Journal of Alzheimer's Disease - Volume 83, issue 4

Authors: Cummings, Jeffrey | Schwartz, Gregory G. | Nicholls, Stephen J. | Khan, Aziz | Halliday, Chris | Toth, Peter P. | Sweeney, Michael | Johansson, Jan O. | Wong, Norman C.W. | Kulikowski, Ewelina | Kalantar-Zadeh, Kamyar | Lebioda, Kenneth | Ginsberg, Henry N. | Winblad, Bengt | Zetterberg, Henrik | Ray, Kausik K.

Article Type: Research Article

Abstract: Background: Epigenetic changes may contribute importantly to cognitive decline in late life including Alzheimer’s disease (AD) and vascular dementia (VaD). Bromodomain and extra-terminal (BET) proteins are epigenetic “readers” that may distort normal gene expression and contribute to chronic disorders. Objective: To assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized trial of patients at high risk for major cardiovascular events (MACE). Methods: The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at the time of randomization. …464 participants were randomized to apabetalone or placebo in the cognition sub-study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score≥26 (normal performance), MoCA score 25–22 (mild cognitive impairment), and MoCA score≤21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group. Results: Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of≤21 (p  = 0.02). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% versus 7.9%). Conclusion: In this randomized controlled study, apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders. Show more

Keywords: Alzheimer’s disease, apabetalone, BET inhibitor, clinical trial, epigenetics, montreal cognitive assessment

DOI: 10.3233/JAD-210570

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1703-1715, 2021

Authors: Bommarito, Giulia | Van De Ville, Dimitri | Frisoni, Giovanni B. | Garibotto, Valentina | Ribaldi, Federica | Stampacchia, Sara | Assal, Frédéric | Allali, Gilles | Griffa, Alessandra

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) pathology impacts the response to treatment in patients with idiopathic normal pressure hydrocephalus (iNPH), possibly through changes in resting-state functional connectivity (rs-FC). Objective: To explore the relationship between cerebrospinal fluid biomarkers of AD and the default mode network (DMN)/hippocampal rs-FC in iNPH patients, based on their outcome after cerebrospinal fluid tap test (CSFTT), and in patients with AD. Methods: Twenty-six iNPH patients (mean age: 79.9±5.9 years; 12 females) underwent MRI and clinical assessment before and after CSFTT and were classified as responders (Resp) or not (NResp), based on the improvement at the …timed up and go test and walking speed. Eleven AD patients (mean age: 70.91±5.2 years; 5 females), matched to iNPH for cognitive status, were also included. DMN and hippocampal rs-FC was related to amyloid-β42 and phosphorylated tau (pTau) levels. Results: Lower amyloid-β42 levels were associated with reduced inter- and intra-network rs-FC in NResp, and the interaction between amyloid-β42 and rs-FC was a predictor of outcome after CSFTT. The rs-FC between DMN and salience networks positively correlated to amyloid-β42 levels in both NResp and AD patients. The increase in the inter-network rs-FC after CSFTT was associated with higher pTau and lower amyloid-β42 levels in NResp, and to lower pTau levels in Resp. Conclusion: Amyloid-β42 and pTau impact on rs-FC and its changes after CSFTT in iNPH patients. The interaction between AD biomarkers and rs-FC might explain the responder status in iNPH. Show more

Keywords: Alzheimer’s disease, amyloid, CSF tap test, default mode network, functional connectivity, hippocampus, normal pressure hydrocephalus, tau

DOI: 10.3233/JAD-210534

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1717-1728, 2021

Authors: Vemuri, Prashanthi | Davey, Cynthia | Johansen, Kirsten L. | Zuk, Samantha M. | Reid, Robert I. | Thostenson, Kaely B. | Reddy, Ashritha L. | Jack Jr., Clifford R. | Knopman, David S. | Murray, Anne M.

Article Type: Research Article

Abstract: Background: Chronic kidney disease (CKD), a growing public health issue in the elderly, is associated with increased risk of cognitive impairment. Objective: To investigate the mechanisms through which CKD impacts brain health using longitudinal imaging. Methods: We identified 97 participants (74 CKD and 23 non-CKD) from the BRINK (BRain IN Kidney Disease), a longitudinal study of CKD with two MRI scans (baseline and 3-year follow-up). We measured the associations between baseline and change in kidney disease biomarkers of estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR), considered a measure of microvascular inflammation, …and imaging outcomes of cortical thickness and ventricular volume from structural MRI, white matter hyperintensities (WMH) volume from FLAIR images, and fractional anisotropy of the corpus callosum (FACC). Results: There were white matter-specific changes as observed by increased WMH volume and decreased FACC in CKD participants, as well as ventricular volume increase in both CKD and non-CKD groups reflective of aging-related changes. Decline in eGFR was associated with decrease in the FACC, suggesting that subtle early white matter changes due to kidney disease can be captured using DTI. An increase in UACR was associated with increase in ventricular volume. Conclusion: Our results support the role of eGFR as a measure of kidney microvascular disease which is associated with concurrent white matter damage in CKD. Future work is needed to investigate the possible link between endothelial microvascular inflammation (as measured by an increased UACR) and ventricular volume increase. Show more

