Journal of Alzheimer's Disease - Volume 79, issue 2

Authors: Horstkötter, Dorothee | Deckers, Kay | Köhler, Sebastian

Article Type: Review Article

Abstract: Dementia poses important medical and societal challenges, and of all health risks people face in life, dementia is one of the most feared. Recent research indicates that up to about 40% of all cases of dementia might be preventable. A series of environmental, social, and medical risk-factors have been identified that should be targeted from midlife onwards when people are still cognitively healthy. At first glance, this seems not merely advisable, but even imperative. However, these new developments trigger a series of new ethical questions and concerns which have hardly been addressed to date. Pro-active ethical reflection, however, is crucial …to ensure that the interests and well-being of those affected, ultimately all of us, are adequately respected. This is the goal of the current contribution. Against the background of a concrete case in primary dementia prevention, it provides a systematic overview of the current ethical literature and sketches an ethical research agenda. First, possible benefits of increased well-being must be balanced with the burdens of being engaged in particularly long-term interventions for which it is unclear whether they will ever pay out on a personal level. Second, while knowledge about one’s options to maintain brain health might empower people, it might also undermine autonomy, put high social pressure on people, medicalize healthy adults, and stigmatize those who still develop dementia. Third, while synergistic effects might occur, the ideals of dementia prevention might also conflict with other health and non-health related values people hold in life. Show more

Keywords: Dementia, ethics, lifestyle, middle aged, prevention

DOI: 10.3233/JAD-201104

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 467-476, 2021

Authors: Carandini, Tiziana | Sacchi, Luca | Ghezzi, Laura | Pietroboni, Anna M. | Fenoglio, Chiara | Arighi, Andrea | Fumagalli, Giorgio G. | De Riz, Milena A. | Serpente, Maria | Rotondo, Emanuela | Scarpini, Elio | Galimberti, Daniela

Article Type: Short Communication

Abstract: Genetics has a major role in early-onset dementia, but the correspondence between genotype and phenotype is largely tentative. We describe a 54-year-old with familial early-onset slowly-progressive episodic memory impairment with the P392L-variant in SQSTM1 . The patient showed cortical atrophy and hypometabolism in the temporal lobes, but no amyloidosis biomarkers. As symptoms/neuroimaging were suggestive for Alzheimer’s disease—but biomarkers were not—and considering the family-history, genetic analysis was performed, revealing the P392L-variant in SQSTM1 , which encodes for sequestosome-1/p62. Increasing evidence suggests a p62 involvement in neurodegeneration and SQSTM1 mutations have been found to cause amyotrophic lateral sclerosis/frontotemporal dementia. Our report …suggests that the clinical spectrum of SQSTM1 variants is wider. Show more

Keywords: Alzheimer’s disease, early-onset dementia, next-generation sequencing, p62, SQSTM1

DOI: 10.3233/JAD-201231

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 477-481, 2021

Authors: Park, Yae Won | Choi, Dongmin | Park, Mina | Ahn, Sung Jun | Ahn, Sung Soo | Suh, Sang Hyun | Lee, Seung-Koo | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Noninvasive identification of amyloid-β (Aβ) is important for better clinical management of mild cognitive impairment (MCI) patients. Objective: To investigate whether radiomics features in the hippocampus in MCI improve the prediction of cerebrospinal fluid (CSF) Aβ42 status when integrated with clinical profiles. Methods: A total of 407 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative were allocated to training (n  = 324) and test (n  = 83) sets. Radiomics features (n  = 214) from the bilateral hippocampus were extracted from magnetic resonance imaging (MRI). A cut-off of <192 pg/mL was applied to define CSF Aβ42 status. …After feature selection, random forest with subsampling methods were utilized to develop three models with which to predict CSF Aβ42 : 1) a radiomics model; 2) a clinical model based on clinical profiles; and 3) a combined model based on radiomics and clinical profiles. The prediction performances thereof were validated in the test set. A prediction model using hippocampus volume was also developed and validated. Results: The best-performing radiomics model showed an area under the curve (AUC) of 0.674 in the test set. The best-performing clinical model showed an AUC of 0.758 in the test set. The best-performing combined model showed an AUC of 0.823 in the test set. The hippocampal volume model showed a lower performance, with an AUC of 0.543 in the test set. Conclusion: Radiomics models from MRI can help predict CSF Aβ42 status in MCI patients and potentially triage the patients for invasive and costly Aβ tests. Show more

Keywords: Amyloid, artificial intelligence, machine learning, mild cognitive impairment, radiomics

