Journal of Alzheimer's Disease - Volume 83, issue 1

Authors: Sutin, Angelina R. | Aschwanden, Damaris | Luchetti, Martina | Stephan, Yannick | Terracciano, Antonio

Article Type: Research Article

Abstract: Background: A sense of purpose in life has been associated with healthier cognitive outcomes across adulthood, including risk of dementia. The robustness and replicability of this association, however, has yet to be evaluated systematically. Objective: To test whether a greater sense of purpose in life is associated with lower risk of dementia in four population-based cohorts and combined with the published literature. Methods: Random-effect meta-analysis of prospective studies (individual participant data and from the published literature identified through a systematic review) that examined sense of purpose and risk of incident dementia. Results: In six …samples followed up to 17 years (four primary data and two published; total N  = 53,499; n  = 5,862 incident dementia), greater sense of purpose in life was associated with lower dementia risk (HR = 0.77, 95%CI = 0.73–0.81, p  < 0.001). The association was generally consistent across cohorts (I2  = 47%), remained significant controlling for clinical (e.g., depression) and behavioral (e.g., physical inactivity) risk factors, and was not moderated by age, gender, or education. Conclusion: Sense of purpose is a replicable and robust predictor of lower risk of incident dementia and is a promising target of intervention for cognitive health outcomes. Show more

Keywords: Cognitive health, dementia risk, meta-analysis, sense of purpose, well-being

DOI: 10.3233/JAD-210364

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 249-258, 2021

Authors: Alexopoulos, Panagiotis | Skondra, Maria | Kontogianni, Evagellia | Vratsista, Aikaterini | Frounta, Maria | Konstantopoulou, Georgia | Aligianni, Suzana Ioanna | Charalampopoulou, Marina | Lentzari, Iliana | Gourzis, Philippos | Kliegel, Matthias | Economou, Polychronis | Politis, Antonios

Article Type: Research Article

Abstract: Background: Telephone-based neurocognitive instruments embody valuable tools in identifying cognitive impairment in research settings and lately also in clinical contexts due to the pandemic crisis. The accuracy of the Cognitive Telephone Screening Instrument (COGTEL) in detecting mild- (MiND) and major (MaND) neurocognitive disorder has not been studied yet. Objective: Comparison of the utility of COGTEL and COGTEL+, which is enriched with orientation items, with the modified Mini-Mental State Examination (3MS) in detecting MiND and MaND due to Alzheimer’s disease (AD) and assessment of the impact of COGTEL face-to-face-versus telephone administration on individual performance. Methods: The …study included 197 cognitively intact individuals (CI), being at least 45 years old, 95 and 65 patients with MiND and MaND due to AD, respectively. In 20 individuals COGTEL was administered both in face-to-face and telephone sessions. Statistical analyses included proportional odds logistic regression models, stratified repeated random subsampling used to recursive partitioning to training and validation set (70/30 ratio), and an appropriate F-test. Results: All studied instruments were significant predictors of diagnostic outcome, but COGTEL+ and 3MS explained more variance relative to the original COGTEL. Except for the validation regression models including COGTEL in which the average misclassification error slightly exceeded 15%, in all other cases the average misclassification errors (%) were lower than 15%. COGTEL administration modality was not related to systematic over- or underestimation of performance on COGTEL. Conclusion: COGTEL+ is a valuable instrument in detecting MiND and MaND and can be administered in face-to-face or telephone sessions. Show more

Keywords: Mild and major neurocognitive disorder, modified Mini-Mental State Examination, telephone-based neurocognitive testing

DOI: 10.3233/JAD-210477

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 259-268, 2021

Authors: van der Lee, Sven J. | van Steenoven, Inger | van de Beek, Marleen | Tesi, Niccolò | Jansen, Iris E. | van Schoor, Natasja M. | Reinders, Marcel J.T. | Huisman, Martijn | Scheltens, Philip | Teunissen, Charlotte E. | Holstege, Henne | van der Flier, Wiesje M. | Lemstra, Afina W.

