Journal of Alzheimer's Disease - Volume 86, issue 4

Authors: Payne, Sarah | Shofer, Jane B. | Shutes-David, Andrew | Li, Ge | Jankowski, Adrienne | Dean, Pamela | Tsuang, Debby

Article Type: Research Article

Abstract: Background: Many patients with dementia with Lewy bodies (DLB) miss out on the best standards of care and psychosocial support due to diagnostic delays or inaccuracies following symptom onset. Objective: This study seeks to identify baseline characteristics in individuals with mild cognitive impairment (MCI) that correlate with eventual conversion to DLB or Alzheimer’s disease (AD). Methods: Baseline neuropsychological and neuropsychiatric data were analyzed in National Alzheimer’s Coordinating Center participants who completed the Uniform Data Set between 2006 and 2020 and subsequently converted from MCI to DLB or AD (n  = 1632). Results: Only 6% of …participants with MCI converted to DLB. Among those who converted to DLB, multidomain amnestic MCI (aMCI) was the most common subtype at study entry. As part of logistic regression analyses, odds ratios (ORs) were estimated for conversion to DLB versus AD based on study-entry characteristics, adjusting for age, sex, education, and years to diagnosis. The strongest predictors of conversion to DLB (p ≤0.0001) were nonamnestic MCI versus aMCI (OR 8.2, CI [5.0, 14]), multidomain MCI versus single-domain MCI (OR 2.7, CI [1.7. 4.2]), male sex (OR 4.2, CI [2.5, 7.1]), and presence of nighttime behaviors (OR 4.4 CI [2.8, 6.9]). Conclusion: A diagnosis of prodromal DLB should be considered in individuals with MCI who present with prominent executive/visuospatial deficits, neuropsychiatric symptoms, and less memory impairment. Early diagnosis of DLB may guide treatment planning, including the avoidance of antipsychotic medications in patients who develop psychotic symptoms, caregiver support, and initiation of early treatment(s) once medications become available. Show more

Keywords: Alzheimer’s disease, amnestic, dementia with Lewy bodies, mild cognitive impairment, multidomain, NACC, nonamnestic, single domain

DOI: 10.3233/JAD-215428

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1643-1654, 2022

Authors: Zhao, Ying | Yang, Yang | Wang, Dongxue | Wang, Jie | Gao, Weiying

Article Type: Research Article

Abstract: Background: Diabetic cognitive dysfunction (DCD) is one of severe diabetic complications and might develop to irreversible dementia. Early diagnosis and detection of DCD is significant for prevention and treatment. Objective: The main objective of this study was to investigate the amino acid profiles of rat with DCD in the cerebrospinal fluid (CSF) to distinguish the early specific biomarkers. Methods: In total, rats were assigned into control and model groups. Model was induced by intraperitoneal injection of streptozotocin. The Morris water maze (MWM) method was used to evaluate learning and memory in rats on the 13th week …after the model established. CSF samples were collected via cisterna magna puncture at the 0th, 5th, 9th, and 13th week, and amino acids profiling of CSF samples were performed via ultra performance liquid chromatography multiple reaction monitoring mass spectrometry (UPLC-MRM-MS). The amino acid profile was processed through multivariate analysis to identify potential biomarkers, and the related metabolic pathways were analyzed by MetaboAnalyst 5.0. Results: Compared to the control group, the escape latency of the MWM was significantly prolonged in model group rats (p  < 0.05). Different amino acid profiles were obtained between two groups. L-Alanine, L-Glutamine, L-Lysine, L-Serine, and L-Threonine were identified as potential biomarkers for DCD. These biomarkers are principally involved in glycine, serine, and threonine metabolism, aminoacyl-tRNA biosynthesis, alanine, aspartate, and glutamate metabolism, and glyoxylate and dicarboxylate metabolism. Conclusion: There are amino acid biomarkers in the CSF of rat with DCD. The mechanism of DCD is related to those pathways, which provide help for the early diagnosis and treatment and mechanism research. Show more

Keywords: Amino acid profiles, cerebrospinal fluid, diabetic cognitive dysfunction, target metabolomics, UPLC-MRM-MS

DOI: 10.3233/JAD-215725

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1655-1665, 2022

Authors: Noel, Margaret A. | Lackey, Elizabeth | Labi, Vanna | Bouldin, Erin D.

