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

Authors: Kang, Sung Hoon | Cheon, Bo Kyoung | Kim, Ji-Sun | Jang, Hyemin | Kim, Hee Jin | Park, Kyung Won | Noh, Young | Lee, Jin San | Ye, Byoung Seok | Na, Duk L. | Lee, Hyejoo | Seo, Sang Won

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) evaluation in amnestic mild cognitive impairment (aMCI) patients is important for predicting conversion to Alzheimer’s disease. However, Aβ evaluation through Aβ positron emission tomography (PET) is limited due to high cost and safety issues. Objective: We therefore aimed to develop and validate prediction models of Aβ positivity for aMCI using optimal interpretable machine learning (ML) approaches utilizing multimodal markers. Methods: We recruited 529 aMCI patients from multiple centers who underwent Aβ PET. We trained ML algorithms using a training cohort (324 aMCI from Samsung medical center) with two-phase modelling: model 1 included age, …gender, education, diabetes, hypertension, apolipoprotein E genotype, and neuropsychological test scores; model 2 included the same variables as model 1 with additional MRI features. We used four-fold cross-validation during the modelling and evaluated the models on an external validation cohort (187 aMCI from the other centers). Results: Model 1 showed good accuracy (area under the receiver operating characteristic curve [AUROC] 0.837) in cross-validation, and fair accuracy (AUROC 0.765) in external validation. Model 2 led to improvement in the prediction performance with good accuracy (AUROC 0.892) in cross validation compared to model 1. Apolipoprotein E genotype, delayed recall task scores, and interaction between cortical thickness in the temporal region and hippocampal volume were the most important predictors of Aβ positivity. Conclusion: Our results suggest that ML models are effective in predicting Aβ positivity at the individual level and could help the biomarker-guided diagnosis of prodromal AD. Show more

Keywords: Aβ PET, amnestic mild cognitive impairment, Aβ positivity, machine learning, magnetic resonance imaging features, neuropsychological tests, prediction model

DOI: 10.3233/JAD-201092

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 143-157, 2021

Authors: Nakano, Masaki | Mitsuishi, Yachiyo | Liu, Lei | Watanabe, Naoki | Hibino, Emi | Hata, Saori | Saito, Takashi | Saido, Takaomi C. | Murayama, Shigeo | Kasuga, Kensaku | Ikeuchi, Takeshi | Suzuki, Toshiharu | Nishimura, Masaki

Article Type: Research Article

Abstract: Background: Brain amyloid-β (Aβ) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and Aβ deposition in Alzheimer’s disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for Aβ generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous Aβ suppressor. Objective: This study aimed to access the mechanism underlying ILEI secretion and its effect on Aβ production in the brain. Methods: ILEI and Aβ levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis …in mutant human Aβ precursor protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA. Results: Extracellular release of ILEI and Aβ was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and Aβ revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of Aβ levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and Aβ levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of Aβ and were reduced in AD and mild cognitive impairment. Conclusion: ILEI and Aβ are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates Aβ production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain Aβ. Show more

Keywords: Alzheimer’s disease, amyloid-β, ILEI, neurotransmitter receptor, synapse

DOI: 10.3233/JAD-201174

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 159-174, 2021

Authors: Grober, Ellen | Qi, Qi | Kuo, Lynn | Hassenstab, Jason | Perrin, Richard J. | Lipton, Richard B.

Article Type: Research Article

Abstract: Background: The ultimate validation of a clinical marker for Alzheimer’s disease (AD) is its association with AD neuropathology. Objective: To identify clinical measures that predict pathology, we evaluated the relationships of the picture version of the Free and Cued Selective Reminding Test (pFCSRT + IR), the Mini-Mental State Exam (MMSE), and the Clinical Dementia Rating scale Sum of Boxes (CDR-SB) to Braak stage. Methods: 315 cases from the clinicopathologic series at the Knight Alzheimer’s Disease Research Center were classified according to Braak stage. Boxplots of each predictor were compared to identify the earliest stage at which decline …was observed and ordinal logistic regression was used to predict Braak stage. Results: Looking at the assessment closest to death, free recall scores were lower in individuals at Braak stage III versus Braak stages 0 and I (combined) while MMSE and CDR scores for individuals did not differ from Braak stages 0/I until Braak stage IV. The sum of free recall and total recall scores independently predicted Braak stage and had higher predictive validity than MMSE and CDR-SB in models including all three. Conclusion: pFCSRT + IR scores may be more sensitive to early pathological changes than either the CDR-SB or the MMSE. Show more

Keywords: Alzheimer’s disease, braak stage, clinical dementia rating scale –sum of boxes, free and cued selective reminding test, mini-mental state exam, neuropathology

DOI: 10.3233/JAD-200980

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 175-183, 2021

Authors: Grober, Ellen | Qi, Qi | Kuo, Lynn | Hassenstab, Jason | Perrin, Richard J. | Lipton, Richard B.