Article Type: Research Article

Abstract: Background: Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity. Objective: We tested if genetic variants in part explain the heterogeneity in DLB. Methods: We tested the effects of variants previously associated with DLB (near APOE, GBA , and SNCA ) and polygenic risk scores for Alzheimer’s disease (AD-PRS) and Parkinson’s disease (PD-PRS). We studied 190 probable DLB patients from the Alzheimer’s dementia cohort and compared them to 2,552 control subjects. The p-tau/Aβ1–42 ratio in cerebrospinal fluid was used as in vivo proxy to separate …DLB cases into DLB with concomitant AD pathology (DLB-AD) or DLB without AD (DLB-pure). We studied the clinical measures age, Mini-Mental State Examination (MMSE), and the presence of core symptoms at diagnosis and disease duration. Results: We found that all studied genetic factors significantly associated with DLB risk (all-DLB). Second, we stratified the DLB patients by the presence of concomitant AD pathology and found that APOE ɛ4 and the AD-PRS associated specifically with DLB-AD, but less with DLB-pure. In addition, the GBA p.E365K variant showed strong associated with DLB-pure and less with DLB-AD. Last, we studied the clinical measures and found that APOE ɛ4 associated with reduced MMSE, higher odds to have fluctuations and a shorter disease duration. In addition, the GBA p.E365K variant reduced the age at onset by 5.7 years, but the other variants and the PRS did not associate with clinical features. Conclusion: These finding increase our understanding of the pathological and clinical heterogeneity in DLB. Show more

Keywords: Dementia with Lewy bodies, genetic risk factors, genotype-phenotype associations, polygenic risk scores

DOI: 10.3233/JAD-210365

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 269-279, 2021

Authors: Takao, Hidemasa | Amemiya, Shiori | Abe, Osamu | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Scan acceleration techniques, such as parallel imaging, can reduce scan times, but reliability is essential to implement these techniques in neuroimaging. Objective: To evaluate the reproducibility of the longitudinal changes in brain morphology determined by longitudinal voxel-based morphometry (VBM) between non-accelerated and accelerated magnetic resonance images (MRI) in normal aging, mild cognitive impairment (MCI), and Alzheimer’s disease (AD). Methods: Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) 2 database, comprising subjects who underwent non-accelerated and accelerated structural T1-weighted MRI at screening and at a 2-year follow-up on 3.0 T Philips scanners, we examined the …reproducibility of longitudinal gray matter volume changes determined by longitudinal VBM processing between non-accelerated and accelerated imaging in 50 healthy elderly subjects, 54 MCI patients, and eight AD patients. Results: The intraclass correlation coefficient (ICC) maps differed among the three groups. The mean ICC was 0.72 overall (healthy elderly, 0.63; MCI, 0.75; AD, 0.63), and the ICC was good to excellent (0.6–1.0) for 81.4%of voxels (healthy elderly, 64.8%; MCI, 85.0%; AD, 65.0%). The differences in image quality (head motion) were not significant (Kruskal–Wallis test, p  = 0.18) and the within-subject standard deviations of longitudinal gray matter volume changes were similar among the groups. Conclusion: The results indicate that the reproducibility of longitudinal gray matter volume changes determined by VBM between non-accelerated and accelerated MRI is good to excellent for many regions but may vary between diseases and regions. Show more

Keywords: Acceleration, aging, Alzheimer’s disease, gray matter, intraclass correlation coefficient, mild cognitive impairment, morphology, parallel imaging, reliability, stability

DOI: 10.3233/JAD-210596

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 281-290, 2021

Authors: Gustavson, Daniel E. | Jak, Amy J. | Elman, Jeremy A. | Panizzon, Matthew S. | Franz, Carol E. | Gifford, Katherine A. | Reynolds, Chandra A. | Toomey, Rosemary | Lyons, Michael J. | Kremen, William S.

