Journal of Alzheimer's Disease - Volume 97, issue 3

Authors: Hou, Yi-Chou | Chueh, Ti-I | Lu, Kuo-Cheng | Liu, Yi-Chien | Chen, Tso-Hsiao | Liu, Shing-Hwa | Chen, Ruei-Ming

Article Type: Research Article

Abstract: Background: Cognitive impairment (CI) is one of the major complications in chronic kidney disease patients, especially those with end-stage renal disease (ESRD). Limited biomarkers have been found that can significantly predict ESRD-associated cognitive decline. Objective: This cohort study aimed to investigate de novo biomarkers for diagnosis of the ESRD-associated CI. Methods: In this cohort study, qualified samples were divided into control (with an estimated glomerular filtration rate (eGFR) of≥60 mL/min and a Mini-Mental State Examination (MMSE) score of > 27), ESRD without CI (eGFR < 15 and MMSE > 27), and ESRD with CI (eGFR < 15 and MMSE < 27) groups. Levels of plasma amyloid-β …(Aβ)1 - 42 , serum indoxyl sulfate, and hematologic and biochemical parameters were measured. Results: Compared to the control group, levels of blood urea nitrogen, creatinine, and indoxyl sulfate were elevated in ESRD patients both without and with CI. Interestingly, ESRD patients with CI had the lowest levels of serum albumin. In contrast, levels of plasma Aβ1 - 42 were significantly higher in the ESRD with CI group than in the control and ESRD without CI groups. In addition, the ratio of plasma Aβ1 - 42 over serum albumin was significantly higher in the ESRD with CI group than in the control or ESRD without CI groups. Importantly, the area under the receiver operating characteristic curve (AUROC) for CI in the total population by the ratio of Aβ1 - 42 over albumin was 0.785 and significant (p  < 0.05). Conclusions: This cohort study has shown that the ratio of plasma Aβ1 - 42 over serum albumin can be a de novo biomarker for the diagnosis and prognosis of ESRD-associated cognitive decline. Show more

Keywords: Albumin, Alzheimer’s disease, amyloid-beta 1-42, biomarker signature, cognitive impairment, end-stage renal disease

DOI: 10.3233/JAD-230747

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1393-1405, 2024

Authors: Gorham, Isabelle K. | Reid, Danielle Marie | Sun, Jie | Zhou, Zhengyang | Barber, Robert C. | Phillips, Nicole R.

Article Type: Research Article

Abstract: Background: Age is known to be the biggest risk factor for Alzheimer’s disease (AD), and Mexican Americans (MAs), who are one of the fastest-aging populations in the United States, are at a uniquely elevated risk. Mitochondrial stress and dysfunction are key players in the progression of AD and are also known to be impacted by lifestyle and environmental exposures/stressors. Objective: This study aimed to identify population-specific differences in indicators of mitochondrial stress and dysfunction associated with AD risk that are detectable in the blood. Methods: Examining blood from both non-Hispanic white (NHW) and MA participants (N = 527, …MA n  = 284, NHW n  = 243), mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) copy numbers were assessed through quantitative PCR. Data was stratified by population and sample type, and multiple linear regression analyses were performed to identify factors that may influence this phenotype of mitochondrial dysfunction. Results: In the MA cohort, there was a significant relationship between cellular mtDNA:nDNA ratio and body mass index, CDR sum of boxes score, the APOE ɛ 2/ɛ 3 genotype, and education. Further, there was a significant relationship between cell-free mtDNA copy number and both education and CDR sum score. In the NHW cohort, there was a significant relationship between cellular mtDNA:nDNA ratio and both age and CDR sum score. Age was associated with cell-free mtDNA in the NHW cohort. Conclusions: This evidence supports the existence of population-based differences in the factors that are predictive of this blood-based phenotype of mitochondrial dysfunction, which may be indicative of cognitive decline and AD risk. Show more

Keywords: Alzheimer’s disease, cognitive decline, mitochondrial dysfunction, mtDNA

DOI: 10.3233/JAD-230880

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1407-1419, 2024

Authors: Takase, Hajime | Hamanaka, Gen | Hoshino, Tomonori | Ohtomo, Ryo | Guo, Shuzhen | Mandeville, Emiri T. | Lo, Eng H. | Arai, Ken