Keywords: Brain health, chronic kidney disease, diffusion tensor imaging, white matter damage, white matter hyperintensities

DOI: 10.3233/JAD-210604

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1729-1740, 2021

Authors: Zhang, Jing-Jing | Li, Lin | Liu, Dan | Hu, Fei-Fei | Cheng, Gui-Rong | Xu, Lang | Yan, Ping-Ting | Tian, Yuan | Hu, Heng | Yu, Ya-Fu | Gan, Xu-Guang | An, Li-Na | Zhang, Bo | Qian, Jin | Fu, Li-Yan | Cheng, Xi | Lian, Peng-Fei | Zou, Ming-Jun | Chen, Cong | Wu, Qing-Ming | Zeng, Yan

Article Type: Research Article

Abstract: Background: Some studies have demonstrated an association between low and high body mass index (BMI) and an increased risk of dementia. However, only a few of these studies were performed in rural areas. Objective: This cross–sectional study investigated the associations between BMI and cognitive impairment among community–dwelling older adults from rural and urban areas. Methods: 8,221 older persons enrolled in the Hubei Memory & Ageing Cohort Study (HMACS) were recruited. Sociodemographic and lifestyle data, comorbidities, physical measurements, and clinical diagnoses of cognitive impairment were analyzed. Logistic regression was performed to assess the associations of BMI categories …with cognitive impairment. A series of sensitivity analyses were conducted to test whether reverse causality could influence our results. Results: Being underweight in the rural–dwelling participants increased the risk of cognitive impairment. Being overweight was a protective factor in rural–dwelling participants aged 65–69 years and 75–79 years, whereas being underweight was significantly associated with cognitive impairment (OR, 1.37; 95% CI: 1.03–1.83; p  < 0.05). Sensitivity analyses support that underweight had an additive effect on the odds of cognitive impairment and was related to risk of dementia. Interaction test revealed that the differences between urban/rural in the relationship between BMI and cognitive impairment are statistically significant. Conclusion: Associations between BMI and cognitive impairment differ among urban/rural groups. Older people with low BMI living in rural China are at a higher risk for dementia than those living in urban areas. Show more

Keywords: Body mass index, cognitive impairment, community–dwelling older adults, cross–sectional study, rural–urban disparity

DOI: 10.3233/JAD-210295

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1741-1752, 2021

Authors: Pisu, Maria | Martin, Roy C. | Shan, Liang | Pilonieta, Giovanna | Kennedy, Richard E. | Oates, Gabriela | Kim, Young-Il | Geldmacher, David S.

Article Type: Research Article

Abstract: Background: Use of specialists and recommended drugs has beneficial effects for older adults living with Alzheimer’s disease and related dementia (ADRD). Gaps in care may exist for minorities, e.g., Blacks, and especially in the United States (U.S.) Deep South (DS), a poor U.S. region with rising ADRD cases and minority overrepresentation. Currently, we have little understanding of ADRD care utilization in diverse populations in this region and elsewhere in the U.S. (non-DS), and the factors that adversely impact it. Objective: To examine utilization of specialists and ADRD drugs (outcomes) in racial/ethnic groups of older adults with ADRD and …the personal or context-level factors affecting these outcomes in DS and non-DS. Methods: We obtained outcomes and personal-level covariates from claims for 127,512 Medicare beneficiaries with ADRD in 2013–2015, and combined county-level data in exploratory factor analysis to define context-level covariates. Adjusted analyses tested significant association of outcomes with Black/White race and other factors in DS and non-DS. Results: Across racial/ethnic groups, 33%–43% in DS and 43%–50% in non-DS used specialists; 47%–55% in DS and 41%–48% in non-DS used ADRD drugs. In adjusted analyses, differences between Blacks and Whites were not significant. Vascular dementia, comorbidities, poverty, and context-level factor “Availability of Medical Resources” were associated with specialist use; Alzheimer’s disease and senile dementia, comorbidities, and specialist use were associated with drug use. In non-DS only, other individual, context-level covariates were associated with the outcomes. Conclusion: We did not observe significant gaps in ADRD care in DS and non-DS; however, research should further examine determinants of low specialist and drug use in these regions. Show more

Keywords: Access to care, affordability, disparities, drug use, equity, physician availability, socioeconomic context, socioeconomic status, specialist use