Article Type: Research Article

Abstract: Background: Although not strongly correlated with current objective cognitive ability, subjective cognitive decline (SCD) is a risk factor for Alzheimer’s disease. Most studies focus on SCD in relation to future decline rather than objective prior decline that it purportedly measures. Objective: We evaluated whether self-report of cognitive decline—as a continuous measure—corresponds to objectively-assessed episodic memory and executive function decline across the same period. Methods: 1,170 men completed the Everyday Cognition Questionnaire (ECog) at mean age 68 assessing subjective changes in cognitive ability relative to 10 years prior. A subset had mild cognitive impairment (MCI), but MCI …was diagnosed without regard to subjective decline. Participants completed up to 3 objective assessments of memory and executive function (M  = 56, 62, and 68 years). Informant-reported ECogs were completed for 1,045 individuals. Analyses controlled for depression and anxiety symptoms assessed at mean age 68. Results: Participant-reported ECog scores were modestly associated with objective decline for memory (β= –0.23, 95%CI [–0.37, –0.10]) and executive function (β= –0.19, 95%CI [–0.33, –0.05]) over the same time period. However, these associations were nonsignificant after excluding MCI cases. Results were similar for informant ratings. Participant-rated ECog scores were more strongly associated with concurrent depression and anxiety symptoms, (β= 0.44, 95%CI [0.36, 0.53]). Conclusion: Continuous SCD scores are correlated with prior objective cognitive changes in non-demented individuals, though this association appears driven by individuals with current MCI. However, participants’ current depression and anxiety ratings tend to be strongly associated with their SCD ratings. Thus, what primarily drives SCD ratings remains unclear. Show more

Keywords: Aging, cognitive decline, cognitive function, executive function, latent growth model, memory

DOI: 10.3233/JAD-210123

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 291-304, 2021

Authors: Goel, Anshika | Roy, Saurav | Punjabi, Khushboo | Mishra, Ritwick | Tripathi, Manjari | Shukla, Deepika | Mandal, Pravat K.

Article Type: Research Article

Abstract: Background: In vivo neuroimaging modalities such as magnetic resonance imaging (MRI), functional MRI (fMRI), magnetoencephalography (MEG), magnetic resonance spectroscopy (MRS), and quantitative susceptibility mapping (QSM) are useful techniques to understand brain anatomical structure, functional activity, source localization, neurochemical profiles, and tissue susceptibility respectively. Integrating unique and distinct information from these neuroimaging modalities will further help to enhance the understanding of complex neurological diseases. Objective: To develop a processing scheme for multimodal data integration in a seamless manner on healthy young population, thus establishing a generalized framework for various clinical conditions (e.g., Alzheimer’s disease). Methods: A …multimodal data integration scheme has been developed to integrate the outcomes from multiple neuroimaging data (fMRI, MEG, MRS, and QSM) spatially. Furthermore, the entire scheme has been incorporated into a user-friendly toolbox- “PRATEEK”. Results: The proposed methodology and toolbox has been tested for viability among fourteen healthy young participants. The data-integration scheme was tested for bilateral occipital cortices as the regions of interest and can also be extended to other anatomical regions. Overlap percentage from each combination of two modalities (fMRI-MRS, MEG-MRS, fMRI-QSM, and fMRI-MEG) has been computed and also been qualitatively assessed for combinations of the three (MEG-MRS-QSM) and four (fMRI-MEG-MRS-QSM) modalities. Conclusion: This user-friendly toolbox minimizes the need of an expertise in handling different neuroimaging tools for processing and analyzing multimodal data. The proposed scheme will be beneficial for clinical studies where geometric information plays a crucial role for advance brain research. Show more

Keywords: Multimodal integration, neuroimaging, region of interest, spatial overlap

DOI: 10.3233/JAD-210440

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 305-317, 2021

Authors: Richard, Erin L. | McEvoy, Linda K. | Oren, Eyal | Alcaraz, John E. | Laughlin, Gail A. | LaCroix, Andrea Z. | Salem, Rany M.

