Journal of Alzheimer's Disease - Volume 92, issue 2

Authors: Stocks, Jane | Heywood, Ashley | Popuri, Karteek | Beg, Mirza Faisal | Rosen, Howie | Wang, Lei

Article Type: Research Article

Abstract: Background: The A/T/N framework allows for the assessment of pathology-specific markers of MRI-derived structural atrophy and hypometabolism on 18 FDG-PET. However, how these measures relate to each other locally and distantly across pathology-defined A/T/N groups is currently unclear. Objective: To determine the regions of association between atrophy and hypometabolism in A/T/N groups both within and across time points. Methods: We examined multivariate multimodal neuroimaging relationships between MRI and 18 FDG-PET among suspected non-Alzheimer’s disease pathology (SNAP) (A–T/N+; n  = 14), Amyloid Only (A+T–N–; n  = 24) and Probable AD (A+T+N+; n  = 77) groups. Sparse canonical correlation analyses were …employed to model spatially disjointed regions of association between MRI and 18 FDG-PET data. These relationships were assessed at three combinations of time points –cross-sectionally, between baseline visits and between month 12 (M-12) follow-up visits, as well as longitudinally between baseline and M-12 follow-up. Results: In the SNAP group, spatially overlapping relationships between atrophy and hypometabolism were apparent in the bilateral temporal lobes when both modalities were assessed at the M-12 timepoint. Amyloid-Only subjects showed spatially discordant distributed atrophy-hypometabolism relationships at all time points assessed. In Probable AD subjects, local correlations were evident in the bilateral temporal lobes when both modalities were assessed at baseline and at M-12. Across groups, hypometabolism at baseline correlated with non-local, or distant, atrophy at M-12. Conclusion: These results support the view that local concordance of atrophy and hypometabolism is the result of a tau-mediated process driving neurodegeneration. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, magnetic resonance imaging, multimodal imaging, neuroimaging, positron emission tomography, suspected non-Alzheimer’s disease pathology, tau

DOI: 10.3233/JAD-220975

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 513-527, 2023

Authors: Makri, M. | Christakidou, A. | Tsolaki, M.

Article Type: Research Article

Abstract: Background: People with mild cognitive impairment (MCI) need to prevent the further decline of their cognitive functions, and one way to do so is by learning a foreign language. Objective: This study describes the development of a protocol for a novel, non-pharmacological intervention for people with MCI that seeks to prevent or reduce cognitive decline by teaching English through songs. Methods: The development of this protocol follows a mixed-methodology approach, consisting of three stages: 1) development of the protocol of the intervention, 2) a randomized controlled trial study with two arms over six …months that includes an intervention group and a control group, and 3) the evaluation of the protocol by trainers. In the second stage, we recruited a total of 128 people with MCI from the five participating countries of this study (Greece, Spain, Croatia, Slovenia, and Italy). This educational program will assess three main outcomes after 6 months of the English Lessons with the Use of Songs for People with Mild Cognitive Impairment (E.L.So.M.C.I.) workshops. Results: Our primary outcome will hopefully be an improvement in general cognition in the intervention group compared to the control group from baseline to 6 months follow-up. Secondary outcomes include a decrease in participants’ anxiety and depression and an improvement in their quality of life. Development of English language skills is the last outcome. Show more

Keywords: Anxiety, cognition, depression, learning English, mild cognitive impairment, non-pharmacological intervention, prevention, randomized controlled trial, songs for learning English

DOI: 10.3233/JAD-220184

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 529-546, 2023

Authors: Petti, Ulla | Baker, Simon | Korhonen, Anna | Robin, Jessica

Article Type: Research Article

Abstract: Background: Language impairment in Alzheimer’s disease (AD) has been widely studied but due to limited data availability, relatively few studies have focused on the longitudinal change in language in the individuals who later develop AD. Significant differences in speech have previously been found by comparing the press conference transcripts of President Bush and President Reagan, who was later diagnosed with AD. Objective: In the current study, we explored whether the patterns previously established in the single AD-healthy control (HC) participant pair apply to a larger group of individuals who later receive AD diagnosis. Methods: We replicated …previous methods on two larger corpora of longitudinal spontaneous speech samples of public figures, consisting of 10 and 9 AD-HC participant pairs. As we failed to find generalizable patterns of language change using previous methodology, we proposed alternative methods for data analysis, investigating the benefits of using different language features and their change with age, and compiling the single features into aggregate scores. Results: The single features that showed the strongest results were moving average type:token ratio (MATTR) and pronoun-related features. The aggregate scores performed better than the single features, with lexical diversity capturing a similar change in two-thirds of the participants. Conclusion: Capturing universal patterns of language change prior to AD can be challenging, but the decline in lexical diversity and changes in MATTR and pronoun-related features act as promising measures that reflect the cognitive changes in many participants. Show more

