Journal of Alzheimer's Disease - Volume 96, issue 4

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. 96, no. 4, pp. 1505-1514, 2023

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. 96, no. 4, pp. 1515-1528, 2023

Authors: Zhang, Fan | Petersen, Melissa | Johnson, Leigh | Hall, James | O’Bryant, Sid E.

Article Type: Research Article

Abstract: Background: Blood biomarkers have the potential to transform Alzheimer’s disease (AD) diagnosis and monitoring, yet their integration with common medical comorbidities remains insufficiently explored. Objective: This study aims to enhance blood biomarkers’ sensitivity, specificity, and predictive performance by incorporating comorbidities. We assess this integration’s efficacy in diagnostic classification using machine learning, hypothesizing that it can identify a confident set of predictive features. Methods: We analyzed data from 1,705 participants in the Health and Aging Brain Study-Health Disparities, including 116 AD patients, 261 with mild cognitive impairment, and 1,328 cognitively normal controls. Blood samples were assayed using …electrochemiluminescence and single molecule array technology, alongside comorbidity data gathered through clinical interviews and medical records. We visually explored blood biomarker and comorbidity characteristics, developed a Feature Importance and SVM-based Leave-One-Out Recursive Feature Elimination (FI-SVM-RFE-LOO) method to optimize feature selection, and compared four models: Biomarker Only, Comorbidity Only, Biomarker and Comorbidity, and Feature-Selected Biomarker and Comorbidity. Results: The combination model incorporating 17 blood biomarkers and 12 comorbidity variables outperformed single-modal models, with NPV12 at 92.78%, AUC at 67.59%, and Sensitivity at 65.70%. Feature selection led to 22 chosen features, resulting in the highest performance, with NPV12 at 93.76%, AUC at 69.22%, and Sensitivity at 70.69%. Additionally, interpretative machine learning highlighted factors contributing to improved prediction performance. Conclusions: In conclusion, combining feature-selected biomarkers and comorbidities enhances prediction performance, while feature selection optimizes their integration. These findings hold promise for understanding AD pathophysiology and advancing preventive treatments. Show more

Keywords: Alzheimer’s disease, blood biomarkers, comorbidities, machine learning, recursive feature elimination, support vector machine

DOI: 10.3233/JAD-230755

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1529-1546, 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. 96, no. 4, pp. 1547-1554, 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. 96, no. 4, pp. 1555-1563, 2023

Authors: Bozkurt, Ahmet Sarper | Görücü Yílmaz, Şenay

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. 96, no. 4, pp. 1565-1578, 2023

Authors: Tian, Jing | Du, Eric | Jia, Kun | Wang, Tienju | Guo, Lan | Zigman, Jeffrey M. | Du, Heng

Article Type: Research Article

Abstract: Background: Emerging evidence has revealed that dysregulation of the hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), contributes to the pathogenesis of Alzheimer’s disease (AD). Specifically, defective GHSR function and resultant hippocampal ghrelin resistance are linked to hippocampal synaptic injury in AD paradigms. Also, AD patients exhibit elevated ghrelin activation. However, the detailed molecular mechanisms of hippocampal GHSR dysfunction and the relevance of ghrelin elevation to hippocampal ghrelin resistance in AD-relevant pathological settings are not fully understood. Objective: In the current study, we employed a recently established mouse line of AD risk [humanized amyloid beta knockin …(hAβ KI mice), also referred to as a mouse model of late-onset AD in previous literature] to further define the role of ghrelin system dysregulation in the development of AD. Methods: We employed multidisciplinary techniques to determine the change of plasma ghrelin and the functional status of GHSR in hAβ KI mice as well as primary neuron cultures. Results: We observed concurrent plasma ghrelin elevation and hippocampal GHSR desensitization with disease progression. Further examination excluded the possibility that ghrelin elevation is a compensatory change in response to GHSR dysfunction. In contrast, further in vitro and in vivo results show that agonist-mediated overstimulation potentiates GHSR desensitization through enhanced GHSR internalization. Conclusions: These findings suggest that circulating ghrelin elevation is a pathological event underlying hippocampal GHSR dysfunction, culminating in hippocampal ghrelin resistance and resultant synaptic injury in late-onset AD-related settings. Show more

Keywords: Alzheimer’s disease, amyloid-β, ghrelin, growth hormone secretagogue receptor, hippocampal synaptic injury

DOI: 10.3233/JAD-231002

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1579-1592, 2023

Authors: El Kadiri, Wafa | Perrignon-Sommet, Manon | Delpont, Benoit | Graber, Mathilde | Mohr, Sophie | Mouillot, Thomas | Devilliers, Hervé | Grall, Sylvie | Lienard, Fabienne | Georges, Marjolaine | Brindisi, Marie-Claude | Brondel, Laurent | Bejot, Yannick | Leloup, Corinne | Jacquin-Piques, Agnès

