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

Authors: Werner, Perla | Kim, Sarang

Article Type: Research Article

Abstract: Background: Despite the increasing amount of research on dementia stigma, there is a dearth of cross-national studies conducted on this subject. This is surprising since the experience of stigma is closely associated to socio-cultural aspects. Objective: The present study intended to expand knowledge about the impact of culture on dementia stigma by comparing the level and correlates of stigmatic beliefs about dementia among the general public in Israel and Australia. Methods: A cross-sectional study using an online survey was conducted with two age-matched samples: 447 adults in Israel and 290 adults in Australia. Results: …Overall, dementia stigma was moderate in both countries. However, the level of dementia stigma was significantly higher in Australia than in Israel. Lower levels of subjective knowledge and higher levels of ageism were associated with increased levels of stigmatic beliefs in both countries. Gender was a significant correlate of dementia stigma, with male participants reporting higher levels of public stigma than women, although this gender difference was mainly driven by the Australian sample. Conclusion: Our findings indicate that providing knowledge and decreasing ageist attitudes should be key considerations in dementia awareness and stigma reduction campaigns despite the cultural context. In addition, developing gender-specific messages should be considered as a way of improving the effects of such campaigns. Show more

Keywords: Ageism, cross-national study, dementia, dementia knowledge, public stigma

DOI: 10.3233/JAD-210277

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 103-110, 2021

Authors: Chen, Shanshan | Song, Yu | Xu, Wenwen | Hu, Guanjie | Ge, Honglin | Xue, Chen | Gao, Ju | Qi, Wenzhang | Lin, Xingjian | Chen, Jiu | the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Anosognosia, or unawareness of memory deficits, is a common manifestation of Alzheimer’s disease (AD), but greatly variable in subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) subjects. Self-referential network (SRN) is responsible for self-referential processing and considered to be related to AD progression. Objective: Our aim is to explore connectivity changes of SRN and its interaction with memory-related network and primary sensorimotor network (SMN) in the AD spectrum. Methods: About 444 Alzheimer’s Disease Neuroimaging Initiative subjects (86 cognitively normal [CN]; 156 SCD; 146 aMCI; 56 AD) were enrolled in our study. The independent …component analysis (ICA) method was used to extract the SRN, SMN, and memory-related network from all subjects. The alteration of functional connectivity (FC) within SRN and its connectivity with memory-related network/SMN were compared among four groups and further correlation analysis between altered FC and memory awareness index as well as episodic memory score were performed. Results: Compared with CN group, individuals with SCD exhibited hyperconnectivity within SRN, while aMCI and AD patients showed hypoconnectivity. Furthermore, aMCI patients and AD patients both showed the interruption of the FC between the SRN and memory-related network compared to CN group. Pearson correlation analysis showed that disruptive FC within SRN and its interaction with memory-related network were related to memory awareness index and episodic memory scores. Conclusion: In conclusion, impaired memory awareness and episodic memory in the AD spectrum are correlated to the disconnection within SRN and its interaction with memory-related network. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, anosognosia, memory awareness index, memory network, network interaction, self-referential network, subjective cognitive decline

DOI: 10.3233/JAD-210541

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 111-126, 2021

Authors: Narbutas, Justinas | Van Egroo, Maxime | Chylinski, Daphne | Bahri, Mohamed Ali | Koshmanova, Ekaterina | Talwar, Puneet | Besson, Gabriel | Muto, Vincenzo | Schmidt, Christina | Luxen, André | Balteau, Evelyne | Phillips, Christophe | Maquet, Pierre | Salmon, Eric | Bastin, Christine | Vandewalle, Gilles | Collette, Fabienne

Article Type: Research Article

Abstract: Background: Cognitive complaints are gaining more attention as they may represent an early marker of increased risk for AD in individuals without objective decline at standard neuropsychological examination. Objective: Our aim was to assess whether cognitive complaints in late middle-aged individuals not seeking medical help are related to objective cognitive outcomes known as early markers for AD risk, concomitant affective state, and amyloid-β (Aβ) burden. Methods: Eighty-seven community-based cognitively normal individuals aged 50–69 years underwent neuropsychological assessment for global cognition, using Preclinical Alzheimer’s Cognitive Composite 5 (PACC5) score, and a more specific episodic memory measure. Affective …state was based on self-assessment questionnaires for depression and anxiety. Aβ PET burden was assessed via [18 F]Flutemetamol (N  = 84) and [18 F]Florbetapir (N  = 3) uptake. Cognitive complaints were evaluated using Cognitive Difficulties Scale. Results: Higher cognitive complaints were significantly associated with lower episodic memory performance and worse affective state. Moreover, higher level of cognitive complaints was related to higher (but still sub-clinical) global Aβ accumulation (at uncorrected significance level). Importantly, all three aspects remained significant when taken together in the same statistical model, indicating that they explained distinct parts of variance. Conclusion: In healthy Aβ negative late middle-aged individuals, a higher degree of cognitive complaints is associated with lower episodic memory efficiency, more anxiety and depression, as well as, potentially, with higher Aβ burden, suggesting that complaints might signal subtle decline. Future studies should untangle how cognitive complaints in healthy aging populations are related to longitudinal changes in objective cognition and AD biomarker correlates. Show more