Article Type: Research Article

Abstract: Background: Reduced kidney function has been associated with cognitive decline. Most studies have examined a single marker of kidney function and have limited duration of follow-up. Objective: This study evaluated associations between markers of kidney function (urine albumin, estimated glomerular filtration rate [eGFR], and hyperuricemia) with cognitive performance over time. Methods: This is a longitudinal study of 1,634 community-dwelling adults (mean age = 71.7 years), with kidney function markers and cognitive ability measured at baseline (1992–1996) and at up to five additional time points with a maximum of 23.4 years (mean = 8.1 years) of follow-up. Associations between kidney function …and cognitive performance were assessed using linear mixed effects models. Testing for interaction by sex was conducted. Results: Albuminuria (urine albumin-to-creatinine ratio [ACR]≥30 mg/g) was associated with steeper annual declines in global cognitive function (MMSE, β= –0.12, p  = 0.003), executive function (Trails B, β= 4.50, p  < 0.0001) and episodic memory (Buschke total recall, β= –0.62, p  = 0.02) scores in men. Results were similar when cognitive test scores were regressed on latent trajectory classes of ACR. In men, hyperuricemia (serum uric acid [SUA]≥6.8 mg/dl for men and SUA≥6.0 mg/dl for women) was associated with lower baseline MMSE (β= –0.70, p  = 0.009) scores but not with MMSE change over time. No such associations were detected in women. There were no significant associations between eGFR and cognitive performance for either sex. Conclusion: In older men, albuminuria is an independent predictor of subsequent cognitive decline. More investigations are needed to explain the observed sex differences and the potential relationship between hyperuricemia and poorer global cognition. Show more

Keywords: Albuminuria, cognitive aging, dementia, glomerular filtration rate, uric acid

DOI: 10.3233/JAD-201605

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 319-331, 2021

Authors: Sontheimer, Nadine | Konnopka, Alexander | König, Hans-Helmut

Article Type: Research Article

Abstract: Background: Dementia is one of the costliest diseases for health care systems with growing importance for policy makers. Objective: The aim of this study is to systematically review the current literature of excess cost studies for dementia and to analyze excess costs in a meta-analysis. Methods: A systematic literature search was conducted in PubMed, EconLit, NHS-EED, and Cochrane Library. 22 studies were included and assigned to one of three subgroups according to the time period that they analyzed during disease progression: the time of diagnosis, the time between diagnosis and death, and the time prior to …death. Excess costs were analyzed using the ratio of means (ROM) and meta-analysis was performed by pooling ROMs in a random effects model. Results: Total costs were significantly higher for demented persons compared to non-demented persons at the time of diagnosis (ROM: 2.08 [1.71, 2.54], p  < 0.00001, I 2  = 98%) and in the time period between diagnosis and death (ROM: 2.19 [1.97, 2.44], p  < 0.00001, I 2  = 100%). The ROM was highest for professional home care (ROM: 4.96 [2.62, 9.40], p  < 0.0001, I 2  = 88%) and for nursing facilities (ROM: 4.02 [2.53, 6.40], p  < 0.00001, I 2  = 100%) for the time period between diagnosis and death. Conclusion: This meta-analysis is the first to assess excess costs of dementia by the ROM method on a global scale. We conclude that our findings demonstrate that costs of dementia constitute a substantial economic burden. Show more

Keywords: Alzheimer’s disease, cost of illness, costs and cost analysis, dementia, economics

DOI: 10.3233/JAD-210174

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 333-354, 2021

Authors: Smailovic, Una | Kåreholt, Ingemar | Koenig, Thomas | Ashton, Nicholas J. | Winblad, Bengt | Höglund, Kina | Nilsson, Per | Zetterberg, Henrik | Blennow, Kaj | Jelic, Vesna

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) neurogranin and quantitative electroencephalography (qEEG) are potential molecular and functional markers of synaptic pathology in Alzheimer’s disease (AD). Synaptic markers have emerged as candidate prognostic indicators of AD since synaptic degeneration was shown to be an early event and the best correlate of cognitive deficits in patients along the disease continuum. Objective: The present study investigated the association between CSF neurogranin and qEEG measures as well as their potential to predict clinical deterioration in mild cognitive impairment (MCI) patients. Methods: Patients diagnosed with MCI (n  = 99) underwent CSF conventional AD biomarkers and …neurogranin analysis and resting-state EEG recordings. The study population was further stratified into stable (n  = 41) and progressive MCI (n  = 31), based on the progression to AD dementia during two years follow-up. qEEG analysis included computation of global field power and global field synchronization in four conventional frequency bands. Results: CSF neurogranin levels were associated with theta power and synchronization in the progressive MCI group. CSF neurogranin and qEEG measures were significant predictors of progression to AD dementia, independent of baseline amyloid status in MCI patients. A combination of CSF neurogranin with global EEG power in theta and global EEG synchronization in beta band exhibited the highest classification accuracy as compared to either of these markers alone. Conclusion: qEEG and CSF neurogranin are independent predictors of progression to AD dementia in MCI patients. Molecular and neurophysiological synaptic markers may have additive value in a multimodal diagnostic and prognostic approach to dementia. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, mild cognitive impairment, neurogranin, prognostic markers, quantitative electroencephalography, synaptic markers