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a widespread neurodegenerative disorder characterized by progressive cognitive decline, affecting a significant portion of the aging population. While the cerebral cortex and hippocampus have been the primary focus of AD research, accumulating evidence suggests that white matter lesions in the brain, particularly in the corpus callosum, play an important role in the pathogenesis of the disease. Objective: This study aims to investigate the gene expression changes in the corpus callosum of 5xFAD transgenic mice, a widely used AD mouse model. Methods: We conducted behavioral tests for spatial learning and memory in …5xFAD transgenic mice and performed RNA sequencing analyses on the corpus callosum to examine transcriptomic changes. Results: Our results show cognitive decline and demyelination in the corpus callosum of 5xFAD transgenic mice. Transcriptomic analysis reveals a predominance of upregulated genes in AD mice, particularly those associated with immune cells, including microglia. Conversely, downregulation of genes related to chaperone function and clock genes such as Per1 , Per2 , and Cry1 is also observed. Conclusions: This study suggests that activation of neuroinflammation, disruption of chaperone function, and circadian dysfunction are involved in the pathogenesis of white matter lesions in AD. The findings provide insights into potential therapeutic targets and highlight the importance of addressing white matter pathology and circadian dysfunction in AD treatment strategies. Show more

Keywords: Alzheimer’s disease, circadian rhythm, corpus callosum, microglia, molecular chaperones, neuroinflammation, RNA-seq

DOI: 10.3233/JAD-231049

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1421-1433, 2024

Authors: Okahashi, Sayaka | Noguchi, Taiji | Ishihara, Masumi | Osawa, Aiko | Kinoshita, Fumie | Ueda, Ikue | Kamiya, Masaki | Nakagawa, Takeshi | Kondo, Izumi | Sakurai, Takashi | Arai, Hidenori | Saito, Tami

Article Type: Research Article

Abstract: Background: Non-pharmacological interventions effective for depressive mood and bilateral relationships among persons with cognitive impairment (PwCI) and their family caregivers (FCGs) have not been established. Objective: To examine the feasibility of a newly developed group-based art appreciation and self-expression program (NCGG-ART) for dyads of PwCI and their FCGs. Methods: This pilot randomized control trial included 34 dyads of PwCI diagnosed with mild to moderate Alzheimer’s disease or mild cognitive impairment, and their FCGs, from an outpatient rehabilitation service (Holistic Physio-Cognitive Rehabilitation [HPCR]). Participants were randomly divided equally into the HPCR (control group) or NCGG-ART and HPCR …(intervention group) groups. Both included 1-hour weekly, 6-week programs. The primary outcome was depressive symptoms among FCGs assessed using the Patient Health Questionnaire-9 (PHQ-9). Feasibility outcomes included participant satisfaction and motivation. FCGs were interviewed about their experiences and feelings regarding the program, which were analyzed using content analysis. Results: Thirty-two dyads (intervention group:16; control group:16) completed the study period. High participation rates, satisfaction, and motivation were demonstrated throughout the intervention. Scores in the PHQ-9 among FCGs did not show positive effects: mean changes in the score were 1.3 for the intervention group and –0.8 for the control group (Cohen d :0.56). However, the qualitative analysis revealed favorable experiences and feelings of the FCGs, such as positive emotions, social interactions, and person-centered attitudes to and positive relationships with PwCI. Conclusions: This program demonstrated high feasibility with FCGs’ favorable responses to emotions and relationships with PwCI, ensuring future investigations with a confirmatory study design. Show more

Keywords: Alzheimer’s disease, art, caregivers, cognitive dysfunction, dementia, depression, person-centered psychotherapy, positive psychology, psychosocial intervention, qualitative research

DOI: 10.3233/JAD-231143

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1435-1448, 2024

Authors: Márquez, Freddie | Tarraf, Wassim | Stickel, Ariana M. | González, Kevin A. | Testai, Fernando D. | Cai, Jianwen | Gallo, Linda C. | Talavera, Gregory A. | Daviglus, Martha L. | Wassertheil-Smoller, Sylvia | DeCarli, Charles | Schneiderman, Neil | González, Hector M.

