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

Authors: Axelsson Andrén, Elin | Kettunen, Petronella | Bjerke, Maria | Rolstad, Sindre | Zetterberg, Henrik | Blennow, Kaj | Wallin, Anders | Svensson, Johan

Article Type: Research Article

Abstract: Background: The subcortical small vessel type of dementia (SSVD) is a common subtype of vascular dementia, but there is a lack of disease-specific cerebrospinal fluid (CSF) biomarkers. Objective: We investigated whether CSF concentrations of neurofilament light chain (NFL), soluble amyloid-β protein precursor α (sAβPPα), sAβPPβ, and CSF/serum albumin ratio could separate SSVD from healthy controls, Alzheimer’s disease (AD), and mixed dementia (combined AD and SSVD). Methods: This was a mono-center study of patients with SSVD (n  = 38), AD (n  = 121), mixed dementia (n  = 62), and controls (n  = 96). The CSF biomarkers were measured using immunoassays, and …their independent contribution to the separation between groups were evaluated using the Wald test. Then, the area under the receiver operating characteristics curve (AUROC) and 95% confidence intervals (CIs) were calculated. Results: Elevated neurofilament light chain (NFL) and decreased sAβPPβ independently separated SSVD from controls, and sAβPPβ also distinguished SSVD from AD and mixed dementia. The combination of NFL and sAβPPβ discriminated SSVD from controls with high accuracy (AUROC 0.903, 95% CI: 0.834–0.972). Additionally, sAβPPβ combined with the core AD biomarkers (amyloid-β42 , total tau, and phosphorylated tau181 ) had a high ability to separate SSVD from AD (AUROC 0.886, 95% CI: 0.830–0.942) and mixed dementia (AUROC 0.903, 95% CI: 0.838–0.968). Conclusions: The high accuracy of NFL and sAβPPβ to separate SSVD from controls supports that SSVD is a specific diagnostic entity. Moreover, SSVD was distinguished from AD and mixed dementia using sAβPPβ in combination with the core AD biomarkers. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, neurofilament light chain, soluble amyloid-β protein precursor β, subcortical small vessel type of dementia

DOI: 10.3233/JAD-230680

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023

Authors: Lopes Boschetti, Júlia Carolina | Soares, Karla Lírio | Carvalho, Glaucimeire Rocha | Filho, Abraão Carlos Verdin | Ton, Alyne Mendonça Marques | Pereira, Thiago de Melo Costa | Scherer, Rodrigo

Article Type: Research Article

Abstract: Background: The consumption of coffee has been associated with beneficial effects when it comes to Alzheimer’s disease (AD). However, to the best of our knowledge, there are no studies on Conilon coffee consumption in elderly people with AD. Objective: Evaluate the effects of Conilon coffee consumption in elderly with AD. Methods: The study was carried out with 9 participants who consumed a minimum of 2 cups (200 mL cup) of Conilon coffee per day for 90 days. Cognitive assessment was done before (T0) and after 90 days (T90). Blood analysis was conducted at T0 and T90, …as well as the assessment of advanced oxidation protein products (AOPP) and thiobarbituric acid reactive species (TBARS). The levels of chlorogenic acids and caffeine in the coffee beverage were quantified by liquid chromatography. Results: During the treatment, the participants consumed at least 550 mg and 540 mg of CGAs and caffeine, respectively. A significant improvement in cognition between T0 and T90 was observed as per MMSE, CTP, and clock drawing tests. Furthermore, there was a significant reduction in AOPP (37%) and TBARS (60%), indicating a reduction in oxidative stress. The consumption of the coffee did not significantly alter any blood parameter, which confirms the safety of the coffee treatment during the 90 days. Conclusions: Our study demonstrated for the first time that regular consumption of coffee with high amounts of CGAs and caffeine improves cognitive functions and reduces oxidative stress, without altering blood parameters that indicate possible signs of toxicity in classical target organs. Show more

Keywords: Alzheimer’s disease, caffeine, chlorogenic acid, Coffea, coffee, Robusta

