dementia relationship in men. More data are needed to confirm or refute these findings in other settings. Show more

Keywords: Body mass index, dementia, Germany, retrospective cohort study, sex differences

DOI: 10.3233/JAD-220147

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 631-639, 2022

Authors: Sun, Lin | Guo, Chunni | Song, Yan | Sheng, Jianhua | Xiao, Shifu | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Bone morphogenetic protein (BMP) plays important roles in the pathology of Alzheimer’s disease (AD). Objective: We sought blood BMP6 involved in the processes underlying cognitive decline and detected them in association with AD. Methods: A total of 309 participants in Shanghai Mental Health Center (SMHC) and 547 participants in Alzheimer’s disease Neuroimaging Initiative (ADNI) cohort were included. Blood BMP6 and cognitive functions were measured in all subjects of both cohorts at baseline, and in 482 subjects of ADNI cohort after one year. A total of 300 subjects in ADNI cohort were detected cerebrospinal fluid (CSF) …tau biomarker, and 244 received 1-year follow-up. Results: AD patients had lower levels of blood BMP6 compared to normal controls, and BMP6 was positively associated with cognitive functions. Longitudinal BMP6 combing with APOE genotype could distinguish probable AD from normal controls. The influence of blood BMP6 on cognition was modulated by tau pathology. Conclusion: Blood BMP6 was associated with cognitive performance and identified as a potential predictor for probable AD. Show more

Keywords: Alzheimer’s disease, APOE, BMP6, mild cognitive impairment, prediction, tau pathology

DOI: 10.3233/JAD-220279

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 641-651, 2022

Authors: Agarwal, Puja | Holland, Thomas M. | James, Bryan D. | Cherian, Laurel J. | Aggarwal, Neelum T. | Leurgans, Sue E. | Bennett, David A. | Schneider, Julie A.

Article Type: Research Article

Abstract: Background: An anthocyanidin, pelargonidin, primarily found in berries, has antioxidant and anti-inflammatory properties, and is associated with better cognition and reduced Alzheimer’s dementia risk. Objective: This study investigated if pelargonidin or berry intake is associated with Alzheimer’s disease (AD) neuropathology in human brains. Methods: The study was conducted among 575 deceased participants (age at death = 91.3±6.1 years; 70% females) of the Rush Memory and Aging Project, with dietary data (assessed using a food frequency questionnaire) and neuropathological evaluations. Calorie-adjusted pelargonidin intake was modeled in quartiles and berry intake as continuous (servings/week). Mean amyloid-beta load and phosphorylated tau …neuronal neurofibrillary tangle density across multiple cortical regions were assessed using immunohistochemistry. Global AD pathology burden, a quantitative summary score of neurofibrillary tangles, and diffuse and neuritic plaques using Bielschowsky silver stains in multiple brain regions, was also assessed. Results: In a linear regression model adjusted for age at death, sex, education, APOE ɛ4 status, vitamin E, and vitamin C, participants in the highest quartile of pelargonidin intake when compared to those in the lowest quartile, had less amyloid-β load (β (SE) = –0.293 (0.14), p  = 0.038), and fewer phosphorylated tau tangles (β (SE) = –0.310, p  = 0.051). Among APOE ɛ4 non-carriers, higher strawberry (β (SE) = –0.227 (0.11), p  = 0.037) and pelargonidin (Q4 versus Q1: β (SE) = –0.401 (0.16), p  = 0.011; p trend = 0.010) intake was associated with less phosphorylated tau tangles, no association was observed in APOE ɛ4 carriers. Berry intake was not associated with AD pathology. However, excluding participants with dementia or mild cognitive impairment at baseline, strawberry (p  = 0.004) and pelargonidin (ptrend = 0.007) intake were associated with fewer phosphorylated tau tangles. Conclusion: Higher intake of pelargonidin, a bioactive present in strawberries, is associated with less AD neuropathology, primarily phosphorylated tau tangles. Show more

Keywords: Alzheimer’s disease pathology, anthocyanidin, berries, pelargonidin

DOI: 10.3233/JAD-215600

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 653-661, 2022

Authors: Schein, Jeff | Houle, Christy R. | Urganus, Annette L. | Jones, Eddie | Pike, James | Husbands, Joseph | Willey, Cynthia J.