DOI: 10.3233/JAD-210240

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1753-1765, 2021

Authors: Ma, Heather | Kiekhofer, Rachel E. | Hooper, Sarah M. | Dulaney, Sarah | Possin, Katherine L. | Chiong, Winston

Article Type: Research Article

Abstract: Background: Advance care planning has been shown to improve end of life decision-making for people with dementia. However, the impact of goals of care conversations between people with dementia and their caregivers has not been characterized. Objective: In this study, we evaluate the association between goals of care conversations and advance care planning outcomes. Methods: Retrospective advance care planning measures were collected via a questionnaire administered to 166 caregivers after the death of the person with dementia for whom they provided care. Results: At time of death, the majority of decedents with dementia had …advance directives, health care agents, and previous goals of care conversations with their caregiver. Goals of care conversations were significantly associated with the perceived usefulness of advance directives, the perceived adherence to advance directives, and decedent dying at their desired place of death, but not with disagreements around end-of-life care. Conclusion: Our findings suggest that goals of care conversations are an important component of advance care planning. These findings support the development of interventions that facilitate such conversations between people with dementia and their caregivers. Show more

Keywords: Advance care planning, Alzheimer’s disease, dementia, patient preference, terminal care

DOI: 10.3233/JAD-210720

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1767-1773, 2021

Authors: Platen, Moritz | Fleßa, Steffen | Rädke, Anika | Wucherer, Diana | Thyrian, Jochen René | Mohr, Wiebke | Scharf, Annelie | Mühlichen, Franka | Hoffmann, Wolfgang | Michalowsky, Bernhard

Article Type: Research Article

Abstract: Background: Low-value care (LvC) is defined as care unlikely to provide a benefit to the patient regarding the patient’s preferences, potential harms, costs, or available alternatives. Avoiding LvC and promoting recommended evidence-based treatments, referred to as high-value care (HvC), could improve patient-reported outcomes for people living with dementia (PwD). Objective: This study aims to determine the prevalence of LvC and HvC in dementia and the associations of LvC and HvC with patients’ quality of life and hospitalization. Methods: The analysis was based on data of the DelpHi trial and included 516 PwD. Dementia-specific guidelines, the “Choosing …Wisely” campaign and the PRISCUS list were used to indicate LvC and HvC treatments, resulting in 347 LvC and HvC related recommendations. Of these, 77 recommendations (51 for LvC, 26 for HvC) were measured within the DelpHi-trial and finally used for this analysis. The association of LvC and HvC treatments with PwD health-related quality of life (HRQoL) and hospitalization was assessed using multiple regression models. Results: LvC was highly prevalent in PwD (31%). PwD receiving LvC had a significantly lower quality of life (b  = –0.07; 95% CI –0.14 – –0.01) and were significantly more likely to be hospitalized (OR = 2.06; 95% CI 1.26–3.39). Different HvC treatments were associated with both positive and negative changes in HRQoL. Conclusion: LvC could cause adverse outcomes and should be identified as early as possible and tried to be replaced. Future research should examine innovative models of care or treatment pathways supporting the identification and replacement of LvC in dementia. Show more

Keywords: Alzheimer’s disease, health-related quality of life, hospitalization, low-value care, patient-centered outcomes

DOI: 10.3233/JAD-210439

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1775-1787, 2021

Authors: Isernia, Sara | Cabinio, Monia | Di Tella, Sonia | Pazzi, Stefania | Vannetti, Federica | Gerli, Filippo | Mosca, Irene Eleonora | Lombardi, Gemma | Macchi, Claudio | Sorbi, Sandro | Baglio, Francesca

Article Type: Research Article

Abstract: Background: The Smart Aging Serious Game (SASG) is an ecologically-based digital platform used in mild neurocognitive disorders. Considering the higher risk of developing dementia for mild cognitive impairment (MCI) and vascular cognitive impairment (VCI), their digital phenotyping is crucial. A new understanding of MCI and VCI aided by digital phenotyping with SASG will challenge current differential diagnosis and open the perspective of tailoring more personalized interventions. Objective: To confirm the validity of SASG in detecting MCI from healthy controls (HC) and to evaluate its diagnostic validity in differentiating between VCI and HC. Methods: 161 subjects (74 …HC: 37 males, 75.47±2.66 mean age; 60 MCI: 26 males, 74.20±5.02; 27 VCI: 13 males, 74.22±3.43) underwent a SASG session and a neuropsychological assessment (Montreal Cognitive Assessment (MoCA), Free and Cued Selective Reminding Test, Trail Making Test). A multi-modal statistical approach was used: receiver operating characteristic (ROC) curves comparison, random forest (RF), and logistic regression (LR) analysis. Results: SASG well captured the specific cognitive profiles of MCI and VCI, in line with the standard neuropsychological measures. ROC analyses revealed high diagnostic sensitivity and specificity of SASG and MoCA (AUCs  > 0.800) in detecting VCI versus HC and MCI versus HC conditions. An acceptable to excellent classification accuracy was found for MCI and VCI (HC versus VCI; RF: 90%, LR: 91%. HC versus MCI; RF: 75%; LR: 87%). Conclusion: SASG allows the early assessment of cognitive impairment through ecological tasks and potentially in a self-administered way. These features make this platform suitable for being considered a useful digital phenotyping tool, allowing a non-invasive and valid neuropsychological evaluation, with evident implications for future digital-health trails and rehabilitation. Show more