DOI: 10.3233/JAD-200734

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 483-491, 2021

Authors: Li, Shumei | Daamen, Marcel | Scheef, Lukas | Gaertner, Florian C. | Buchert, Ralph | Buchmann, Martina | Buerger, Katharina | Catak, Cihan | Dobisch, Laura | Drzezga, Alexander | Ertl-Wagner, Birgit | Essler, Markus | Fliessbach, Klaus | Haynes, John Dylan | Incesoy, Enise Irem | Kilimann, Ingo | Krause, Bernd J. | Lange, Catharina | Laske, Christoph | Priller, Josef | Ramirez, Alfredo | Reimold, Matthias | Rominger, Axel | Roy, Nina | Scheffler, Klaus | Maurer, Angelika | Schneider, Anja | Spottke, Annika | Spruth, Eike Jakob | Teipel, Stefan J. | Tscheuschler, Maike | Wagner, Michael | Wolfsgruber, Steffen | Düzel, Emrah | Jessen, Frank | Peters, Oliver | Boecker, Henning | the DELCODE Study Group

Article Type: Research Article

Abstract: Background: Amyloid-β accumulation was found to alter precuneus-based functional connectivity (FC) in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia, but its impact is less clear in subjective cognitive decline (SCD), which in combination with AD pathologic change is theorized to correspond to stage 2 of the Alzheimer’s continuum in the 2018 NIA-AA research framework. Objective: This study addresses how amyloid pathology relates to resting-state fMRI FC in SCD, especially focusing on the precuneus. Methods: From the DELCODE cohort, two groups of 24 age- and gender-matched amyloid-positive (SCDAβ+) and amyloidnegative SCD (SCDβ−) patients were selected …according to visual [18F]-Florbetaben (FBB) PET readings, and studied with resting-state fMRI. Local (regional homogeneity [ReHo], fractional amplitude of low-frequency fluctuations [fALFF]) and global (degree centrality [DC], precuneus seed-based FC) measures were compared between groups. Follow-up correlation analyses probed relationships of group differences with global and precuneal amyloid load, as measured by FBB standard uptake value ratios (SUVR=⫖FBB). Results: ReHo was significantly higher (voxel-wise p < 0.01, cluster-level p < 0.05) in the bilateral precuneus for SCDAβ+patients, whereas fALFF was not altered between groups. Relatively higher precuneus-based FC with occipital areas (but no altered DC) was observed in SCDAβ+ patients. In this latter cluster, precuneus-occipital FC correlated positively with global (SCDAβ+) and precuneus SUVRFBB (both groups). Conclusion: While partial confounding influences due to a higher APOE ε4 carrier ratio among SCDAβ+ patients cannot be excluded, exploratory results indicate functional alterations in the precuneus hub region that were related to amyloid-β load, highlighting incipient pathology in stage 2 of the AD continuum. Show more

Keywords: Alzheimer’s disease, amyloid, functional magnetic resonance imaging, occipital cortex, PET, precuneus, prodromal symptoms, subjective cognitive decline

DOI: 10.3233/JAD-200472

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 493-509, 2021

Authors: Berger, Miles | Cooter, Mary | Roesler, Alexander S. | Chung, Stacey | Park, John | Modliszewski, Jennifer L. | VanDusen, Keith W. | Thompson, J. Will | Moseley, Arthur | Devinney, Michael J. | Smani, Shayan | Hall, Ashley | Cai, Victor | Browndyke, Jeffrey N. | Lutz, Michael W. | Corcoran, David L.

Article Type: Research Article

Abstract: Background: APOE4 has been hypothesized to increase Alzheimer’s disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. Objective: Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number. Methods: We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction. Results: Increasing APOE4 copy number …was associated with a significant decrease in a CRP peptide level across all five models (q  < 0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q  < 0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million. Conclusion: Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies. Show more

Keywords: Alzheimer disease, apolipoprotein E4, biomarker, C-reactive protein, cerebrospinal fluid, complement activation, mass spectrometry, neurogenic inflammation

DOI: 10.3233/JAD-200747

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 511-530, 2021

Authors: Jiang, Yang | Li, Juan | Schmitt, Frederick A. | Jicha, Gregory A. | Munro, Nancy B. | Zhao, Xiaopeng | Smith, Charles D. | Kryscio, Richard J. | Abner, Erin L.