Article Type: Research Article

Abstract: Background: Dementia patients frequently depend on caregivers. Agitation is a common behavioral dementia symptom particularly burdensome to patients and caregivers. Objective: To assess the association of agitation severity with non-professional caregiver hours, burden, health status, and productivity. Secondarily, to assess the association of agitation severity with these outcomes for patients receiving remote (not living with the patient) and proximate (living with the patient) caregiving. Methods: A retrospective analysis of physician and non-professional caregiver-reported data from a US point-in-time survey. Patients were aged ≥50 years, with early cognitive impairment or dementia. Regression analyses compared outcomes by agitation …severity; covariates included age, sex, and clinical characteristics. Results: Data were included for 1,349 patients (non-agitated n  = 656, agitated n  = 693; no care n  = 305, remote care n  = 248, proximate care n  = 691; unknown care n  = 105). Greater agitation was significantly associated (p  < 0.05) in all caregivers with increasing: Zarit Burden Interview (ZBI) Total Caregiver Burden, Personal Strain, Role Strain, and Guilt; Work Productivity and Activity Index (WPAI) presenteeism, overall work impairment, and total activity impairment. Higher ZBI Total Caregiver Burden, Personal Strain, and Role Strain were associated with greater agitation in proximate caregivers and higher ZBI Guilt associated with greater agitation in remote caregivers (p  < 0.05). Higher WPAI presenteeism and total activity impairment were associated (p  < 0.05) with greater agitation in proximate caregivers. Caregiving hours increased with increasing agitation for proximate caregiving (p  = 0.001). Conclusion: Greater agitation severity was associated with higher caregiver burden and lower productivity, with higher indirect costs a likely outcome of agitation. Show more

Keywords: Alzheimer’s disease, caregiver burden, cognitive impairment, dementia, real-world

DOI: 10.3233/JAD-215670

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 663-677, 2022

Authors: Gamble, Laura D. | Parker, Sophie | Quinn, Catherine | Bennett, Holly Q. | Martyr, Anthony | Sabatini, Serena | Pentecost, Claire | Collins, Rachel | Dawson, Eleanor | Hunt, Anna | Allan, Louise | Burns, Alistair | Litherland, Rachael | Victor, Christina | Matthews, Fiona E. | Clare, Linda

Article Type: Research Article

Abstract: Background: Social restriction measures imposed to curb the spread of COVID-19 in the United Kingdom impacted on carers of people with dementia, limiting access to support services and increasing perceived burden of caring. Few studies have compared data collected both during and before the pandemic to examine the effect of these changes. Objective: To explore whether the COVID-19 pandemic affected the well-being of carers of people with dementia living in the community, and their ability to cope with their caring responsibilities. Methods: Analysis was conducted on two groups of carers who were enrolled in the IDEAL …programme; the ‘pre-pandemic group’ (n  = 312), assessed at two time points prior to the pandemic, and the ‘pandemic group’, assessed prior to and several months into the pandemic (n  = 156). For the pre-pandemic group, carers were matched 2:1 to carers in the pandemic group on certain characteristics. Differences in change over time between the two groups on self-reported well-being, quality of life, coping, perceived competence, and role captivity, were investigated using mixed effect modelling. Results: Compared to the pre-pandemic group, those in the pandemic group appeared to cope better and had more stable self-rated competency and role captivity. They did not differ in terms of well-being or quality of life. Conclusions: Despite reports of negative impacts on carers early in the pandemic, the findings suggest the pandemic had little negative longer-term impact on carers of people with dementia, and in fact they appeared to have a more positive attitude towards coping several months into the pandemic. Show more

Keywords: Alzheimer’s disease, competence, coping, quality of life, role captivity, well-being

DOI: 10.3233/JAD-220221

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 679-692, 2022

Authors: Duan, Wenna | Sehrawat, Parshant | Zhou, Tony D. | Becker, James T. | Lopez, Oscar L. | Gach, H. Michael | Dai, Weiying