Keywords: Affective disorders, amyloid, cognition, cognitive decline, episodic memory, middle-age

DOI: 10.3233/JAD-210332

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 127-141, 2021

Authors: Soares, Caroline Bitencourt | Daré, Leticia Rossi | Lima, Karine Ramires | Lopes, Luiza Freitas | Santos, Alexandre Garcia dos | Schimidt, Helen Lidiane | Carpes, Felipe Pivetta | Lloret, Ana | Viña, Jose | Mello-Carpes, Pâmela Billig

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by the accumulation of the amyloid-β peptide in the brain, leading to early oxidative stress and neurotoxicity. It has been suggested that physical exercise could be beneficial in preventing AD, but studies with multicomponent training are scanty. Objective: Verify the effects of multicomponent exercise training to prevent deficits in recognition memory related to Aβ neurotoxicity. Methods: We subjected Wistar rats to multicomponent training (including aerobic and anaerobic physical exercise and cognitive exercise) and then infused amyloid-β peptide into their hippocampus. Results: We show that long-term multicomponent training prevents …the amyloid-β-associated neurotoxicity in the hippocampus. It reduces hippocampal lipid peroxidation, restores antioxidant capacity, and increases glutathione levels, finally preventing recognition memory deficits. Conclusion: Multicomponent training avoids memory deficits related to amyloid-β neurotoxicity on an animal model. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, exercise therapy, oxidative stress

DOI: 10.3233/JAD-210424

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 143-154, 2021

Authors: Zebhauser, Paul Theo | Berthele, Achim | Franz, Marie-Sophie | Goldhardt, Oliver | Diehl-Schmid, Janine | Priller, Josef | Ortner, Marion | Grimmer, Timo

Article Type: Research Article

Abstract: Background: Tau proteins are established biomarkers of neuroaxonal damage in a wide range of neurodegenerative conditions. Although measurement of total-Tau in the cerebrospinal fluid is widely used in research and clinical settings, the relationship between age and total-Tau in the cerebrospinal fluid is yet to be fully understood. While past studies reported a correlation between age and total-Tau in the cerebrospinal fluid of healthy adults, in clinical practice the same cut-off value is used independently of patient’s age. Objective: To further explore the relationship between age and total-Tau and to disentangle neurodegenerative from drainage-dependent effects. Methods: …We analyzed cerebrospinal fluid samples of 76 carefully selected cognitively healthy adults and included amyloid-β 1–40 as a potential marker of drainage from the brain’s interstitial system. Results: We found a significant correlation of total-Tau and age, which was no longer present when correcting total-Tau for amyloid-β 1–40 concentrations. These findings were replicated under varied inclusion criteria. Conclusion: Results call into question the association of age and total-Tau in the cerebrospinal fluid. Furthermore, they suggest diagnostic utility of amyloid-β 1–40 as a possible proxy for drainage-mechanisms into the cerebrospinal fluid when interpreting biomarker concentrations for neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, amyloid-beta 1–40, tau proteins, total-Tau

DOI: 10.3233/JAD-210286

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 155-162, 2021

Authors: Wang, Fang | 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. 83, no. 1, pp. 163-178, 2021

Authors: Kawamura, Kaito | Miyajima, Masakazu | Nakajima, Madoka | Kanai, Mitsuyasu | Motoi, Yumiko | Nojiri, Shuko | Akiba, Chihiro | Ogino, Ikuko | Xu, Hanbing | Kamohara, Chihiro | Yamada, Shinya | Karagiozov, Kostadin | Ikeuchi, Takeshi | Kondo, Akihide | Arai, Hajime

Article Type: Research Article

Abstract: Background: The amyloid-β oligomers, consisting of 10–20 monomers (AβO10–20 ), have strong neurotoxicity and are associated with cognitive impairment in Alzheimer’s disease (AD). However, their role in patients with idiopathic normal pressure hydrocephalus (iNPH) is poorly understood. Objective: We hypothesized that cerebrospinal fluid (CSF) AβO10–20 accumulates in patients with iNPH, and its clearance after CSF shunting contributes to neurological improvement. We measured CSF AβO10–20 levels before and after CSF shunting in iNPH patients evaluating their diagnostic and prognostic role. Methods: We evaluated two iNPH cohorts: “evaluation” (cohort-1) with 32 patients and “validation” (cohort-2) with …13 patients. Comparison cohorts included: 27 neurologically healthy controls (HCs), and 16 AD, 15 Parkinson’s disease (PD), and 14 progressive supranuclear palsy (PSP) patients. We assessed for all cohorts CSF AβO10–20 levels and their comprehensive clinical data. iNPH cohort-1 pre-shunting data were compared with those of comparison cohorts, using cohort-2 for validation. Next, we compared cohort-1’s clinical and CSF data: 1) before and after CSF shunting, and 2) increased versus decreased AβO10–20 levels at baseline, 1 and 3 years after shunting. Results: Cohort-1 had higher CSF AβO10–20 levels than the HCs, PD, and PSP cohorts. This result was validated with data from cohort-2. CSF AβO10–20 levels differentiated cohort-1 from the PD and PSP groups, with an area under receiver operating characteristic curve of 0.94. AβO10–20 levels in cohort-1 decreased after CSF shunting. Patients with AβO10–20 decrease showed better cognitive outcome than those without. Conclusion: AβO10–20 accumulates in patients with iNPH and is eliminated by CSF shunting. AβO10–20 can be an applicable diagnostic and prognostic biomarker. Show more