Article Type: Research Article

Abstract: Background: Early prognosis of high-risk older adults for amnestic mild cognitive impairment (aMCI), using noninvasive and sensitive neuromarkers, is key for early prevention of Alzheimer’s disease. We have developed individualized measures in electrophysiological brain signals during working memory that distinguish patients with aMCI from age-matched cognitively intact older individuals. Objective: Here we test longitudinally the prognosis of the baseline neuromarkers for aMCI risk. We hypothesized that the older individuals diagnosed with incident aMCI already have aMCI-like brain signatures years before diagnosis. Methods: Electroencephalogram (EEG) and memory performance were recorded during a working memory task at baseline. …The individualized baseline neuromarkers, annual cognitive status, and longitudinal changes in memory recall scores up to 10 years were analyzed. Results: Seven of the 19 cognitively normal older adults were diagnosed with incident aMCI for a median 5.2 years later. The seven converters’ frontal brainwaves were statistically identical to those patients with diagnosed aMCI (n  = 14) at baseline. Importantly, the converters’ baseline memory-related brainwaves (reduced mean frontal responses to memory targets) were significantly different from those who remained normal. Furthermore, differentiation pattern of left frontal memory-related responses (targets versus nontargets) was associated with an increased risk hazard of aMCI (HR = 1.47, 95% CI 1.03, 2.08). Conclusion: The memory-related neuromarkers detect MCI-like brain signatures about five years before diagnosis. The individualized frontal neuromarkers index increased MCI risk at baseline. These noninvasive neuromarkers during our Bluegrass memory task have great potential to be used repeatedly for individualized prognosis of MCI risk and progression before clinical diagnosis. Show more

Keywords: Amnestic mild cognitive impairment, cognitive ERP, delayed match-to-sample, dementia risk, EEG, memory-related potentials, working memory

DOI: 10.3233/JAD-200931

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 531-541, 2021

Authors: Murchison, Charles F. | Kennedy, Richard E. | McConathy, Jonathan E. | Roberson, Erik D.

Article Type: Research Article

Abstract: Background: African Americans are at increased risk for Alzheimer’s disease (AD) but barriers to optimal clinical care are unclear. Objective: To comprehensively evaluate potential racial differences in the diagnosis and treatment of AD in an academic medical center. Methods: We used the clinical informatics tool, i2b2, to analyze all patient encounters for AD or mild cognitive impairment (MCI) in the University of Alabama at Birmingham Health System over a three-year period, examining neuroimaging rates and dementia-related medication use by race and clinic site using ratio tests on contingency tables of stratified patient counts. Results: …Enterprise-wide, African Americans were not underrepresented among outpatients seen for AD/MCI. However, there were differences in the clinic setting where visits occurred, with African Americans overrepresented in Geriatrics and primary care clinics and underrepresented in Memory Disorders specialty clinics. There were no racial differences in the rates at which any clinic ordered PET neuroimaging tests or dementia-related medications. However, unsurprisingly, specialty clinics ordered both PET neuroimaging and dementia-related medications at a higher rate than primary care clinics, and overall across the medical enterprise, African Americans were statistically less likely to have PET neuroimaging or dementia-related medications ordered. Conclusion: African Americans with AD/MCI were not underrepresented at this academic medical center but were somewhat less likely to have PET neuroimaging or to be on dementia-related medications, potentially in part from underrepresentation in the specialty clinics where these orders are more likely. The reasons for this underrepresentation in specialty clinics are likely multifactorial and important to better understand. Show more

Keywords: African Americans, Alzheimer’s disease, cognition, dementia, geriatrics, mild cognitive impairment, neuroimaging, racial factors, referral and consultation

DOI: 10.3233/JAD-200796

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 543-557, 2021

Authors: Mozersky, Jessica | Hartz, Sarah | Linnenbringer, Erin | Levin, Lillie | Streitz, Marissa | Stock, Kristin | Moulder, Krista | Morris, John C.

Article Type: Research Article

Abstract: Background: Cognitively normal (CN) older adults participating in Alzheimer’s disease (AD) research increasingly ask for their research results—including genetic and neuroimaging findings—to understand their risk of developing AD dementia. AD research results are typically not returned for multiple reasons, including possible psychosocial harms of knowing one is at risk of a highly feared and untreatable disease. Objective: We developed materials that convey information about 5-year absolute risk of developing AD dementia based on research results. Methods: 20 CN older adults who received a research brain MRI result were interviewed regarding their wishes for research results to …inform material development (Pilot 1). Following material development, 17 CN older adults evaluated the materials for clarity and acceptability (Pilot 2). All participants were community-dwelling older adults participating in longitudinal studies of aging at a single site. Results: Participants want information on their risk of developing AD dementia to better understand their own health, satisfy curiosity, inform family, and future planning. Some articulated concerns, but the majority wanted to know their risk despite the limitations of information. Participants found the educational materials and results report clear and acceptable, and the majority would want to know their research results after reviewing them. Conclusion: These materials will be used in a clinical study examining the psychosocial and cognitive effects of offering research results to a cohort of CN older adults. Future AD research may incorporate the return of complex risk information to CN older adults, and materials are needed to communicate this information. Show more

Keywords: Alzheimer’s disease dementia, biomarkers, cognitively normal older adults, genetics, health communication, imaging, pre-symptomatic, research ethics, return of research results, risk