Article Type: Research Article

Abstract: Background: Biomarkers for Alzheimer’s disease (AD) are crucial for early diagnosis and treatment monitoring once disease modifying therapies become available. Objective: This study aims to quantify the forward magnetization transfer rate (k for ) map from brain tissue water to macromolecular protons and use it to identify the brain regions with abnormal k for in AD and AD progression. Methods: From the Cardiovascular Health Study (CHS) cognition study, magnetization transfer imaging (MTI) was acquired at baseline from 63 participants, including 20 normal controls (NC), 18 with mild cognitive impairment (MCI), and 25 AD …subjects. Of those, 53 participants completed a follow-up MRI scan and were divided into four groups: 15 stable NC, 12 NC-to-MCI, 12 stable MCI, and 14 MCI/AD-to-AD subjects. kfor maps were compared across NC, MCI, and AD groups at baseline for the cross-sectional study and across four longitudinal groups for the longitudinal study. Results: We found a lower kfor in the frontal gray matter (GM), parietal GM, frontal corona radiata (CR) white matter (WM) tracts, frontal and parietal superior longitudinal fasciculus (SLF) WM tracts in AD relative to both NC and MCI. Further, we observed progressive decreases of kfor in the frontal GM, parietal GM, frontal and parietal CR WM tracts, and parietal SLF WM tracts in stable MCI. In the parietal GM, parietal CR WM tracts, and parietal SLF WM tracts, we found trend differences between MCI/AD-to-AD and stable NC. Conclusion: Forward magnetization transfer rate is a promising biomarker for AD diagnosis and progression. Show more

Keywords: Alzheimer’s disease, magnetization transfer imaging, magnetization transfer rate, mild cognitive impairment

DOI: 10.3233/JAD-220335

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 693-705, 2022

Authors: García-Alberca, José María | Gris, Esther | de la Guía, Paz | Mendoza, Silvia

Article Type: Research Article

Abstract: Background: Depression is a common manifestation in Alzheimer’s disease (AD). In clinical practice, antidepressant medication is often used for depression in AD. Objective: We explore the effectiveness of the atypical antidepressant tianeptine compared with other conventional antidepressants in AD patients with depression in a real-life setting. Methods: We retrospectively identified 126 AD patients who had received antidepressant treatment for 12 months with tianeptine or other antidepressants. Subjects were divided into two groups according to the treatment they had received: tianeptine group (n  = 38) or other antidepressant group (n  = 88). Drug effects on depression, cognition, behavior, and …functional performance were evaluated at baseline, 6, and 12 months. A Mixed Effects Model Analysis was carried out to evaluate changes in performance scores. Results: Both tianeptine and other antidepressants showed an antidepressant effect after 12 months with significant improvement on the Cornell Scale for Depression in Dementia, the Hamilton Depression Rating Scale, and the Neuropsychiatric Inventory-Depression subscale. A statistically significant improvement at 12 months was shown in the tianeptine group versus the other antidepressants group on most of the cognitive measures such as the Mini-Mental State Examination, the Letter and Category Fluency Test, the Rey Auditory Verbal Learning Test, and the Boston Naming Test. Conclusion: Our results suggest that tianeptine reduces depressive symptoms and improves cognition in AD patients. This could be considered clinically relevant and should inspire the design of future long-term randomized controlled trials that contribute to supporting the use of tianeptine for improving cognitive function in AD patients. Show more

Keywords: Alzheimer’s disease, antidepressants, dementia, depressive symptoms, tianeptine

DOI: 10.3233/JAD-215630

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 707-720, 2022

Authors: Ramirez-Gomez, Liliana | Albers, Mark W. | Baena, Ana | Vila-Castelar, Clara | Fox-Fuller, Joshua T. | Sanchez, Justin | Jain, Felipe | Albers, Alefiya D. | Lopera, Francisco | Quiroz, Yakeel T.

Article Type: Research Article

Abstract: Background: Olfactory dysfunction is one of the earliest signs of Alzheimer’s disease (AD), highlighting its potential use as a biomarker for early detection. It has also been linked to progression from mild cognitive impairment (MCI) to dementia. Objective: To study olfactory function and its associations with markers of AD brain pathology in non-demented mutation carriers of an autosomal dominant AD (ADAD) mutation and non-carrier family members. Methods: We analyzed cross-sectional data from 16 non-demented carriers of the Presenilin1 E280A ADAD mutation (mean age [SD]: 40.1 [5.3], and 19 non-carrier family members (mean age [SD]: 36.0 …[5.5]) from Colombia, who completed olfactory and cognitive testing and underwent amyloid and tau positron emission tomography (PET) imaging. Results: Worse olfactory identification performance was associated with greater age in mutation carriers (r  = –0.52 p  = 0.037). In carriers, worse olfactory identification performance was related to worse MMSE scores (r  = 0.55, p  = 0.024) and CERAD delayed recall (r  = 0.63, p  = 0.007) and greater cortical amyloid-β (r  = –0.53, p  = 0.042) and tau pathology burden (entorhinal: r  = –0.59, p  = 0.016; inferior temporal: r  = –0.52, p  = 0.038). Conclusion: Worse performance on olfactory identification tasks was associated with greater age, a proxy for disease progression in this genetically vulnerable ADAD cohort. In addition, this is the first study to report olfactory dysfunction in ADAD mutation carriers with diagnosis of MCI and its correlation with abnormal accumulation of tau pathology in the entorhinal region. Taken together, our findings suggest that olfactory dysfunction has promise as an early marker of brain pathology and future risk for dementia. Show more