Keywords: Amyloid-β peptides, biomarkers, cerebrospinal fluid, neurodegenerative diseases, normal pressure hydrocephalus

DOI: 10.3233/JAD-210226

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 179-190, 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 FID 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. 83, no. 1, pp. 191-207, 2021

Authors: Beishon, Lucy | Haunton, Victoria | Subramaniam, Hari | Mukaetova-Ladinska, Elizabeta B. | Panerai, Ronney B. | Robinson, Thompson | Evley, Rachel

Article Type: Research Article

Abstract: Background: Cognitive training (CT) may have benefits for both healthy older adults (HC) and those with early cognitive disorders [mild cognitive impairment (MCI) and dementia]. However, few studies have qualitatively evaluated home-based, computerized CT programs. Objective: We present the qualitative arm of a feasibility randomized controlled trial evaluating a CT program for HC and people living with MCI or dementia. Methods: Participants underwent semi-structured interviews after 12 weeks of CT. Where possible, participants were interviewed with their carers. The interview schedule and analysis were underpinned by the health belief model. Interviews were audio-recorded, transcribed, open-coded, and …categorized into themes. The analytical framework was developed, and themes were condensed under five major categories: benefits, barriers, threat, self-efficacy, and cues to action. Results: 37 participants underwent interviews. CT was feasible and acceptable to participants. Benefits included: enjoyment, improved awareness, benchmarking cognitive function, reassurance of abilities and giving back control. Barriers were more prevalent among those with dementia: problems with technology, frustration, conflict between patients and carers, apathy and lack of insight, anxiety or low mood, and lack of portability. HC and MCI perceived the severity of dementia risk as high, partially mitigated by CT. Participants living with dementia valued a more individualized approach to training, accounting for baseline characteristics. Conclusion: CT was a feasible intervention for HC and people living with dementia and MCI. Benefits were present, but the identified barriers need to be addressed for CT to be implemented successfully. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, healthy aging, mild cognitive impairment

DOI: 10.3233/JAD-210428

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 209-225, 2021

Authors: Ibañez, Agustín | Fittipaldi, Sol | Trujillo, Catalina | Jaramillo, Tania | Torres, Alejandra | Cardona, Juan F. | Rivera, Rodrigo | Slachevsky, Andrea | García, Adolfo | Bertoux, Maxime | Baez, Sandra

Article Type: Research Article

Abstract: Background: Social cognition is critically compromised across neurodegenerative diseases, including the behavioral variant frontotemporal dementia (bvFTD), Alzheimer’s disease (AD), and Parkinson’s disease (PD). However, no previous study has used social cognition and other cognitive tasks to predict diagnoses of these conditions, let alone reporting the brain correlates of prediction outcomes. Objective: We performed a diagnostic classification analysis using social cognition, cognitive screening (CS), and executive function (EF) measures, and explored which anatomical and functional networks were associated with main predictors. Methods: Multiple group discriminant function analyses (MDAs) and ROC analyses of social cognition (facial emotional recognition, …theory of mind), CS, and EF were implemented in 223 participants (bvFTD, AD, PD, controls). Gray matter volume and functional connectivity correlates of top discriminant scores were investigated. Results: Although all patient groups revealed deficits in social cognition, CS, and EF, our classification approach provided robust discriminatory characterizations. Regarding controls, probabilistic social cognition outcomes provided the best characterization for bvFTD (together with CS) and PD, but not AD (for which CS alone was the best predictor). Within patient groups, the best MDA probabilities scores yielded high classification rates for bvFTD versus PD (98.3%, social cognition), AD versus PD (98.6%, social cognition + CS), and bvFTD versus AD (71.7%, social cognition + CS). Top MDA scores were associated with specific patterns of atrophy and functional networks across neurodegenerative conditions. Conclusion: Standardized validated measures of social cognition, in combination with CS, can provide a dimensional classification with specific pathophysiological markers of neurodegeneration diagnoses. Show more

Keywords: Classification, dementia, diagnosis, neurodegenerative diseases, social cognition

DOI: 10.3233/JAD-210163

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 227-248, 2021