DOI: 10.3233/JAD-230843

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2023

Authors: Zeng, Xiao Xue | Zeng, Jie Bangzhe

Article Type: Review Article

Abstract: The traits of Alzheimer’s disease (AD) include amyloid plaques made of Aβ1-40 and Aβ1-42 , and neurofibrillary tangles by the hyperphosphorylation of tau protein. AD is a complex disorder that is heterogenous in genetical, neuropathological, and clinical contexts. Current available therapeutics are unable to cure AD. Systems medicine is a strategy by viewing the body as a whole system, taking into account each individual’s unique health profile, provide treatment and associated nursing care clinically for the patient, aiming for precision. Since the onset of AD can lead towards cognitive impairment, it is vital to intervene and diagnose early and …prevent further progressive loss of neurons. Moreover, as the individual’s brain functions are impaired due to neurodegeneration in AD, it is essential to reconstruct the neurons or brain cells to enable normal brain functions. Although there are different subtypes of AD due to varied pathological lesions, in the majority cases of AD, neurodegeneration and severe brain atrophy develop at the chronic stage. Novel approaches including RNA based gene therapy, stem cell based technology, bioprinting technology, synthetic biology for brain tissue reconstruction are researched in recent decades in the hope to decrease neuroinflammation and restore normal brain function in individuals of AD. Systems medicine include the prevention of disease, diagnosis and treatment by viewing the individual’s body as a whole system, along with systems medicine based nursing as a strategy against AD that should be researched further. Show more

Keywords: Alzheimer’s disease, gene therapy, synthetic biology, systems medicine

DOI: 10.3233/JAD-230739

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023

Authors: Tao, Shuqi | Fan, Wenyuan | Liu, Jinmeng | Wang, Tong | Zheng, Haoning | Qi, Gaoxiu | Chen, Yanchun | Zhang, Haoyun | Guo, Zhangyu | Zhou, Fenghua

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is currently the most prevalent neurological disease, and no effective and practical treatments and therapies exist. The nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain- containing receptor 3 (NLRP3) inflammasome is vital in the human innate immune response. However, when the NLRP3 inflammasome is overactivated by persistent stimulation, several immune-related diseases, including AD, atherosclerosis, and obesity, result. This review will focus on the composition and activation mechanism of the NLRP3 inflammasome, the relevant mechanisms of involvement in the inflammatory response to AD, and AD treatment targeting NLRP3 inflammasome. This review aims to reveal the pathophysiological mechanism of …AD from a new perspective and provide the possibility of more effective and novel strategies for preventing and treating AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, inhibitors, NLRP3 inflammasome, tau, treatment

DOI: 10.3233/JAD-230567

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023

Authors: Grasso, Stephanie M. | Wagner Rodríguez, Camille A. | Montagut Colomer, Núria | Marqués Kiderle, Sonia-Karin | Sánchez-Valle, Raquel | Santos Santos, Miguel Ángel

Article Type: Research Article

Abstract: Background: Primary progressive aphasia (PPA) is a neurodegenerative syndrome characterized by speech and/or language impairment with relatively spared cognition. Research investigating behavioral speech-language intervention and methods for cognitive-linguistic assessment in PPA has predominantly centered around monolingual speakers. This gap hinders the widespread adoption of evidence-based approaches and exacerbates the inequities faced by culturally and linguistically diverse populations living with PPA. Objective: This scoping review synthesizes the current evidence for assessment and treatment practices in bilingual PPA as well as the operationalization of bilingualism in PPA. Methods: Arksey & O’Malley’s scoping review methodology was utilized. Information was …extracted from each study and entered into a data-charting template designed to capture information regarding operationalization of bilingualism in PPA and assessment and treatment practices. Results: Of the 16 identified studies, 14 reported the results of assessments conducted in both languages. Three studies reported positive naming treatment outcomes. Thirteen studies included English-speaking participants, revealing linguistic bias. Most studies reported age of acquisition, proficiency, and patterns of language use rather than providing an operational definition for bilingualism. Conclusions: Neither formal assessment measures nor clear guidelines for assessment of bilingual PPA currently exist; however, language-specific measures are emerging. Speech-language intervention in bilingual PPA has been relatively unexplored, representing a significant gap in the literature. In order to improve diagnostic and treatment options for bilingual PPA, targeted efforts to increase representation of bilinguals from various sociocultural contexts, as well as those who speak a variety of language pairs, is necessary. Show more