Keywords: Alzheimer’s disease, autosomal dominant Alzheimer’s disease, mild cognitive impairment, olfactory function

DOI: 10.3233/JAD-220075

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 721-729, 2022

Authors: Kuriyama, Nagato | Koyama, Teruhide | Ozaki, Etsuko | Saito, Satoshi | Ihara, Masafumi | Matsui, Daisuke | Watanabe, Isao | Kondo, Masaki | Marunaka, Yoshinori | Takada, Akihiro | Akazawa, Kentaro | Tomida, Satomi | Nagamitsu, Reo | Miyatani, Fumitaro | Miyake, Masahiro | Nakano, Eri | Kobayashi, Daiki | Watanabe, Yoshiyuki | Mizuno, Shigeto | Maekawa, Mizuho | Yoshida, Tamami | Nukaya, Yukiko | Mizuno, Toshiki | Yamada, Kei | Uehara, Ritei

Article Type: Research Article

Abstract: Background: Mid-regional pro-adrenomedullin (MR-proADM) is a novel biomarker for cognitive decline based on its association with cerebral small vessel disease (SVD). Cerebral microbleeds (MBs) are characteristic of SVD; however, a direct association between MR-proADM and MBs has not been explored. Objective: We aimed to examine whether circulating levels of MR-proADM are associated with the identification of MBs by brain magnetic resonance imaging (MRI) and whether this association could be linked with cognitive impairment. Methods: In total, 214 participants (mean age: 75.9 years) without history of cerebral infarction or dementia were prospectively enrolled. All participants underwent brain …MRI, higher cognitive function testing, blood biochemistry evaluation, lifestyle examination, and blood MR-proADM measurement using a time-resolved amplified cryptate emission technology assay. For between-group comparisons, the participants were divided into two groups according to whether their levels of MR-proADM were normal (< 0.65 nmol/L) or high (≥0.65 nmol/L). Results: The mean MR-proADM level was 0.515±0.127 nmol/L. There were significant between-group differences in age, hypertension, and HbA1c levels (p  < 0.05). In the high MR-proADM group, the MR-proADM level was associated with the identification of MBs on brain MR images and indications of mild cognitive impairment (MCI). In participants with ≥3 MBs and MCI, high MR-proADM levels remained a risk factor after multivariate adjustment (OR: 2.94; p  < 0.05). Conclusion: High levels of MR-proADM may be a surrogate marker for the early detection of cognitive decline associated with the formation of cerebral MBs. This marker would be valuable during routine clinical examinations of geriatric patients. Show more

Keywords: Adrenomedullin, biomarkers, cerebral small vessel diseases, cognitive dysfunction, magnetic resonance imaging, peptides

DOI: 10.3233/JAD-220195

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 731-741, 2022

Authors: Haehner, Antje | Chen, Ben | Espin, Melanie | Haussmann, Robert | Matthes, Claudia | Desser, Dmitriy | Loessner, Lorenz | Brandt, Moritz D. | Donix, Markus | Hummel, Thomas