DOI: 10.3233/JAD-201234

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 355-366, 2021

Authors: Zhu, Min | Jia, Longfei | Jia, Jianping

Article Type: Research Article

Abstract: Background: Imbalance between amyloid-β (Aβ) production and clearance results in Aβ accumulation. Regulating Aβ levels is still a hot point in the research of Alzheimer’s disease (AD). Objective: To identify the differential expression of ATP-binding cassette transporter A1 (ABCA1) and its upstream microRNA (miRNA) in AD models, and to explore their relationships with Aβ levels. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were performed to determine the expression of ABCA1 in 5xFAD mice, SH-SY5Y cells treated with Aβ oligomers and SH-SY5YA βPP 695 cells (AD models). TargetScan was used to predict …the upstream miRNAs for ABCA1. Dual-luciferase assay was conducted to identify the regulation of the miRNA on ABCA1. qRT-PCR was used to measure the expression of miRNA in AD models. Finally, enzyme-linked immunosorbent assays were performed to detect Aβ42 and Aβ40 levels. Results: The expression of ABCA1 was significantly downregulated in AD models at both mRNA and protein levels. Dual-luciferase assay showed that miR-96-5p could regulate the expression of ABCA1 through binding to the 3 untranslated region of ABCA1. The level of miR-96-5p was significantly elevated in AD models. The expression of ABCA1 was enhanced while Aβ42 levels and Aβ42 /Aβ40 ratios were reduced in SH-SY5YA βPP 695 cells after treated with miR-96-5p inhibitor. Conclusion: The current study found that miR-96-5p is the upstream miRNA for ABCA1. Suppression of miR-96-5p in AD models could reduce Aβ42 /Aβ40 ratios via upregulating the expression of ABCA1, indicating that miR-96-5p plays an important role in regulating the content of Aβ. Show more

Keywords: Alzheimer’s disease, amyloid-β, ATP-binding cassette transporter A1, microRNA

DOI: 10.3233/JAD-210411

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 367-377, 2021

Authors: Cross, Donna J. | Huber, Bertrand R. | Silverman, Michael A. | Cline, Marcella M. | Gill, Trevor B. | Cross, Chloe G. | Cook, David G. | Minoshima, Satoshi

Article Type: Research Article

Abstract: Background: Microtubule stabilizing drugs, commonly used as anti-cancer therapeutics, have been proposed for treatment of Alzheimer’s disease (AD); however, many do not cross the blood-brain barrier. Objective: This research investigated if paclitaxel (PTX) delivered via the intranasal (IN) route could alter the phenotypic progression of AD in 3xTg-AD mice. Methods: We administered intranasal PTX in 3XTg-AD mice (3xTg-AD n  = 15, 10 weeks and n  = 10, 44 weeks, PTX: 0.6 mg/kg or 0.9%saline (SAL)) at 2-week intervals. After treatment, 3XTg-AD mice underwent manganese-enhanced magnetic resonance imaging to measure in vivo axonal transport. In a separate 3XTg-AD …cohort, PTX-treated mice were tested in a radial water tread maze at 52 weeks of age after four treatments, and at 72 weeks of age, anxiety was assessed by an elevated-plus maze after 14 total treatments. Results: PTX increased axonal transport rates in treated 3XTg-AD compared to controls (p ≤0.003). Further investigation using an in vitro neuron model of Aβ-induced axonal transport disruption confirmed PTX prevented axonal transport deficits. Confocal microscopy after treatment found fewer phospho-tau containing neurons (5.25±3.8 versus 8.33±2.5, p  < 0.04) in the CA1, altered microglia, and reduced reactive astrocytes. PTX improved performance of 3xTg-AD on the water tread maze compared to controls and not significantly different from WT (Day 5, 143.8±43 versus 91.5±77s and Day 12, 138.3±52 versus 107.7±75s for SAL versus PTX). Elevated plus maze revealed that PTX-treated 3xTg-AD mice spent more time exploring open arms (Open arm 129.1±80 versus 20.9±31s for PTX versus SAL, p ≤0.05). Conclusion: Taken collectively, these findings indicate that intranasal-administered microtubule-stabilizing drugs may offer a potential therapeutic option for treating AD. Show more