Article Type: Research Article

Abstract: Background: Family caregivers of people with dementia often experience negative impacts including stress and burden. Psychoeducational programs can reduce these negative outcomes. Objective: To evaluate whether this virtual caregiver education program changes caregiver confidence, self-efficacy, and burden relative to controls. Methods: This was a pre-post comparison of a five-week, synchronous, virtual caregiver education program delivered by a clinician and caregiver support specialist covering aspects of dementia, including changes in cognition, behavior, functional abilities, caregiver-care recipient roles, communication, and caregiver self-care. Caregivers (n  = 90) were surveyed at baseline, at completion of intervention, and three months thereafter; controls …(n  = 44) were surveyed at two points six weeks apart. We compared validated measures of caregiver confidence, self-efficacy, and burden using generalized estimating equations. Results: Participants’ confidence and self-efficacy increased over follow-up compared with controls (p  < 0.01 for intervention* time in regression models). There was no difference in burden. All participants (100%) reported perceived increased knowledge, 97% perceived increased confidence, and 95% perceived increased ability to manage dementia-related behaviors after the course. Conclusion: This virtual caregiver education program was effective in improving caregiver confidence and self-efficacy and participants’ self-reported impact was equivalent to those who had taken previous courses in person. Caregivers with greater confidence and self-efficacy have been shown to have better health outcomes and decreased stress and depressive symptoms. Health professionals, health care organizations, and public health agencies should consider using efficacious virtual caregiver education programs in rural and other community settings, during public health crises, or in standard practice as an alternative to in-person programs. Show more

Keywords: Alzheimer’s disease, caregiver education, dementia, health education, internet-based intervention, program evaluation, rural population, self-concept, self efficacy

DOI: 10.3233/JAD-215359

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1667-1678, 2022

Authors: Li, Chaolin | Liu, Mianxin | Xia, Jing | Mei, Lang | Yang, Qing | Shi, Feng | Zhang, Han | Shen, Dinggang

Article Type: Research Article

Abstract: Background: The detection of amyloid-β (Aβ) deposition in the brain provides crucial evidence in the clinical diagnosis of Alzheimer’s disease (AD). However, the current positron emission tomography (PET)-based brain Aβ examination suffers from the problems of coarse visual inspection (in many cases, with 2-class stratification) and high scanning cost. Objective: 1) To characterize the non-binary Aβ deposition levels in the AD continuum based on clustering of PET data, and 2) to explore the feasibility of predicting individual Aβ deposition grades with non-invasive functional magnetic resonance imaging (fMRI). Methods: 1) Individual whole-brain Aβ-PET images from the OASIS-3 …dataset (N  = 258) were grouped into three clusters (grades) with t -SNE and k -means. The demographical data as well as global and regional standard uptake value ratios (SUVRs) were compared among the three clusters with Chi-square tests or ANOVA tests. 2) From resting-state fMRI, both conventional functional connectivity (FC) and high-order FC networks were constructed and the topological architectures of the two networks were jointly learned with graph convolutional networks (GCNs) to predict the Aβ-PET grades for each individual. Results: We found three clearly separated clusters, indicating three Aβ-PET grades. There were significant differences in gender, age, cognitive ability, APOE type, as well as global and regional SUVRs among the three grades we found. The prediction of Aβ-PET grades with GCNs on FC for the 258 samples in the AD continuum reached a satisfactory averaged accuracy (78.8%) in the two-class classification tasks. Conclusion: The results demonstrated the feasibility of using deep learning on a non-invasive brain functional imaging technique to approximate PET-based Aβ deposition grading. Show more

Keywords: Amyloid-β, brain network, functional connectivity, graph convolutional neural network, positron emission tomography

DOI: 10.3233/JAD-215497

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1679-1693, 2022

Authors: Zhang, Lingyu | Fu, Yu | Zhao, Ziyang | Cong, Zhaoyang | Zheng, Weihao | Zhang, Qin | Yao, Zhijun | Hu, Bin | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI), which is generally regarded as the prodromal stage of Alzheimer’s disease (AD), is associated with morphological changes in brain structures, particularly the hippocampus. However, the indicators for characterizing the deformation of hippocampus in conventional methods are not precise enough and ignore the evolution information with the course of disease. Objective: The purpose of this study was to investigate the temporal evolution pattern of MCI and predict the conversion of MCI to AD by using the multivariate morphometry statistics (MMS) as fine features. Methods: First, we extracted MMS features from MRI scans …of 64 MCI converters (MCIc), 81 MCI patients who remained stable (MCIs), and 90 healthy controls (HC). To make full use of the time information, the dynamic MMS (DMMS) features were defined. Then, the areas with significant differences between pairs of the three groups were analyzed using statistical methods and the atrophy/expansion were identified by comparing the metrics. In parallel, patch selection, sparse coding, dictionary learning and maximum pooling were used for the dimensionality reduction and the ensemble classifier GentleBoost was used to classify MCIc and MCIs. Results: The longitudinal analysis revealed that the atrophy of both MCIc and MCIs mainly distributed in dorsal CA1, then spread to subiculum and other regions gradually, while the atrophy area of MCIc was larger and more significant. And the introduction of longitudinal information promoted the accuracy to 91.76% for conversion prediction. Conclusion: The dynamic information of hippocampus holds a huge potential for understanding the pathology of MCI. Show more