Article Type: Research Article

Abstract: Background: The olfactory system is affected early in Alzheimer’s disease and olfactory loss can already be observed in patients with mild cognitive impairment (MCI). Olfactory training is effective for improving olfactory and cognitive function by stimulating the olfactory pathway, but its effect on patients with MCI remains unclear. Objective: The aim of this randomized, prospective, controlled, blinded study was to assess whether a 4-month period of olfactory training (frequent short-term sniffing various odors) may have an effect on olfactory function, cognitive function, and morphology of medial temporal lobe (MTL) subregions and olfactory bulb in MCI patients. …Methods: A total of thirty-seven MCI patients were randomly assigned to the training group or a placebo group, which were performed twice a day for 4 months. Olfactory assessments, cognitive tests and magnetic resonance imaging were performed at the baseline and follow-up period. Results: After the training, there was an increase in odor discrimination, and increased cortical thickness of bilateral hippocampus (CA23DG and CA1) and mean MTL. Additionally, the change of olfactory score was positively associated with change of volume of olfactory bulb and hippocampus; the change of global cognition was positively associated with change of cortical thickness of hippocampus, entorhinal cortex and mean MTL; the change of cortical thickness of entorhinal cortex was positively associated with change of executive function. Conclusion: Olfactory training was associated with an increase in cortical thickness of the hippocampus but not olfactory bulb volume in patients with MCI. Olfactory training may serve as an early intervention of preventing hippocampal atrophy. Show more

Keywords: Cortical thickness, hippocampus, mild cognitive impairment, olfactory bulb, olfactory training

DOI: 10.3233/JAD-220248

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 743-755, 2022

Authors: Pyun, Jung-Min | Park, Young Ho | Kim, SangYun

Article Type: Research Article

Abstract: Background: Although thyroid dysfunction has been considered as a cause of reversible cognitive impairment, association between subclinical hypothyroidism and cognitive impairment is controversial. Objective: We compared cognitive profiles of patients in an euthyroid or subclinical hypothyroid (sHypo) state, as well as their disease progression from mild cognitive impairment (MCI) to dementia within 3 years. Methods: We included 2,181 patients in a euthyroid and 284 in a sHypo state over 60 years of age who underwent an extensive cognitive assessment at Seoul National University Bundang Hospital but were not prescribed levothyroxine, methimazole, carbimazole, or propylthiouracil. After propensity …score matching for age, sex, and education level, 1,118 patients in a euthyroid and 283 patients in a sHypo state were included. Attention, language, memory, visuocontructive, and executive functions were compared between the groups using Student’s t -test or the Mann-Whitney U test. To investigate the association between disease progression and subclinical hypothyroidism, a Cox regression analyses was performed in 379 patients with MCI. Patients with thyroid-stimulating hormone levels over 10 mlU/L was classified as the “sHypo10”, and hazard ratios for sHypo or sHypo10 were assessed. Results: There was no difference in attention, language, memory, visuoconstructive, and executive functions between the patient groups. Progression from MCI to dementia was not associated with sHypo or sHypo10. Conclusion: There was no difference in cognitive profile between euthyroid and sHypo patients, and no association between subclinical hypothyroidism and disease progression. This might suggest a clue of strategies regarding hormone therapy in subclinical hypothyroidism with cognitive impairment. Show more

Keywords: cognition, dementia, mild cognitive impairment, subclinical hypothyroidism

DOI: 10.3233/JAD-220302

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 757-762, 2022

Authors: Zhu, Liu-Ying | Shi, Lin | Luo, Yishan | Leung, Jason | Kwok, Timothy

Article Type: Research Article

Abstract: Background: Structural magnetic resonance imaging markers predicting symptomatic progression at the individual level can be highly beneficial for early intervention and treatment planning for Alzheimer’s disease (AD). However, the correlation between baseline MRI findings and AD progression has not been fully established. Objective: To explore the correlation between baseline MRI findings and AD progression. Methods: Brain volumetric measures were applied to differentiate the patients at risk of fast deterioration in AD. We included 194 AD patients with a 24-month follow-up: 65 slow decliners, 63 normal decliners, and 66 fast decliners categorized by changes in Alzheimer’s Disease …Assessment Scale-Cognitive Subscale (ADAS-Cog). ANOVA analyses were used to identify baseline brain atrophy between groups. Logistic regressions were further performed to explore the relative merits of AD resemblance structural atrophy index (AD-RAI) and individual regional volumetric measures in prediction of disease progression. Results: Atrophy in the temporal and insular lobes was associated with fast cognitive decline over 24 months. Smaller volumes of temporal and insular lobes in the left but not the right brain were associated with fast cognitive decline. Baseline AD-RAI predicted fast versus slow progression of cognitive decline (odds ratio 3.025 (95% CI: 1.064–8.600), high versus low, AUC 0.771). Moreover, AD-RAI was significantly lower among slow decliners when compared with normal decliners (p  = 0.039). Conclusion: AD-RAI on MRI showed potential in identifying clinical AD patients at risk of accelerated cognitive decline. Show more