Article Type: Research Article

Abstract: Background: The ultimate validation of a clinical marker for Alzheimer’s disease (AD) is its association with AD neuropathology. Objective: To examine how well the Stages of Objective Memory Impairment (SOMI) system predicts intermediate/high AD neuropathologic change and extent of neurofibrillary tangle (NFT) pathology defined by Braak stage, in comparison to the Clinical Dementia Rating (CDR) Scale sum of boxes (CDR-SB). Methods: 251 well-characterized participants from the Knight ADRC clinicopathologic series were classified into SOMI stage at their last assessment prior to death using the free recall and total recall scores from the picture version of the …Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT + IR). Logistic regression models assessed the predictive validity of SOMI and CDR-SB for intermediate/high AD neuropathologic change. Receiver operating characteristics (ROC) analysis evaluated the discriminative validity of SOMI and CDR-SB for AD pathology. Ordinal logistic regression was used to predict Braak stage using SOMI and CDR-SB in separate and joint models. Results: The diagnostic accuracy of SOMI for AD diagnosis was similar to that of the CDR-SB (AUC: 85%versus 83%). In separate models, both SOMI and CDR-SB predicted Braak stage. In a joint model SOMI remained a significant predictor of Braak stage but CDR-SB did not. Conclusion: SOMI provides a neuropathologically validated staging system for episodic memory impairment in the AD continuum and should be useful in predicting tau positivity based on its association with Braak stage. Show more

Keywords: Alzheimer’s disease, braak stage, clinical dementia rating scale –sum of boxes, free and cued selective reminding test, neuropathology

DOI: 10.3233/JAD-200946

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 185-195, 2021

Authors: Kim, Jaehyun | Ha, Tae Hyon | Kim, Kiwon | Lee, Eun-Mi | Kim, Hyekyeong | Kim, Doh Kwan | Won, Hong-Hee | Lewis, Matthew | Lee, Hyewon | Myung, Woojae

Article Type: Research Article

Abstract: Background: While atypical antipsychotic medications are widely used for treating depressive disorders, their long-term effects on the risk of subsequent dementia have not been studied adequately. Objective: To investigate whether the risk of dementia differs according to the use of atypical antipsychotic drugs, and compare the effects of antipsychotic agents on dementia risk in individuals with late-life depressive disorders. Methods: A nationwide population-based retrospective cohort study was conducted using data from the National Health Insurance Service—Senior Cohort of South Korea. Atypical antipsychotic dosages were standardized using a defined daily dose, and the cumulative dosage was calculated. …Participants were observed from January 2008 to December 2015. Cox proportional hazard regression analysis was used to estimate the hazard ratios. Results: The cohort included 43,788 elderly adults with depressive disorders: 9,901 participants (22.6%) were diagnosed with dementia. Findings showed that atypical antipsychotics were prescribed to 1,967 participants (4.5%). Compared with non-users, users of atypical antipsychotics experienced a significantly higher risk for dementia with an adjusted hazard ratio (aHR) of 1.541 (95% confidence interval [CI], 1.415–1.678). A cumulative dose-response relationship was observed (test for trend, p  < 0.0001). Among atypical antipsychotics, risperidone displayed the highest risk for dementia (aHR 1.767, [95% CI, 1.555–2.009]). Conclusion: In this study of elderly individuals with depressive disorders, atypical antipsychotic use was associated with a significantly higher risk of subsequent dementia. Healthcare professionals should be aware of this potential long-term risk. A limitation that should be mentioned is that we could not exclude patients with bipolar depression. Show more

Keywords: Antipsychotic agents, dementia, depression, mood disorders

DOI: 10.3233/JAD-200994

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 197-207, 2021

Authors: Macedo, Ana | Gómez, Carlos | Rebelo, Miguel Ângelo | Poza, Jesús | Gomes, Iva | Martins, Sandra | Maturana-Candelas, Aarón | Pablo, Víctor Gutiérrez-de | Durães, Luis | Sousa, Patrícia | Figueruelo, Manuel | Rodríguez, María | Pita, Carmen | Arenas, Miguel | Álvarez, Luis | Hornero, Roberto | Lopes, Alexandra M. | Pinto, Nádia