Article Type: Research Article

Abstract: Background: The need for early diagnosis biomarkers in Alzheimer’s disease (AD) is growing. Only few studies have reported gustatory dysfunctions in AD using subjective taste tests. Objective: The main purpose of the study was to explore gustatory functions using subjective taste tests and recordings of gustatory evoked potentials (GEPs) for sucrose solution in patients with minor or major cognitive impairment (CI) linked to AD, and to compare them with healthy controls. The secondary objective was to evaluate the relationships between GEPs and the results of cognitive assessments and fasting blood samples. Methods: A total of 45 …subjects (15 healthy subjects, 15 minor CI patients, 15 major CI patients) were included to compare their gustatory functions and brain activity by recording GEPs in response to a sucrose stimulation. CI groups were combined in second analyses in order to keep a high power in the study. Correlations were made with cognitive scores and hormone levels (ghrelin, leptin, insulin, serotonin). Results: Increased P1 latencies and reduced N1 amplitudes were observed in minor or major patients compared to controls. GEPs were undetectable in 6 major and 4 minor CI patients. Thresholds for sucrose detection were significantly higher in the major CI group than in controls or the minor CI group. No correlation was found with hormone levels. Conclusions: The cortical processing of sensory taste information seems to be altered in patients with minor or major CI linked to AD. This disturbance was identifiable with subjective taste tests only later, at the major CI stage. Show more

Keywords: Alzheimer’s disease, diagnosis, ghrelin, gustatory evoked potential, taste

DOI: 10.3233/JAD-230270

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1593-1607, 2023

Authors: García-Alberca, José María | de la Rosa, María Dolores | Solo de Zaldívar, Paloma | Ledesma, María | Oltra, Estela | Gris, Esther | Ocejo, Olga | Torrecilla, Javier | Zafra, Carmen | Sánchez-Fernández, Ana | Mancilla, Tomás | López-Romero, Mercedes | Jerez, Raquel | Santana, Nuria | Lara, José Pablo | Barbancho, Miguel Ángel | Blanco-Reina, Encarnación

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) are present in most people with dementia (PwD), including Alzheimer’s disease. There is consensus that non-pharmacological therapies represent the first line of treatment to address BPSD. Objective: We explore the efficacy of the use of a rocking chair (Nordic Sensi® Chair, NSC) in the treatment of BPSD in nursing home residents with moderate and severe dementia. Methods: We carried out a 16-week randomized, single-blind, controlled, clinical trial with PwD admitted to nursing homes. Participants were assigned to a treatment group (n  = 40) that received three times a …week one session per day of 20 minutes in the NSC and a control group (n  = 37). The Neuropsychiatric Inventory-Nursing Home (NPI-NH) was used as primary efficacy outcome. Occupational distress for the staff was evaluated using the NPI-NH Occupational Disruptiveness subscale (NPI-NH-OD). Statistical analyses were conducted by means of a Mixed Effects Model Analysis. Results: Treatment with the NSC was associated with a beneficial effect in most of BPSD, as reflected by differences between the treatment and control group on the NPI-NH total score (mean change score –18.87±5.56 versus –1.74±0.67, p  = 0.004), agitation (mean change score –2.32±2.02 versus –0.78±1.44, p  = 0.003) and irritability (mean change score –3.35±2.93 versus –1.42±1.31, p  = 0.004). The NPI-NH-OD total score also improved the most in the treatment group (mean change score –9.67±7.67 versus –7.66±6.08, p  = 0.003). Conclusions: The reduction in overall BPSD along with decreased caregiver occupational disruptiveness represent encouraging findings, adding to the potential of nonpharmacological interventions for nursing home residents living with dementia. Show more

Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, dementia, non-pharmacological intervention, nursing home

DOI: 10.3233/JAD-230391

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1609-1622, 2023

Authors: Kawarabayashi, Takeshi | Nakamura, Takumi | Miyashita, Kazuya | Segawa, Tatsuya | Fukamachi, Isamu | Sugawara, Takashi | Oka, Hironori | Ishizawa, Kunihiko | Amari, Masakuni | Kasahara, Hiroo | Makioka, Kouki | Ikeda, Yoshio | Takatama, Masamitsu | Shoji, Mikio

Article Type: Research Article

Abstract: Background: The cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 217 (p217tau) or 181 (p181tau), and neurofilament light chain (NfL) are definite biomarkers of tauopathy and neurodegeneration in Alzheimer’s disease (AD). Objective: To validate their utility in excluding other neurological diseases and age-related changes in clinical settings. Methods: We developed monoclonal antibodies against p217tau and NfL, established novel ELISAs, and analyzed 170 CSF samples from patients with AD or other neurological diseases. Results: In AD, p217tau is a more specific and abundant CSF component than p181tau. However, CSF NfL levels increase age-dependently and …to a greater extent in central and peripheral nervous diseases than in AD. Conclusions: CSF p217tau correlates better with AD neurodegeneration than other tau-related biomarkers and the major phosphorylated tau species. The clinical usage of NfL as a neurodegeneration biomarker in AD requires exclusion of various central and peripheral neurological diseases. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, neurofilament light chain, neurological diseases, p181tau, p217tau, total tau

DOI: 10.3233/JAD-230419

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1623-1638, 2023