Keywords: Dementia, digital medicine, mild cognitive impairment, mild neurocognitive disorder, neuropsychological assessment, serious games, telemonitoring, vascular cognitive impairment, virtual reality

DOI: 10.3233/JAD-210347

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1789-1801, 2021

Authors: Briceño, Emily M. | Gross, Alden L. | Giordani, Bruno J. | Manly, Jennifer J. | Gottesman, Rebecca F. | Elkind, Mitchell S.V. | Sidney, Stephen | Hingtgen, Stephanie | Sacco, Ralph L. | Wright, Clinton B. | Fitzpatrick, Annette | Fohner, Alison E. | Mosley, Thomas H. | Yaffe, Kristine | Levine, Deborah A.

Article Type: Research Article

Abstract: Background: Meta-analyses of individuals’ cognitive data are increasing to investigate the biomedical, lifestyle, and sociocultural factors that influence cognitive decline and dementia risk. Pre-statistical harmonization of cognitive instruments is a critical methodological step for accurate cognitive data harmonization, yet specific approaches for this process are unclear. Objective: To describe pre-statistical harmonization of cognitive instruments for an individual-level meta-analysis in the blood pressure and cognition (BP COG) study. Methods: We identified cognitive instruments from six cohorts (the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Coronary Artery Risk Development in Young Adults study, Framingham Offspring Study, Multi-Ethnic …Study of Atherosclerosis, and Northern Manhattan Study) and conducted an extensive review of each item’s administration and scoring procedures, and score distributions. Results: We included 153 cognitive instrument items from 34 instruments across the six cohorts. Of these items, 42%were common across ≥2 cohorts. 86%of common items showed differences across cohorts. We found administration, scoring, and coding differences for seemingly equivalent items. These differences corresponded to variability across cohorts in score distributions and ranges. We performed data augmentation to adjust for differences. Conclusion: Cross-cohort administration, scoring, and procedural differences for cognitive instruments are frequent and need to be assessed to address potential impact on meta-analyses and cognitive data interpretation. Detecting and accounting for these differences is critical for accurate attributions of cognitive health across cohort studies. Show more

Keywords: Cognition, dementia, epidemiology, methods

DOI: 10.3233/JAD-210459

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1803-1813, 2021

Authors: Zhang, Zhizhong | Wang, Mengmeng | Yuan, Shuai | Cai, Huan | Zhu, Shuang-Gen | Liu, Xinfeng

Article Type: Research Article

Abstract: Background: Observational studies have reported that coffee consumption was associated with Alzheimer’s disease (AD) and stroke risk. However, the results are inconclusive. Objective: We aimed to evaluate whether genetically predicted coffee consumption is associated with AD and stroke using Mendelian randomization (MR) design. Methods: Summary-level data for AD (n  = 54,162), ischemic stroke (n  = 440,328), and intracerebral hemorrhage (ICH, n  = 3,026) were adopted from publicly available databases. Summary-level data for coffee consumption were obtained from two genome-wide association studies, comprising up to 375,833 subjects. Results: Genetically predicted coffee consumption (cups/day) was associated with an increased …risk of AD (OR = 1.26, 95%CI = 1.05–1.51). Moreover, genetically predicted 50%increase of coffee consumption was associated with an increased risk of ICH (OR: 2.27, 95%CI: 1.08–4.78) but a decreased risk of small vessel stroke (OR: 0.71, 95%CI: 0.51–0.996). Estimate for AD and ICH in FinnGen consortium is directionally consistent. Combined analysis of different databases further confirmed that genetically predicted coffee consumption was associated with an increased risk of AD and ICH. In the multivariable MR analysis, genetically predicted coffee consumption retained a stable effect with AD and ICH when adjusting for smoking (p  < 0.05), while the association with AD attenuated when adjusting for alcohol use. Conclusion: Our results indicate that genetically predicted coffee consumption may be associated with an increased risk of AD and ICH. The underlying biological mechanisms warrant further study. Show more

Keywords: Alzheimer’s disease, coffee, mendelian randomization, stroke

DOI: 10.3233/JAD-210678

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1815-1823, 2021