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

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