Keywords: Alzheimer’s disease, aphasia, assessment, bilingualism, cultural and linguistic diversity, dementia, intervention, language, primary progressive aphasia, scoping review, speech-language pathology

DOI: 10.3233/JAD-230673

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-24, 2023

Article Type: Other

DOI: 10.3233/JAD-239012

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023

Authors: Li, Jie-Qiong | Zhong, Xiao-Ling | Song, Jing-Hui | Chi, Song | Xie, An-Mu | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Recent genetic research identified a protective factor against late-onset Alzheimer’s disease (AD) in Caucasians, a variant called rs3747742-C in the TREML2 gene. However, the roles of other TREML2 variants in AD have not been fully explored. Objective: We conducted a focused analysis of 16 TREML2 variants, examining their connection to AD by studying their correlation with cerebrospinal fluid (CSF) proteins, neuroimage, and cognition in the Alzheimer’s Disease Neuroimaging Initiative database (ADNI). Methods: A multiple linear regression model was utilized to estimate potential associations between TREML2 genotypes and various …endophenotypes in the entire ADNI sample at baseline, with age, gender, years of education, and APOE ɛ4 status included as covariates. To examine changes in clinical outcomes over time, linear mixed-effects models were employed. Results: We found that the SNP rs17328707-A was associated with higher ADNI-VS scores, smaller ventricles, and larger middle temporal volume at baseline. The SNP rs6915083-G was linked to lower CSF t-tau and p-tau levels, and higher CSF Aβ levels. The SNP rs9394766-G was associated with a smaller hippocampus and larger ventricles at baseline. In longitudinal cohorts, the rs6915083-G SNP was associated with changes in ADNI-MEM and ADNI-EF scores, as well as the rate of hippocampal and middle temporal atrophy. Conclusion: Our findings reveal that TREML2 gene variants have different effects on AD. Two variants are protective, while one may be a risk factor. This enhances our understanding of AD genetics and could guide future research and personalized treatments. Show more

Keywords: Alzheimer’s disease, cognition, gene, single nucleotide polymorphisms, TREML2

DOI: 10.3233/JAD-230936

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2023

Authors: Yang, Zhengshi | Banks, Sarah J. | Ritter, Aaron R. | Cummings, Jeffrey L. | Sreenivasan, Karthik | Kinney, Jefferson W. | Caldwell, Jessica K. | Wong, Christina G. | Miller, Justin B. | Cordes, Dietmar

Article Type: Research Article

Abstract: Background: Emerging evidence suggests a potential causal role of neuroinflammation in Alzheimer’s disease (AD). Using positron emission tomography (PET) to image overexpressed 18 kDA translocator protein (TSPO) by activated microglia has gained increasing interest. The uptake of 18 F-GE180 TSPO PET was observed to co-localize with inflammatory markers and have a two-stage association with amyloid PET in mice. Very few studies evaluated the diagnostic power of 18 F-GE180 PET in AD population and its interpretation in human remains controversial about whether it is a marker of microglial activation or merely reflects disrupted blood-brain barrier integrity in humans. Objective: …The goal of this study was to study human GE180 from the perspective of the previous animal observations. Methods: With data from twenty-four participants having 18 F-GE180 and 18 F-AV45 PET scans, we evaluated the group differences of 18 F-GE180 uptake between participants with and without cognitive impairment. An association analysis of 18 F-GE180 and 18 F-AV45 was then conducted to test if the relationship in humans is consistent with the two-stage association in AD mouse model. Results: Elevated 18 F-GE180 was observed in participants with cognitive impairment compared to those with normal cognition. No regions showed reduced 18 F-GE180 uptake. Consistent with mouse model, a two-stage association between 18 F-GE180 and 18 F-AV45 was observed. Conclusions: 18 F-GE180 PET imaging showed promising utility in detecting pathological alterations in a symptomatic AD population. Consistent two-stage association between 18 F-GE180 and amyloid PET in human and mouse suggested that 18 F-GE180 uptake in human might be considerably influenced by microglial activation. Show more