Keywords: Alzheimer’s disease, axonal transport, cognitive impairment, intranasal drug administration, microtubule stabilization

DOI: 10.3233/JAD-210109

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 379-394, 2021

Authors: Romero-Moreno, Rosa | Márquez-González, María | Barrera-Caballero, Samara | Vara-García, Carlos | Olazarán, Javier | Pedroso-Chaparro, María del Sequeros | Jiménez-Gonzalo, Lucía | Losada-Baltar, Andrés

Article Type: Research Article

Abstract: Background: While most intervention studies conducted with dementia family caregivers have focused on depressive symptoms as the main outcome, no study has analyzed the effects of an intervention on comorbid clinical presentations of depressive and anxious symptomatology. Objective: The aim of this study was to examine the association between clinical depressive and anxious symptomatology at baseline and treatment responses of dementia family caregivers using samples from two randomized intervention trials with the same pre-post design. Methods: Specifically, the effects on depressive and anxious comorbidity of three intervention conditions (Cognitive Behavioral Therapy (CBT), Acceptance and Commitment Therapy …(ACT), and a control group (CG)) were analyzed. Participants were 130 dementia family caregivers. In addition to sociodemographic variables, depressive and anxious symptomatology were measured. Results: Caregivers with clinical depressive and anxiety comorbid symptoms at baseline recovered less well from depressive symptoms after CBT (45.45%) and ACT (47.72%) interventions than caregivers with non-comorbidity (100% recovery in both treatments). No significant association between comorbidity and treatment responses on depression was found for the control group. Regarding anxiety, among participants with comorbidity at baseline, 36.36% of caregivers in CBT and 30.9 % in the ACT group recovered from anxiety symptoms after treatment, compared to 6.45% in the control group. Similar results were obtained regarding those caregivers who recovered both from clinical depressive and anxiety symptoms and showed comorbidity at baseline. Conclusion: Caregivers that show comorbid depressive and anxiety symptoms at baseline may benefit less from interventions than caregivers who do not show comorbidity. Show more

Keywords: acceptance and commitment therapy, carers, cognitive behavioral therapy, emotional distress, intervention, recovery

DOI: 10.3233/JAD-210348

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 395-405, 2021

Authors: Hojjati, Seyed Hani | Feiz, Farnia | Ozoria, Sindy | Razlighi, Qolamreza R. | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: While amyloid-β (Aβ) plaques and tau tangles are the well-recognized pathologies of Alzheimer’s disease (AD), they are more often observed in healthy individuals than in AD patients. This discrepancy makes it extremely challenging to utilize these two proteinopathies as reliable biomarkers for the early detection as well as later diagnosis of AD. Objective: We hypothesize and provide preliminary evidence that topographically overlapping Aβ and tau within the default mode network (DMN) play more critical roles in the underlying pathophysiology of AD than each of the tau and/or Aβ pathologies alone. Methods: We used our newly …developed quantification methods and publicly available neuroimaging data from 303 individuals to provide preliminary evidence of our hypothesis. Results: We first showed that the probability of observing overlapping Aβ and tau is significantly higher within than outside the DMN. We then showed evidence that using Aβ and tau overlap can increase the reliability of the prediction of healthy individuals converting to mild cognitive impairment (MCI) and to a lesser degree converting from MCI to AD. Finally, we provided evidence that while the initial accumulations of Aβ and tau seems to be started independently in the healthy participants, the accumulations of the two pathologies interact in the MCI and AD groups. Conclusion: These findings shed some light on the complex pathophysiology of AD and suggest that overlapping Aβ and tau pathologies within the DMN might be a more reliable biomarker of AD for early detection and later diagnosis of the disease. Show more

Keywords: Alzheimer’s disease, amyloid-β plaques, default mode network, mild cognitive impairment, tau tangles