Article Type: Research Article

Abstract: Background: Dementia due to Alzheimer’s disease (AD) is a complex neurodegenerative disorder, which much of heritability remains unexplained. At the clinical level, one of the most common physiological alterations is the slowing of oscillatory brain activity, measurable by electroencephalography (EEG). Relative power (RP) at the conventional frequency bands (i.e., delta, theta, alpha, beta-1, and beta-2) can be considered as AD endophenotypes. Objective: The aim of this work is to analyze the association between sixteen genes previously related with AD: APOE , PICALM , CLU , BCHE , CETP , CR1 , SLC6A3 , GRIN2 β, SORL1 , …TOMM40 , GSK3 β, UNC5C , OPRD1 , NAV2 , HOMER2 , and IL1RAP , and the slowing of the brain activity, assessed by means of RP at the aforementioned frequency bands. Methods: An Iberian cohort of 45 elderly controls, 45 individuals with mild cognitive impairment, and 109 AD patients in the three stages of the disease was considered. Genomic information and brain activity of each subject were analyzed. Results: The slowing of brain activity was observed in carriers of risk alleles in IL1RAP (rs10212109, rs9823517, rs4687150), UNC5C (rs17024131), and NAV2 (rs1425227, rs862785) genes, regardless of the disease status and situation towards the strongest risk factors: age, sex, and APOE ɛ4 presence. Conclusion: Endophenotypes reduce the complexity of the general phenotype and genetic variants with a major effect on those specific traits may be then identified. The found associations in this work are novel and may contribute to the comprehension of AD pathogenesis, each with a different biological role, and influencing multiple factors involved in brain physiology. Show more

Keywords: Alzheimer’s disease, EEG, electroencephalography, endophenotypes, genetics

DOI: 10.3233/JAD-200963

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 209-223, 2021

Authors: Welstead, Miles | Luciano, Michelle | Muniz-Terrera, Graciela | Saunders, Stina | Mullin, Donncha S. | Russ, Tom C.

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) describes a borderland between healthy cognition and dementia. Progression to and reversion from MCI is relatively common but more research is required to understand the factors affecting this fluidity and improve clinical care interventions. Objective: We explore these transitions in MCI status and their predictive factors over a six-year period in a highly-phenotyped longitudinal study, the Lothian Birth Cohort 1936. Methods: MCI status was derived in the LBC1936 at ages 76 (n  = 567) and 82 years (n  = 341) using NIA-AA diagnostic guidelines. Progressions and reversions between healthy cognition and MCI over …the follow-up period were assessed. Multinomial logistic regression assessed the effect of various predictors on the likelihood of progressing, reverting, or maintaining cognitive status. Results: Of the 292 participants who completed both time points, 41 (14%) participants had MCI at T1 and 56 (19%) at T2. Over the follow-up period, 74%remained cognitively healthy, 12%transitioned to MCI, 7%reverted to healthy cognition, and 7%maintained their baseline MCI status. Findings indicated that membership of these transition groups was affected by age, cardiovascular disease, and number of depressive symptoms. Conclusion: Findings that higher baseline depressive symptoms increase the likelihood of reverting from MCI to healthy cognition indicate that there may be an important role for the treatment of depression for those with MCI. However, further research is required to identify prevention strategies for those at high risk of MCI and inform effective interventions that increase the likelihood of reversion to, and maintenance of healthy cognition. Show more

Keywords: Aged, cognitive dysfunction, memory, public health

DOI: 10.3233/JAD-201282

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 225-232, 2021

Authors: Yu, Fang | Vock, David M. | Zhang, Lin | Salisbury, Dereck | Nelson, Nathaniel W. | Chow, Lisa S. | Smith, Glenn | Barclay, Terry R. | Dysken, Maurice | Wyman, Jean F.

Article Type: Research Article

Abstract: Background: Aerobic exercise has shown inconsistent cognitive effects in older adults with Alzheimer’s disease (AD) dementia. Objective: To examine the immediate and longitudinal effects of 6-month cycling on cognition in older adults with AD dementia. Methods: This randomized controlled trial randomized 96 participants (64 to cycling and 32 to stretching for six months) and followed them for another six months. The intervention was supervised, moderate-intensity cycling for 20–50 minutes, 3 times a week for six months. The control was light-intensity stretching. Cognition was assessed at baseline, 3, 6, 9, and 12 months using the AD Assessment …Scale-Cognition (ADAS-Cog). Discrete cognitive domains were measured using the AD Uniform Data Set battery. Results: The participants were 77.4±6.8 years old with 15.6±2.9 years of education, and 55% were male. The 6-month change in ADAS-Cog was 1.0±4.6 (cycling) and 0.1±4.1 (stretching), which were both significantly less than the natural 3.2±6.3-point increase observed naturally with disease progression. The 12-month change was 2.4±5.2 (cycling) and 2.2±5.7 (control). ADAS-Cog did not differ between groups at 6 (p  = 0.386) and 12 months (p  = 0.856). There were no differences in the 12-month rate of change in ADAS-Cog (0.192 versus 0.197, p  = 0.967), memory (–0.012 versus –0.019, p  = 0.373), executive function (–0.020 versus –0.012, p  = 0.383), attention (–0.035 versus –0.033, p  = 0.908), or language (–0.028 versus –0.026, p  = 0.756). Conclusion: Exercise may reduce decline in global cognition in older adults with mild-to-moderate AD dementia. Aerobic exercise did not show superior cognitive effects to stretching in our pilot trial, possibly due to the lack of power. Show more