Keywords: Alzheimer’s disease, biomarker, cognitive dysfunction, dementia, early diagnosis, language, medical informatics, natural language processing, speech

DOI: 10.3233/JAD-220847

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 547-564, 2023

Authors: Lee, Seunghoon | Jeong, Hyunsuk | Koh, Im-Seok | Suh, Jeewon | Cho, HyunSung | Kim, YongBok | Cho, EunJung | Chang, Jhin Goo | Hong, Minha | Lee, Su Young

Article Type: Research Article

Abstract: Background: Providing correct information about dementia and people living with dementia and improving the attitude toward the disease have important implications in overcoming prejudice and negative perceptions and strengthening the social support system. However, studies are limited about which aspects of dementia knowledge affect attitudes toward it and the influence of such knowledge on particular aspects of such attitudes. Objective: This study examined which part of dementia knowledge affects attitudes toward dementia and, furthermore, the influence of such knowledge on two aspects of attitudes in the general population. Methods: A population-based cross-sectional survey of 1,200 participants …aged 20 years or older was adopted. A landline and wireless telephone survey was conducted from October 12 to October 22, 2021. The survey data included self-report questions about dementia knowledge, dementia attitudes, demographics, and family information. Multiple linear regression analysis was performed. Results: Dementia knowledge was positively associated with global dementia attitudes. In terms of the relationship between the two dimensions of dementia attitudes and knowledge, the latter displayed a significant positive association with accepting attitudes (β = 0.121, p  < 0.001) but not with affective attitudes (β = 0.064, p  = 0.084). Among dementia knowledge, dementia symptom/diagnosis and policy categories were positively associated with accepting attitudes (β = 0.198, p  = 0.006; β = 0.357, p  < 0.001). Conclusion: Our study suggests that people with more dementia knowledge have more accepting attitudes toward dementia. It may be effective to continue education on dementia to improve the public accepting attitudes. However, to improve negative emotional attitudes toward dementia, various approaches beyond education may be needed. Show more

Keywords: Attitude, dementia, knowledge, population

DOI: 10.3233/JAD-220736

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 565-572, 2023

Authors: Tan, Yi Jayne | Siow, Isabel | Saffari, Seyed Ehsan | Ting, Simon K.S. | Li, Zeng | Kandiah, Nagaendran | Tan, Louis C.S. | Tan, Eng King | Ng, Adeline S.L.

Article Type: Research Article

Abstract: Background: Suppressor of tumorgenicity 2 (ST2) is highly expressed in brain tissue and is a receptor for interleukin 33 (IL-33). ST2 exists in two forms, a transmembrane receptor (ST2L) and a soluble decoy receptor (sST2). IL-33 binds to ST2L, triggering downstream signaling pathways involved in amyloid plaque clearance. Conversely, sST2 binds competitively to IL-33, attenuating its neuroprotective effects. High sST2 levels have been reported in mild cognitive impairment (MCI) and Alzheimer’s disease (AD), suggesting that the IL-33/ST2 signaling pathway may be implicated in neurodegenerative diseases. Objective: To investigate plasma sST2 levels in controls and patients with MCI, AD, …frontotemporal dementia (FTD), and Parkinson’s disease (PD). Methods: Plasma sST2 levels were measured using ELISA in 397 subjects (91 HC, 46 MCI, 38 AD, 28 FTD, and 194 PD). Cerebrospinal fluid (CSF) levels of sST2 were measured in 22 subjects. Relationship between sST2 and clinical outcomes were analyzed. Results: Plasma sST2 levels were increased across all disease groups compared to controls, with highest levels seen in FTD followed by AD and PD. Dementia patients with higher sST2 had lower cross-sectional cognitive scores in Frontal Assessment Battery and Digit Span Backward. At baseline, PD-MCI patients had higher sST2, associated with worse attention. In the longitudinal PD cohort, higher sST2 significantly associated with decline in global cognition and visuospatial domains. Plasma sST2 levels correlated with CSF sST2 levels. Conclusion: Plasma sST2 is raised across neurodegenerative diseases and is associated with poorer cognition. Higher baseline sST2 is a potential biomarker of disease severity in neurodegeneration. Show more