DOI: 10.3233/JAD-210419

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 407-421, 2021

Authors: Walden, Lucas M. | Hu, Song | Madabhushi, Anant | Prescott, Jeffrey W. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Histopathologic studies have demonstrated differential amyloid-β (Aβ) burden between cortical sulci and gyri in Alzheimer’s disease (AD), with sulci having a greater Aβ burden. Objective: To characterize Aβ deposition in the sulci and gyri of the cerebral cortex in vivo among subjects with normal cognition (NC), mild cognitive impairment (MCI), and AD, and to evaluate if these differences could improve discrimination between diagnostic groups. Methods: T1-weighted 3T MR and florbetapir (amyloid) positron emission tomography (PET) data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). T1 images were segmented and the cortex was separated …into sulci/gyri based on pial surface curvature measurements. T1 images were registered to PET images and regional standardized uptake value ratios (SUVr) were calculated. A linear mixed effects model was used to analyze the relationship between clinical variables and amyloid PET SUVr measurements in the sulci/gyri. Receiver operating characteristic (ROC) analysis was performed to define amyloid positivity. Logistic models were used to evaluate predictive performance of clinical diagnosis using amyloid PET SUVr measurements in sulci/gyri. Results: 719 subjects were included: 272 NC, 315 MCI, and 132 AD. Gyral and sulcal Aβ increased with worsening cognition, however there was a greater increase in gyral Aβ. Females had a greater gyral and sulcal Aβ burden. Focusing on sulcal and gyral Aβ did not improve predictive power for diagnostic groups. Conclusion: While there were significant differences in Aβ deposition in cerebral sulci and gyri across the AD spectrum, these differences did not translate into improved prediction of diagnosis. Females were found to have greater gyral and sulcal Aβ burden. Show more

Keywords: Alzheimer’s disease, amyloid PET 31 imaging, gyral/gyri, sulcal/sulci

DOI: 10.3233/JAD-210308

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 423-433, 2021

Authors: Watson, Yassin | Nelson, Brenae | Kluesner, Jamie Hernandez | Tanzy, Caroline | Ramesh, Shreya | Patel, Zoey | Kluesner, Kaci Hernandez | Singh, Anita | Murthy, Vibha | Mitchell, Cassie S.

Article Type: Research Article

Abstract: Background: Apolipoprotein E (APOE ) genotypes typically increase risk of amyloid-β deposition and onset of clinical Alzheimer’s disease (AD). However, cognitive assessments in APOE transgenic AD mice have resulted in discord. Objective: Analysis of 31 peer-reviewed AD APOE mouse publications (n  = 3,045 mice) uncovered aggregate trends between age, APOE genotype, gender, modulatory treatments, and cognition. Methods: T -tests with Bonferroni correction (significance = p  < 0.002) compared age-normalized Morris water maze (MWM) escape latencies in wild type (WT), APOE2 knock-in (KI2), APOE3 knock-in (KI3), APOE4 knock-in (KI4), and APOE knock-out (KO) mice. …Positive treatments (t+) to favorably modulate APOE to improve cognition, negative treatments (t–) to perturb etiology and diminish cognition, and untreated (t0) mice were compared. Machine learning with random forest modeling predicted MWM escape latency performance based on 12 features: mouse genotype (WT, KI2, KI3, KI4, KO), modulatory treatment (t+, t–, t0), mouse age, and mouse gender (male = g_m; female = g_f, mixed gender = g_mi). Results: KI3 mice performed significantly better in MWM, but KI4 and KO performed significantly worse than WT. KI2 performed similarly to WT. KI4 performed significantly worse compared to every other genotype. Positive treatments significantly improved cognition in WT, KI4, and KO compared to untreated. Interestingly, negative treatments in KI4 also significantly improved mean MWM escape latency. Random forest modeling resulted in the following feature importance for predicting superior MWM performance: [KI3, age, g_m, KI4, t0, t+, KO, WT, g_mi, t–, g_f, KI2] = [0.270, 0.094, 0.092, 0.088, 0.077, 0.074, 0.069, 0.061, 0.058, 0.054, 0.038, 0.023]. Conclusion: APOE3 , age, and male gender was most important for predicting superior mouse cognitive performance. Show more