Keywords: Alzheimer’s disease, cognition, dementia, exercise, physical activity

DOI: 10.3233/JAD-201100

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 233-244, 2021

Authors: Lai, Zhongmeng | Min, Jia | Li, Jun | Shan, Weiran | Yu, Weifeng | Zuo, Zhiyi

Article Type: Research Article

Abstract: Background: Perioperative, modifiable factors contributing to perioperative neurocognitive disorders (PND) have not been clearly defined. Objective: To determine the contribution of anesthesia lengths and the degrees of surgical trauma to PND and neuroinflammation, a critical process for PND. Methods: Three-month-old C57BL/6J mice were subjected to 2 h or 6 h isoflurane anesthesia plus a 5 min or 15 min left common carotid artery exposure (surgery) in a factorial design (two factors: anesthesia with two levels and surgery with three levels). Their learning and memory were tested by Barnes maze and novel object recognition paradigms. Blood, spleen, and hippocampus were harvested …for measuring interleukin (IL)-6 and IL-1β. Eighteen-month-old C57BL/6J mice (old mice) were subjected to 6 h isoflurane anesthesia or 2 h isoflurane anesthesia plus 15 min surgery and then had learning and memory tested. Results: Three-month-old mice with 15 min surgery (long surgery) under 2 h or 6 h anesthesia performed poorly in the learning and memory tests compared with controls. Anesthesia alone or anesthesia plus 5 min surgery did not affect mouse performance in these tests. Similarly, only mice with long surgery but not mice with other experimental conditions had increased IL-6 and IL-1β in the blood, spleen, and hippocampus and decreased spleen weights. Splenocytes were found in the hippocampus after surgery. Similarly, old mice with long surgery but not the mice with isoflurane anesthesia alone had poor performance in the Barnes maze and novel object recognition tests. Conclusion: Surgical trauma, but not anesthesia, contributes to the development of PND and neuroinflammation. Splenocytes may modulate these processes. Show more

Keywords: Inflammatory cytokines, mice, postoperative cognitive dysfunction, spleen, surgery

DOI: 10.3233/JAD-201232

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 245-257, 2021

Authors: Chuang, Yu-Chen | Chiu, Ming-Jang | Chen, Ta-Fu | Chang, Yu-Ling | Lai, Ya-Mei | Cheng, Ting-Wen | Hua, Mau-Sun

Article Type: Research Article

Abstract: Background: The issue of whether there exists an own-effect on facial recognition in the elderly remains equivocal. Moreover, currently the literature of this issue in pathological aging is little. Objective: Our study was thus to explore the issue in both of healthy older people and patients with AD Methods: In study 1, 27 older and 31 younger healthy adults were recruited; in study 2, 27 healthy older adults and 80 patients (including subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer’s disease (AD) groups) were recruited. Participants received the Taiwan Facial Emotion Recognition Task (FER …Task), and a clinical neuropsychological assessment. Results: No significant differences on the FER test were found among our groups, except for sadness recognition in which our MCI and AD patients’ scores were remarkably lower than their healthy counterparts. The own-age effect was not significantly evident in healthy younger and older adults, except for recognizing neutral photos. Our patients with MCI and AD tended to have the effect, particularly for the sad recognition in which the effect was significantly evident in terms of error features (mislabeling it as anger in younger-face and neutral in older-face photos). Conclusion: Our results displayed no remarkable own-age effect on facial emotional recognition in the healthy elderly (including SCD). However, it did not appear the case for MCI and AD patients, especially their recognizing those sadness items, suggesting that an inclusion of the FER task particularly involving those items of low-intensity emotion in clinical neuropsychological assessment might be contributory to the early detection of AD-related pathological individuals. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, early detection, facial emotion recognition task, subjective memory decline, Taiwanese

DOI: 10.3233/JAD-200916

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 259-269, 2021