Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: van der Lee, Sven J. | van Steenoven, Inger | van de Beek, Marleen | Tési, Niccolo | 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/Aβ 1–42 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. Pre-press, no. Pre-press, pp. 1-11, 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. Pre-press, no. Pre-press, pp. 1-16, 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 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. Pre-press, no. Pre-press, pp. 1-11, 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. Pre-press, no. Pre-press, pp. 1-14, 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. Pre-press, no. Pre-press, pp. 1-10, 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 profiling, and tissue susceptibility respectively. Integrating unique and distinct information from these neuroimaging modalities will further help to enhance the understanding of complex neurological disease. Objective: To develop a processing scheme for multimodal data integration in 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 for bilateral occipital cortices as the region of interest. This scheme can also be extended to other anatomical regions of interest. 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 in 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. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Tsapanou, Angeliki | Zoi, Panagiota | Kalligerou, Faidra | Blekou, Patra | Sakka, Paraskevi

Article Type: Research Article

Abstract: Background: The impact of the new coronavirus disease (COVID-19) is deteriorating as time passes and the virus keeps spreading, with people with dementia and their caregivers being affected significantly. Objective: The aim of this study was to examine the effect of prolonged isolation because of the COVID-19 pandemic on people with dementia and their caregivers. Methods: Caregivers answered online questions regarding their own physical and psychological burden, and of the person they take care of. Participants were mostly members of online seminars of the Athens Alzheimer’s Association. Questions referred to their own burden, the overall decline …of the persons they take care of, and changes in specific domains as well. Further, participants were asked about any changes between the two major lockdown periods. Analysis was performed including the total sample and then, by three different stages of dementia. Results: A total of 339 caregivers took part in the study. Results indicated significant decline, both in an overall aspect of the people with dementia, and in specific domains (mostly communication and mood). Regarding the caregivers, they reported having significantly increased physical and psychological burden, and also, noticing an overall change between the two lockdown periods in their own burden. Analysis by dementia-stage group indicated that significant decline occurred both in the middle-stage and the late-stage group. Conclusion: An urgency for further support of both the people with neurodegenerative disorders and their caregivers is needed. Collaboration among care workers, online programs, governmental support, and day-care centers should be planned to ensure continuity of care for those in need during the pandemic. Show more

Keywords: Caregivers, COVID-19, dementia

DOI: 10.3233/JAD-210702

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Wang, Fng | Xu, Chun-Shuang | Chen, Wei-Hua | Duan, Shi-Wei | Xu, Shu-Jun | Dai, Jun-Jie | Wang, Qin-Wen

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is one of many common neurodegenerative diseases without ideal treatment, but early detection and intervention can prevent the disease progression. Objective: This study aimed to identify AD-related glycolysis gene for AD diagnosis and further investigation by integrated bioinformatics analysis. Methods: 122 subjects were recruited from the affiliated hospitals of Ningbo University between 1 October 2015 and 31 December 2016. Their clinical information and methylation levels of 8 glycolysis genes were assessed. Machine learning algorithms were used to establish an AD prediction model. Receiver operating characteristic curve (AUC) and decision curve analysis (DCA) …were used to assess the model. An AD risk factor model was developed by SHapley Additive exPlanations (SHAP) to extract features that had important impacts on AD. Finally, gene expression of AD-related glycolysis genes were validated by AlzData. Results: An AD prediction model was developed using random forest algorithm with the best average ROC_AUC (0.969544). The threshold probability of the model was positive in the range of 0∼0.9875 by DCA. Eight glycolysis genes (GAPDHS, PKLR, PFKFB3, LDHC, DLD, ALDOC, LDHB, HK3 ) were identified by SHAP. Five of these genes (PFKFB3, DLD, ALDOC, LDHB , LDHC ) have significant differences in gene expression between AD and control groups by Alzdata, while three of the genes (HK3, ALDOC, PKLR ) are related to the pathogenesis of AD. GAPDHS is involved in the regulatory network of AD risk genes. Conclusion: We identified 8 AD-related glycolysis genes (GAPDHS, PFKFB3, LDHC, HK3, ALDOC, LDHB, PKLR , DLD ) as promising candidate biomarkers for early diagnosis of AD by integrated bioinformatics analysis. Machine learning has the advantage in identifying genes. Show more

Keywords: Alzheimer’s disease, DNA methylation, glycolysis gene, machine learning

DOI: 10.3233/JAD-210540

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Dimitriadis, Stavros I. | Lyssoudis, Christos | Tsolaki, Anthoula C. | Lazarou, Eftychia | Kozori, Mahi | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: Extra virgin olive oil (EVOO) constitutes a natural compound with high protection over cognitive function that could positively alter brain dynamics and the mixture of within and between-frequency connectivity. Objective: The balance of cross-frequency coupling over within-frequency coupling can build a nonlinearity index (NI) that encapsulates the over-excitation of information flow between brain areas and across experimental time. The present study investigated for the very first time how the Greek High Phenolic Early Harvest Extra Virgin Olive Oil (HP-EH-EVOO) versus Moderate Phenolic (MP-EVOO) and Mediterranean Diet (MeDi) intervention in people with mild cognitive impairment (MCI) could affect …their spontaneous EEG dynamic connectivity. Methods: Forty-three subjects (14 in MeDi, 16 in MP-EVOO, and 13 in HP-EH-EVOO) followed an EEG resting-state recording session (eyes-open and closed) before and after the treatment. Following our dominant coupling mode model, we built a dynamic integrated dynamic functional connectivity graph that tabulates the functional strength and the dominant coupling mode model of every pair of brain areas. Results: Signal spectrum within 1–13 Hz and theta/beta ratio have decreased in the HP-EH-EVOO group in the eyes-open condition. The intervention improved the FI D oCM across groups and conditions but was more prominent in the HP-EH-EVOO group (p  <  0.001). Finally, we revealed a significant higher post-intervention reduction of NI (Δ NITotal and α ) for the HP-EH-EVOO compared to the MP-EVOO and MeDi groups (p  <  0.0001). Conclusion: Long-term intervention with HP-EH-EVOO reduced the over-excitation of information flow in spontaneous brain activity and altered the signal spectrum of EEG rhythms. Show more

Keywords: Alzheimer’s disease, chronnectomics, cross-frequency coupling, EEG, extra virgin olive oil, mediterranean diet, mild cognitive impairment, multiplexity, non-pharmaceutical interventions

DOI: 10.3233/JAD-210454

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Dekker, Alain D. | Ulgiati, Aurora M. | Groen, Henk | Boxelaar, Vincent A. | Sacco, Silvia | Falquero, Ségolène | Carfi, Angelo | di Paola, Antonella | Benejam, Bessy | Valldeneu, Silvia | Fopma, Roelie | Oosterik, Marjo | Hermelink, Marloes | Beugelsdijk, Gonny | Schippers, Mieke | Henstra, Hepie | Scholten-Kuiper, Martine | Willink-Vos, Judith | de Ruiter, Lisa | Willems, Liesbeth | Loonstra-de Jong, Anneke | Coppus, Antonia M.W. | Tollenaere, Marleen | Fortea, Juan | Onder, Graziano | Rebillat, Anne-Sophie | Van Dam, Debby | De Deyn, Peter P.

Article Type: Correction

DOI: 10.3233/JAD-219007

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 2021