Keywords: Alzheimer’s disease, classification, hippocampus, longitudinal study, mild cognitive impairment

DOI: 10.3233/JAD-215568

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1695-1710, 2022

Authors: Khandia, Rekha | Ali Khan, Azmat | Alexiou, Athanasios | Povetkin, Sergey Nikolaevich | Verevkina, Marina Nikolaevna

Article Type: Research Article

Abstract: Background: Bim is a Bcl-2 homology 3 (BH3)-only proteins, a group of pro-apoptotic proteins involved in physiological and pathological conditions. Both the overexpression and under-expression of Bim protein are associated with the diseased condition, and various isoforms of Bim protein are present with differential apoptotic potential. Objective: The present study attempted to envisage the association of various molecular signatures with the codon choices of Bim isoforms. Methods: Molecular signatures like composition, codon usage, nucleotide skews, the free energy of mRNA transcript, physical properties of proteins, codon adaptation index, relative synonymous codon usage, and dinucleotide …odds ratio were determined and analyzed for their associations with codon choices of Bim gene. Results: Skew analysis of the Bim gene indicated the preference of C nucleotide over G, A, and T and preference of G over T and A nucleotides was observed. An increase in C content at the first and third codon position increased gene expression while it decreased at the second codon position. Compositional constraints on nucleotide C at all three codon positions affected gene expression. The analysis revealed an exceptionally high usage of CpC dinucleotide in all the envisaged 31 isoforms of Bim . We correlated it with the requirement of rapid demethylation machinery to fine-tune the Bim gene expression. Also, mutational pressure played a dominant role in shaping codon usage bias in Bim isoforms. Conclusion: An exceptionally high usage of CpC dinucleotide in all the envisaged 31 isoforms of Bim indicates a high order selectional force to fine tune Bim gene expression. Show more

Keywords: Bim gene, CAI, CpC dinucleotide, codon usage, pro-apoptotic gene

DOI: 10.3233/JAD-215691

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1711-1725, 2022

Authors: Sandberg, Alexandra A. | Manning, Evan | Wilkins, Heather M. | Mazzarino, Randall | Minckley, Taylor | Swerdlow, Russell H. | Patterson, David | Qin, Yan | Linseman, Daniel A.

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) is a principal cleavage product of amyloid-β protein precursor (AβPP) and is widely recognized as a key pathogenic player in Alzheimer’s disease (AD). Yet, there is increasing evidence of a neurotoxic role for the AβPP intracellular domain (AICD) which has been proposed to occur through its nuclear function. Intriguingly, there is a γ-secretase resident at the mitochondria which could produce AICD locally. Objective: We examined the potential of AICD to induce neuronal apoptosis when targeted specifically to the mitochondria and compared its mechanism of neurotoxicity to that of Aβ. Methods: We utilized transient …transfection of HT22 neuronal cells with bicistronic plasmids coding for DsRed and either empty vector (Ires), Aβ, AICD59 , or mitochondrial-targeted AICD (mitoAICD) in combination with various inhibitors of pathways involved in apoptosis. Results: AICD induced significant neuronal apoptosis only when targeted to the mitochondria. Apoptosis required functional mitochondria as neither Aβ nor mitoAICD induced significant toxicity in cells devoid of mitochondrial DNA. Both glutathione and a Bax inhibitor protected HT22 cells from either peptide. However, inhibition of the mitochondrial permeability transition pore only protected from Aβ, while pan-caspase inhibitors uniquely rescued cells from mitoAICD. Conclusion: Our results show that AICD displays a novel neurotoxic function when targeted to mitochondria. Moreover, mitoAICD induces apoptosis via a mechanism that is distinct from that of Aβ. These findings suggest that AICD produced locally at mitochondria via organelle-specific γ-secretase could act in a synergistic manner with Aβ to cause mitochondrial dysfunction and neuronal death in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor intracellular domain (AICD), caspase, mitochondria

DOI: 10.3233/JAD-215108

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1727-1744, 2022

Authors: O’Bryant, Sid E. | Petersen, Melissa | Hall, James | Johnson, Leigh | for the HABS-HD Study Team