Keywords: Age, Alzheimer’s disease, APOE, cognitive function, gender, Morris water maze, treatment

DOI: 10.3233/JAD-210492

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 435-450, 2021

Authors: Yemm, Heather | Robinson, Dame Louise | Paddick, Stella-Maria | Dotchin, Catherine | Goodson, Michaela Louise | Narytnyk, Alla | Poole, Marie | Mc Ardle, Ríona

Article Type: Research Article

Abstract: Background: The largest proportion of people with dementia worldwide live in low- and middle- income countries (LMICs), with dementia prevalence continuing to rise. Assessment and diagnosis of dementia involves identifying the impact of cognitive decline on function, usually measured by instrumental activities of daily living (IADLs). Objective: This review aimed to identify IADL measures which are specifically developed, validated, or adapted for use in LMICs to guide selection of such tools. Methods: A systematic search was conducted (fourteen databases) up to April 2020. Only studies reporting on development, validation, or adaptation of IADL measures for dementia …or cognitive impairment among older adults (aged over 50) in LMICs were included. The QUADAS 2 was used to assess quality of diagnostic accuracy studies. Results: 22 papers met inclusion criteria; identifying 19 discrete IADL tools across 11 LMICs. These were either translated from IADL measures used in high-income countries (n  = 6), translated and adapted for cultural differences (n  = 6), or newly developed for target LMIC populations (n  = 7). Seven measures were investigated in multiple studies; overall quality of diagnostic accuracy was moderate to good. Conclusion: Reliability, validity, and accuracy of IADL measures for supporting dementia diagnosis within LMICs was reported. Key components to consider when selecting an IADL tool for such settings were highlighted, including choosing culturally appropriate, time-efficient tools that account for gender- and literacy-bias, and can be conducted by any volunteer with appropriate training. There is a need for greater technical and external validation of IADL tools across different regions, countries, populations, and cultures. Show more

Keywords: Activities of daily living, cognitive dysfunction, cross-cultural comparison, dementia, developing countries, diagnosis, functional status

DOI: 10.3233/JAD-210532

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 451-474, 2021

Authors: Oliveira, Alexandra Martini | Radanovic, Marcia | Mello, Patricia Cotting Homem de | Buchain, Patricia Cardoso | Vizzotto, Adriana Dias Barbosa | Harder, Janaína | Stella, Florindo | Gitlin, Laura N. | Piersol, Catherine Verrier | Valiengo, Leandro L.C. | Forlenza, Orestes Vicente

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) such as aggression, apathy, agitation, and wandering may occur in up to 90%of dementia cases. International guidelines have suggested that non-pharmacological interventions are as effective as pharmacological treatments, however without the side effects and risks of medications. An occupational therapy method, called Tailored Activity Program (TAP), was developed with the objective to treat NPS in the elderly with dementia and has been shown to be effective. Objective: Evaluate the efficacy of the TAP method (outpatient version) in the treatment of NPS in individuals with dementia and in the burden reduction of their caregivers. …Methods: This is a randomized, double-blind, controlled clinical trial for the treatment of NPS in dementia. Outcome measures consisted of assessing the NPS of individuals with dementia, through the Neuropsychiatric Inventory-Clinician rating scale (NPI-C), and assessing the burden on their caregivers, using the Zarit Scale. All the participants were evaluated pre-and post-intervention. Results: 54 individuals with dementia and caregivers were allocated to the experimental (n  = 28) and control (n  = 26) groups. There was improvement of the following NPS in the experimental group: delusions, agitation, aggressiveness, depression, anxiety, euphoria, apathy, disinhibition, irritability, motor disturbance, and aberrant vocalization. No improvement was observed in hallucinations, sleep disturbances, and appetite disorders. The TAP method for outpatient settings was also clinically effective in reducing burden between caregivers of the experimental group. Conclusion: The use of personalized prescribed activities, coupled with the caregiver training, may be a clinically effective approach to reduce NPS and caregiver burden of individuals with dementia. Show more

Keywords: Caregiver burden, dementia, family caregiving, neuropsychiatric behaviors, non-pharmacologic intervention, occupational therapy

DOI: 10.3233/JAD-210142

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 475-486, 2021