DOI: 10.3233/JAD-200993

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 559-572, 2021

Authors: Seino, Yusuke | Nakamura, Takumi | Harada, Tomoo | Nakahata, Naoko | Kawarabayashi, Takeshi | Ueda, Tetsuya | Takatama, Masamitsu | Shoji, Mikio

Article Type: Research Article

Abstract: Background: High sensitivity liquid chromatography mass spectrometry (LC-MS/MS) was recently introduced to measure amyloid-β (Aβ) species, allowing for a simultaneous assay that is superior to ELISA, which requires more assay steps with multiple antibodies. Objective: We validated the Aβ1-38 , Aβ1-40 , Aβ1-42 , and Aβ1-43 assay by LC-MS/MS and compared it with ELISA using cerebrospinal fluid (CSF) samples to investigate its feasibility for clinical application. Methods: CSF samples from 120 subjects [8 Alzheimer’s disease (AD) with dementia (ADD), 2 mild cognitive dementia due to Alzheimer’s disease (ADMCI), 14 cognitively unimpaired (CU), and 96 neurological …disease subjects] were analyzed. Aβ species were separated using the Shimadzu Nexera X2 system and quantitated using a Qtrap 5500 LC-MS/MS system. Aβ1-40 and Aβ1-42 levels were validated using ELISA. Results: CSF levels in CU were 666±249 pmol/L in Aβ1-38 , 2199±725 pmol/L in Aβ1-40 , 153.7±79.7 pmol/L in Aβ1-42 , and 9.78±4.58 pmol/L in Aβ1-43 . The ratio of the amounts of Aβ1-38 , Aβ1-40 , Aβ1-42 , and Aβ1-43 was approximately 68:225:16:1. Linear regression analyses showed correlations among the respective Aβ species. Both Aβ1-40 and Aβ1-42 values were strongly correlated with ELISA measurements. No significant differences were observed in Aβ1-38 or Aβ1-40 levels between AD and CU. Aβ1-42 and Aβ1-43 levels were significantly lower, whereas the Aβ1-38/1-42 , Aβ1-38/1-43 , and Aβ1-40/ Aβ1-43 ratios were significantly higher in AD than in CU. The basic assay profiles of the respective Aβ species were adequate for clinical usage. Conclusion: A quantitative LC-MS/MS assay of CSF Aβ species is as reliable as specific ELISA for clinical evaluation of CSF biomarkers for AD. Show more

Keywords: Aβ1-38, Aβ1-40, Aβ1-42 Aβ1-43, cerebrospinal fluid, ELISA, liquid chromatography mass spectrometry

DOI: 10.3233/JAD-200987

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 573-584, 2021

Authors: Wang, Qiang | Chen, Ben | Zhong, Xiaomei | Zhou, Huarong | Zhang, Min | Mai, Naikeng | Wu, Zhangying | Huang, Xingxiao | Haehner, Antje | Chen, Xinru | Auber, Lavinia Alberi | Peng, Qi | Hummel, Thomas | Ning, Yuping

Article Type: Research Article

Abstract: Background: Odor identification dysfunction occurs early in Alzheimer’s disease (AD) and is considered a preclinical symptom along with subjective cognitive decline (SCD). Nevertheless, whether subjects with SCD are co-symptomatic with odor identification dysfunction remains unclear. Objective: To compare the degree of odor identification dysfunction and assess the relation between odor identification and cognitive performance in the AD spectrum (including SCD, mild cognitive impairment (MCI), and AD). Methods: Patients (84 SCD, 129 MCI, 52 AD) and 35 controls underwent the Sniffin’ Sticks Screen 16 test and comprehensive neuropsychological examination. Results: Odor identification scores were progressively …lower moving from normal older adult to SCD, MCI, and AD. Additionally,the proportion of odor identification dysfunction were increasingly higher in the AD spectrum (p for trend <0.001), but no significant difference was found in the proportion of subjective olfactory dysfunction. No significant correlation was found between odor identification and cognition in the normal older adults and SCD subjects, but odor identification correlated with global cognition in the MCI (r = 0.199, p = 0.033) and in the AD (r = 0.300, p = 0.036) patients. Multiple linear regression showed that odor identification dysfunction was most strongly associated with memory among different cognitive subdomains and was most strongly associated with immediate verbal recall among different memory subdomains. Conclusion: Odor identification dysfunction is already present with SCD and deepens with disease severity in the AD spectrum, and it may contribute to predicting cognitive decline and identifying SCD subjects who are at risk of developing AD. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, neuropsychology, olfactory dysfunction, subjective cognitive decline

DOI: 10.3233/JAD-201168

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 585-595, 2021