Article Type: Research Article

Abstract: Background: Hypertension can have deleterious effects on cognitive function; however, few studies have examined its effects on cognition among Hispanics/Latinos. Objective: To assess associations between hypertension status with 1) change in cognitive performance, and 2) having mild cognitive impairment (MCI) among diverse Hispanics/Latinos. Methods: This population-based, prospective cohort, multisite study included Hispanic/Latino adults aged 45 to 72 years in enrolled in the Hispanic Community Health Study/Study of Latinos at Visit 1 (2008–2011; mean age of 63.40±8.24 years), and the Study of Latinos-Investigation of Neurocognitive Aging at Visit 2 (2016–2018), with a mean follow-up duration …of 7 years (n  = 6,173). Hypertension status was assessed at both visits: normotension (no hypertension), incident hypertension (only at Visit 2), and persistent hypertension (at both visits). We examined change in cognitive performance and having MCI (only assessed at Visit 2) relative to hypertension status and adjusted for demographics and cardiovascular disease risk factors. Results: Compared to normotension, persistent hypertension was associated with significantly increased decline in verbal fluency (β= –0.08; CI = [–0.16;–0.01]; p  < 0.05), and processing speed (β= –0.11; CI = [–0.20;–0.02]; p  < 0.05). Incident hypertension was not associated with significant change in cognitive performance. Both incident (OR = 1.70; CI = [1.16;2.50]; p  < 0.01) and persistent hypertension (OR = 2.13; CI = [1.57;2.88]; p  < 0.001) were associated with significantly higher odds ratios of having MCI. Conclusions: These findings indicate that persistent hypertension is associated with clinical impairment and domain-specific cognitive decline in middle-aged and older Hispanics/Latinos. It underscores the importance of monitoring blood pressure in routine healthcare visits beginning at midlife in this population to reduce the burden of cognitive decline. Show more

Keywords: Alzheimer’s disease, blood pressure, cognitive decline, cognitive function, dementia, epidemiology, Hispanics, hypertension, Latinos, mild cognitive impairment, neuroepidemiology, neuropsychology, population neuroscience

DOI: 10.3233/JAD-230424

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1449-1461, 2024

Authors: Villemagne, Victor L. | Doré, Vincent | Chong, Lee | Kassiou, Michael | Mulligan, Rachel | Feizpour, Azadeh | Taylor, Jack | Roesner, Miriam | Miller, Tamara | Rowe, Christopher C.

Article Type: Research Article

Abstract: Background: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates intracellular cortisol and its inhibition by the small molecule inhibitor, Xanamem™, may provide a disease-modifying strategy for Alzheimer’s disease (AD). Animal models suggest a range of 30–60% enzyme inhibition may suffice to provide neuroprotection. Objective: To determine the regional brain occupancy of 11β-HSD1 by Xanamem™ in cognitively normal participants (CN) and mild cognitive impairment (MCI)/mild AD patients to investigate potential dosing ranges for future efficacy studies. Methods: Seventeen MCI/AD and 23 CN were included. Regional brain time-activity curves (TAC), standardized uptake values (SUV40–60 ) and volume of distribution (VT …) from Logan plot with image derived input function from 11 C-TARACT positron emission tomography (PET) were used to assess the degree of 11β-HSD1 occupancy by increasing doses of Xanamem™ (5 mg, 10 mg, 20 mg or 30 mg daily for 7 days). Results: All measures showed high 11β-HSD1 occupancy with Xanamem to similar degree in CN and MCI/AD. The dose-response relationship was relatively flat above 5 mg. Respective median (interquartile range [Q1-Q3]) 11β-HSD1 occupancy in the MCI/AD and CN groups after treatment with 10 mg Xanamem were 80% [79–81%] and 75% [71–76%] in the neocortex, 69% [64–70%] and 61% [52–63%] in the medial temporal lobe, 80% [79–80%] and 73% [68–73%] in the basal ganglia, and 71% [67–75%] and 66% [62–68%] in the cerebellum. Conclusions: TAC, SUV40–60 , and VT measures indicate Xanamem achieves high target occupancy levels with near saturation at 10 mg daily. These data support exploration of doses of≤10 mg daily in future clinical studies. Show more

Keywords: Alzheimer’s disease, 11beta-hydroxysteroid dehydrogenase type 1, cortisol, drug development, positron emission tomography, target occupancy

DOI: 10.3233/JAD-220542

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1463-1475, 2024

Authors: García-Alberca, José María | de la Rosa, María Dolores | Solo de Zaldívar, Paloma | Ledesma, María | Oltra, Estela | Esther, Gris | 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: Correction

DOI: 10.3233/JAD-249001

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1477-1477, 2024