Keywords: Cognition, dementia, neurodegeneration, Parkinson’s disease, ST2

DOI: 10.3233/JAD-221072

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 573-580, 2023

Authors: Zhao, Yong-Li | Ou, Ya-Nan | Ma, Ya-Hui | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is considered as a preclinical hallmark of Alzheimer’s disease (AD). However, the characteristics of SCD associated with amyloid pathology remain unclear. Objective: We aimed to explore the associations between SCD characteristics with amyloid pathology. Methods: Using logistic regression analyses, we analyzed the associations between cerebrospinal fluid (CSF) amyloid pathology with AD risk factors, SCD-specific characteristics (onset of SCD within the last five years, age at onset ≥60 years, feelings of worse performance, informant confirmation of complaints, worries, other domains of cognition complaints), as well as subthreshold depressive and anxiety symptoms among …individuals with SCD. Results: A total of 535 SCD individuals with available CSF Aβ42 information from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study (mean age of 63.5 years, range 40 to 88 years; 47.10% female) were enrolled. The characteristics of informant confirmation of complaints (OR, 95% CI = 2.00, 1.19–3.36), subthreshold depressive symptoms (OR, 95% CI = 2.31, 1.05–5.09), and subthreshold anxiety symptoms (OR, 95% CI = 2.22, 1.09–4.51) were found to be significantly associated with pathological amyloid in multivariate analyses when adjusting for age, sex, education, and APOE ɛ4. Besides, age and females were observed risks for amyloid pathology in subscale analyses. Nonetheless, we did not find any associations of other SCD-specific characteristics with amyloid pathology in this study. Conclusion: Our study suggested that informant confirmed complaints and subthreshold psychiatric symptoms might be critical for discriminating AD-related SCD from non-AD related SCD. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, subjective cognitive decline

DOI: 10.3233/JAD-221154

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 581-590, 2023

Authors: Gabrielli, Alexander P. | Weidling, Ian | Ranjan, Amol | Wang, Xiaowan | Novikova, Lesya | Chowdhury, Subir Roy | Menta, Blaise | Berkowicz, Alexandra | Wilkins, Heather M. | Peterson, Kenneth R. | Swerdlow, Russell H.

Article Type: Research Article

Abstract: Background: Mitochondria can trigger Alzheimer’s disease (AD)-associated molecular phenomena, but how mitochondria impact apolipoprotein E (APOE ; apoE) is not well known. Objective: Consider whether and how mitochondrial biology influences APOE and apoE biology. Methods: We measured APOE expression in human SH-SY5Y neuronal cells with different forms of mitochondrial dysfunction including total, chronic mitochondrial DNA (mtDNA) depletion (ρ0 cells); acute, partial mtDNA depletion; and toxin-induced mitochondrial dysfunction. We further assessed intracellular and secreted apoE protein levels in the ρ0 cells and interrogated the impact of transcription factors and stress signaling pathways known to influence …APOE expression. Results: SH-SY5Y ρ0 cells exhibited a 65-fold increase in APOE mRNA, an 8-fold increase in secreted apoE protein, and increased intracellular apoE protein. Other models of primary mitochondrial dysfunction including partial mtDNA-depletion, toxin-induced respiratory chain inhibition, and chemical-induced manipulations of the mitochondrial membrane potential similarly increased SH-SY5Y cell APOE mRNA. We explored potential mediators and found in the ρ0 cells knock-down of the C/EBPα and NFE2L2 (Nrf2) transcription factors reduced APOE mRNA. The activity of two mitogen-activated protein kinases, JNK and ERK, also strongly influenced ρ0 cell APOE mRNA levels. Conclusion: Primary mitochondrial dysfunction either directly or indirectly activates APOE expression in a neuronal cell model by altering transcription factors and stress signaling pathways. These studies demonstrate mitochondrial biology can influence the biology of the APOE gene and apoE protein, which are implicated in AD. Show more

Keywords: Alzheimer’s disease, APOE , apolipoprotein E, mitochondria, mitochondrial DNA

DOI: 10.3233/JAD-221177

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 591-604, 2023

Authors: Gyllenhammar, Måns | Rennie, Anna | Padilla, Daniel Ferreira | Wallert, John | Rydström, Anders | Wahlund, Lars-Olof | Eriksdotter, Maria | Westman, Eric | Ekman, Urban