Keywords: Alzheimer’s disease, atrophy index, automated brain volumetry, progression

DOI: 10.3233/JAD-215189

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 763-769, 2022

Authors: Ma, Xiaowei | Zhang, Yizhou | Gou, Dongyun | Ma, Jingle | Du, Juan | Wang, Chang | Li, Sha | Cui, Huixian

Article Type: Research Article

Abstract: Background: The activation of microglia and neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD), but the exact roles of microglia and the underlying mechanisms remain unclear. Objective: To clarify how the metabolic reprogramming of microglia induce by amyloid-β (Aβ)1-42 to affect the release of proinflammatory cytokines in AD. Methods: MTS assay was used to detect the viability of BV2 cells treated with different concentrations of Aβ1-42 for different periods of time. The expression levels of proinflammatory cytokines were determined by qRT-PCR and western blot assay in BV2 cells and hippocampus of …mice. RNA sequencing was applied to evaluate the gene expression profiles in response to HK2 knockdown in BV2 cells treated with Aβ1-42 . Results: Low concentrations of Aβ1-42 increased the viability of BV2 cells and promoted the release of proinflammatory cytokines, and this process is accompanied by increased glycolysis. Inhibition of glycolysis significantly downregulated the release of proinflammatory cytokines in BV2 cells and hippocampus of mice treated with Aβ1-42 . The results of RNA sequencing revealed the expression of chemokine ligand 2 (Cxcl2) and ephrin receptor tyrosine kinase A2 (EphA2) were significantly downregulated when knocked down HK2 in BV2 cells. Subsequently, the expression of proinflammatory cytokines was downregulated in BV2 cell after knocking down EphA2. Conclusion: This study demonstrated that EphA2/p38 MAPK pathway is involved the release of proinflammatory cytokines in microglia induced by Aβ1-42 in AD, which is accompanied by metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis. Show more

Keywords: Alzheimer’s disease, EphA2, glycolysis, metabolic reprogramming, microglia, p38 MAPK

DOI: 10.3233/JAD-220227

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 771-785, 2022

Authors: Harper, Jordan D. | Fan, Kang-Hsien | Aslam, M. Muaaz | Snitz, Beth E. | DeKosky, Steven T. | Lopez, Oscar L. | Feingold, Eleanor | Kamboh, M. Ilyas

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a complex disease influenced by the environment and genetics; however, much of the genetic component remains unaccounted for. Objective: The purpose of this work was to use genome-wide association analyses to detect genetic associations with incident AD in a sample of older adults aged 75 and above. Methods: We performed a genome-wide association study (GWAS) on genome-wide genotyped and imputed data (14,072,053 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia (mean age = 84.46±3.91) and 2,206 non-demented (mean age = 84.55±3.23) subjects. Results: The established association …of APOE* 4 carriers with AD was confirmed in this community-based sample of older subjects (odds ratio (OR) = 2.22; p  = 9.36E-14) and was stronger in females (OR = 2.72; p  = 1.74E-10) than in males (OR = 1.88; p  = 2.43E-05). We observed a novel genome-wide significant (GWS) locus on chromosome 12 near ncRNA LOC105369711 /rs148377161 (OR = 3.31; p  = 1.66E-08). In addition, sex-stratified analyses identified two novel associations in males: one near ncRNA LOC729987/ rs140076909 on chromosome 1 (OR = 4.51; p  = 3.72E-08) and the other approaching GWS near ncRNA LOC105375138/ rs117803234 on chromosome 7 (OR = 3.76; p  = 6.93E-08). Conclusion: The use of community-based samples of older individuals and incident dementia as a phenotype may be a helpful approach for the identification of novel genes for AD, which may not be detected in standard case-control studies. Replication of these signals and further studies of these regions and genes will help to provide a clearer picture for their role in AD. Show more

Keywords: Alzheimer’s disease, genome-wide association study (GWAS), incident dementia, non-coding RNA genes

DOI: 10.3233/JAD-220293

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 787-798, 2022

Article Type: Correction

DOI: 10.3233/JAD-229007

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 799-799, 2022