Article Type: Research Article

Abstract: Background: Despite the tremendous amount of research on Alzheimer’s disease (AD) biomarkers, very little data is available regarding the fundamental biomarkers of AD among Mexican Americans. Objective: Here we sought to examine the link between metabolic markers and brain amyloid among Mexican Americans as compared to non-Hispanic whites from the Health & Aging Brain Study –Health Disparities (HABS-HD) cohort. Methods: PET amyloid (florbetaben) data was analyzed from 34 Mexican American and 22 non-Hispanic white participants. Results: Glucagon (t  = 3.84, p  < 0.001) and insulin (t  = –2.56, p  = 0.02) were both significantly related to global SUVR …levels among Mexican Americans. Glucagon and insulin were both related to most ROIs. No metabolic markers were significantly related to brain amyloid levels among non-Hispanic whites. Conclusion: Metabolic markers are related to brain amyloid burden among Mexican Americans. Given the increased risk for diabetes, additional research is needed to determine the impact of diabetes on core AD biomarkers among this underserved population. Show more

Keywords: Alzheimer’s disease, amyloid, health disparities, Hispanic

DOI: 10.3233/JAD-215620

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1745-1750, 2022

Authors: Ibarrondo, Oliver | Huerta, José María | Amiano, Pilar | Andreu-Reinón, María Encarnación | Mokoroa, Olatz | Ardanaz, Eva | Larumbe, Rosa | Colorado-Yohar, Sandra M. | Navarro-Mateu, Fernando | Chirlaque, María Dolores | Mar, Javier

Article Type: Research Article

Abstract: Background: Dementia prevention can be addressed if the intervention is applied early. Objective: The objective of this study was to develop and validate competing risk models to predict the late risk of dementia based on variables assessed in middle age in a southern European population. Methods: We conducted a prospective observational study of the EPIC-Spain cohort that included 25,015 participants. Dementia cases were identified from electronic health records and validated by neurologists. Data were gathered on sociodemographic characteristics and cardiovascular risk factors. To stratify dementia risk, Fine and Gray competing risk prediction models were constructed for …the entire sample and for over-55-year-olds. Risk scores were calculated for low (the 30% of the sample with the lowest risk), moderate (> 30% –60%), and high (> 60% –100%) risk. Results: The 755 cases of dementia identified represented a cumulative incidence of 3.1% throughout the study period. The AUC of the model for over-55-year-olds was much higher (80.8%) than the overall AUC (68.5%) in the first 15 years of follow-up and remained that way in the subsequent follow-up. The weight of the competing risk of death was greater than that of dementia and especially when the entire population was included. Conclusion: This study presents the first dementia risk score calculated in a southern European population in mid-life and followed up for 20 years. The score makes it feasible to achieve the early identification of individuals in a southern European population who could be targeted for the prevention of dementia based on the intensive control of risk factors. Show more

Keywords: Alzheimer’s disease, competing risks, dementia, predictive models, prevention, risk score

DOI: 10.3233/JAD-215211

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1751-1762, 2022

Authors: Jester, Dylan J. | Vyhnálek, Martin | Andel, Ross | Marková, Hana | Nikolai, Tomás | Laczó, Jan | Matusková, Veronika | Cechová, Katerina | Sheardova, Katerina | Hort, Jakub

Article Type: Research Article

Abstract: Background: Older adults with subjective cognitive decline (SCD) are at an increased risk of progression to mild cognitive impairment (MCI) or dementia. However, few have examined the specific cognitive tests that are associated with progression. Objective: This study examined performance on 18 neuropsychological tests among participants with SCD who later progressed to MCI or dementia. Methods: We included 131 participants from the Czech Brain Aging Study that had SCD at baseline. They completed a comprehensive neuropsychological battery including cognitive tests from the Uniform Data Set 2.0 enriched by the verbal memory test Rey Auditory Verbal Learning …Test (RAVLT) and Rey-Osterrieth Complex Figure Test (ROCFT). Results: Fifty-five participants progressed: 53% to non-amnestic MCI (naMCI), 44% to amnestic MCI (aMCI), and 4% to dementia. Scoring one SD below the mean at baseline on the RAVLT 1 and RAVLT 1–5 was associated with 133% (RAVLT 1; HR: 2.33 [1.50, 3.62 ]) and 122% (RAVLT 1–5; HR: 2.22 [1.55, 3.16 ]) greater risk of progression to MCI or dementia over 3.84 years on average. Worse performance on the RAVLT 5, RAVLT 1–5, RAVLT 30, and ROCFT–Recall was associated with progression to aMCI whereas worse performance on the RAVLT 1, TMT B, and Boston Naming Test was associated with progression to naMCI. Conclusion: At baseline, lower verbal memory performance was most strongly associated with progression to aMCI whereas lower executive or language performance was most strongly associated with progression to naMCI. Show more

Keywords: Cognitive aging, immediate recall, subjective memory complaints, verbal memory

DOI: 10.3233/JAD-215291

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1763-1774, 2022