Article Type: Research Article

Abstract: Background: Cognitive reserve (CR) is hypothesized to partially explain the discrepancy between Alzheimer’s disease related brain pathology and cognitive performance. Educational attainment is often used as a proxy for CR. Objective: To examine the association of years of education and the relationship between atrophy in the medial temporal lobe and episodic memory, in a cross-sectional ecological multi-center memory clinic cohort. Methods: Included patients (n  = 702) had undergone memory clinic examination and were diagnosed with subjective cognitive impairment (n  = 99), mild cognitive impairment (n  = 471), or dementia (n  = 132). Total years of education were used as a …moderating variable and neuropathology was operationalized as visual ratings of medial temporal lobe atrophy (MTA) on magnetic resonance imaging and computer tomography images. Weighted least squares regression and multiple regression were used to analyze moderation and the effect of education separately by diagnostic group. A composite score of two episodic memory tests constituted the dependent variable. Results: After controlling for age and gender the interaction term between MTA and years of education was significant indicating moderation. In particular, the regression model showed that at low levels of MTA, high education individuals had better episodic memory performance. However, at higher MTA levels, high education individuals had the lowest episodic memory performance. Education had a significant positive effect on episodic memory in SCI and MCI, but not dementia. Conclusion: These results extend the findings of education moderating the effect of MTA on cognition to a naturalistic memory clinic setting. Implications of the findings for theories on CR are discussed. Show more

Keywords: Cognitive aging, cognitive impairments, cognitive neuroscience, cognitive reserve, magnetic resonance imaging, neuropsychology

DOI: 10.3233/JAD-220741

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 605-614, 2023

Authors: Chatterjee, Pratishtha | Doré, Vincent | Pedrini, Steve | Krishnadas, Natasha | Thota, Rohith | Bourgeat, Pierrick | Ikonomovic, Milos D. | Rainey-Smith, Stephanie R. | Burnham, Samantha C. | Fowler, Christopher | Taddei, Kevin | Mulligan, Rachel | Ames, David | Masters, Colin L. | Fripp, Jürgen | Rowe, Christopher C. | Martins, Ralph N. | Villemagne, Victor L.

Article Type: Research Article

Abstract: Background: Astrocyte reactivity is an early event along the Alzheimer’s disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18 F-SMBT-1 PET in AD. Objective: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers. Methods: Plasma GFAP and Aβ were measured using the Simoa® platform in participants who underwent brain 18 F-SMBT-1 and Aβ–PET imaging, comprising 54 healthy control (13 Aβ–PET+ …and 41 Aβ–PET–), 11 mild cognitively impaired (3 Aβ–PET+ and 8 Aβ–PET–) and 6 probable AD (5 Aβ–PET+ and 1 Aβ–PET–) individuals. Linear regressions were used to assess associations of interest. Results: Plasma GFAP was associated with 18 F-SMBT-1 signal in brain regions prone to early Aβ deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, and soluble Aβ (plasma Aβ42/40 ratio), plasma GFAP was associated with 18 F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ɛ4 genotype and insoluble Aβ (Aβ–PET), plasma GFAP was associated with 18 F-SMBT-1 signal in the SG. Conclusion: There is an association between plasma GFAP and regional 18 F-SMBT-1 PET, and this association appears to be dependent on brain Aβ load. Show more

Keywords: Astrocyte reactivity, biomarkers, 18F-SMBT-1, glial fibrillary acidic protein, monoamine oxidase B, positron emission tomography

DOI: 10.3233/JAD-220908

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 615-628, 2023

Authors: Atef, Roaa Zayed | Michalowsky, Bernhard | Raedke, Anika | Platen, Moritz | Mohr, Wiebke | Mühlichen, Franka | Thyrian, Jochen René | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Hearing loss is common in people with dementia (PwD) and a modifiable risk factor for cognitive decline. Recent studies revealed that hearing loss could cause social isolation and depression, which is associated with health-related quality of life (HRQoL). However, there is a lack of knowledge about the impact of the utilization of hearing aids on these outcomes. Objective: To assess whether hearing aids use might be positively associated with the progression of cognitive function, depression, and HRQoL among PwD. Methods: We analyzed two-year follow-up data from 258 PwD (≥70 years, living at home). Cognitive decline …was measured with Mini-Mental Status Examination (MMSE), depression using Geriatric Depression Scale (GDS), and HRQoL with Quality of Life in Alzheimer’s Disease Scale (QoL-AD). The impact of hearing aid utilization on the progression of outcomes was assessed using multivariate regression models. Results: 123 patients had hearing loss (47.7%), from which n  = 54 (43.9%) used hearing aids. Patients with hearing loss were older and had a lower HRQoL than those without hearing loss. Use of hearing aids in patients with hearing loss was associated with a lower increase in depressive symptoms (b = –0.74, CI95 –1.48 ––0.01, p  = 0.047) over time as compared to those not using hearing aids. There was no effect on PwD’s cognition, and the association with higher HRQoL was significant after one, but not consistently over two years. Conclusion: Early detection and intervention of presbycusis using hearing aids might improve mental health and HRQoL in dementia. Show more

Keywords: Cognitive decline, dementia, depression, health-related quality of life, hearing aids, hearing loss

DOI: 10.3233/JAD-220938

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 629-638, 2023