Keywords: Alzheimer’s disease, amyloid, 18F-GE180, neuroinflammation, translocator protein

DOI: 10.3233/JAD-230631

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2023

Authors: Bozkurt, Ahmet Sarper | Yílmaz, Şenay Görücü

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by two main pathological mechanisms, mostly hyperphosphorylated tau and amyloid-β toxicity. Although many studies focus on these basic mechanisms, ferroptosis draws attention as an important pathway responsible for neurodegeneration in AD. There is no definitive treatment for AD but alternative phytochemicals to drugs come into prominence. Betulin is usually obtained from the birch tree. It is an abundant triterpene and has a high antioxidant capacity. Isthmin-1 (ISM1) is a secreted adipokine. Objective: In this study, we investigated the potential treatment of AD in the ferroptosis-ISM1-betulin triangle. …Methods: For this, we created an AD model with okadaic acid (200 ng/kg)) in 36 Wistar albino male rats and treated with betulin (20 mg/kg/day, i.p). We evaluated ISM1 gene expression, iron accumulation, and total oxidative metabolism parameters (TAS, TOS, OSI) in hippocampal tissue. We analyzed cognitive recovery in AD with Morris Water Maze Test and general locomotor activity, explore, and anti-anxiolytic effect with Open Field Test. Results: We compared the obtained data with metabolic and genetic results. In conclusion, betulin may have a role in neuronal ferroptotic mechanisms by reducing iron accumulation by ISM1 regulation. Conclusions: Betulin may have a role in neuronal ferroptotic mechanisms by reducing iron accumulation by ISM1 regulation. Although this study suggests the corrective effect of betulin and ISM1 on cognitive gain and anxiety, it is the first study to show the total antioxidant capacity of betulin in AD. Show more

Keywords: Alzheimer’s disease, betulin, iron, ISM1, neurodegeneration, oxidative stress

DOI: 10.3233/JAD-230940

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023

Authors: Wang, Mu-Cyun | Chiou, Jeng-Min | Chen, Yen-Ching | Chen, Jen-Hau

Article Type: Research Article

Abstract: Background: Previous studies assessing olfactory function and cognition have mostly been cross-sectional, and few have investigated the Asian geriatric population. Objective: To examine the relationships of olfaction with global or domain-specific cognitive function in Taiwanese community-dwelling older adults. Methods: This cohort study (2015–2019) is part of the Taiwan Initiative for Geriatric Epidemiological Research. The Taiwanese version of the Montreal Cognitive Assessment (MoCA-T) and a battery of neuropsychological tests were assessed at baseline and at a two-year follow-up. The cross-culture modified Sniffin’ Sticks Identification Test (SSIT) was utilized to measure olfactory function. Generalized linear mixed models were …used to examine the association of olfaction with cognitive performance over two years. Results: Data were collected from 376 participants (55.1% women), with a mean age of 75.6 years. A one-point decrease in the SSIT score (worsening of olfaction) was associated with worse global cognition (MoCA-T: β ˆ = –0.13), memory ( β ˆ = –0.08 to –0.06), and verbal fluency ( β ˆ = –0.07). Compared with an SSIT score ≥ 11 (normosmia), an SSIT score < 8 (anosmia) was associated with worse global cognition (MoCA-T: β ˆ = –0.99), memory ( β ˆ = –0.48 to –0.42), executive function (Trail Making Test A: β ˆ = –0.36), attention (digit span backward: β ˆ = –0.34), and verbal fluency ( β ˆ = –0.45). After stratified analyses, the associations remained in older adults ≥ 75 years, males, and non-carriers of apolipoprotein E ɛ4 in terms of global cognition, memory, and verbal fluency. Conclusions: Odor identification deficits were associated with poor global or domain-specific cognitive function in a four-year cohort of community-dwelling older adults. Cognitive assessments should be conducted in dementia-free elderly individuals with impaired odor identification. Show more

Keywords: Cognition, Montreal Cognitive Assessment, odor identification, older adults, olfaction

DOI: 10.3233/JAD-230319

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023