Journal of Alzheimer's Disease Reports - Volume 8, issue 1

Authors: Cubas Guillen, Jonathan | Rojas, Galeno | Demey, Ignacio | Sarasola, Diego | Merchán del Hierro, Xavier | Persi, Gabriel | Aldinio, Victoria | Pereira de Silva, Nahuel | Fernández Boccazzi, Julián | Seguí, Josefina | Muniagurria, Santiago | Gilbert, Afra | Gatto, Emilia

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) presents a significant global health challenge. Understanding the current and upcoming treatment landscape is crucial for effectively managing patients. Objective: The aim of this study was to assess the pattern of prescription and knowledge about new therapies by physicians who treat AD patients in Argentina. Methods: A cross- sectional and analytic study was conducted. A survey was elaborated about pharmacological treatment in AD. Statistical analysis of answers of specialists in cognitive disorders (SCD), non-specialists in cognitive disorders (NSCD), recommended treatment, non-recommended treatment (NRT), and off-label treatment was performed. Results: …155 physicians answered the survey. A 19.35%prescribed at least one NRT for dementia. 78.06%prescribed at least an off-label treatment or an NRT for mild cognitive impairment (MCI). 31%would prescribe monoclonal antibodies (MABs) against cerebral amyloid-β (Aβ) to AD patients, and 42.6%responded that they were not aware of any adverse effect of these. Quetiapine was the most frequent treatment for psychotic symptoms (88.4%) and escitalopram (32.3%) for apathy. A 70%of potential prescribers of MABs (n  = 100) would request biomarkers of cerebral Aβ in the initial assessment. There were significant differences between the responses of SCD and NSCD regarding the prescription of MABs (52.17%versus 23.08, respectively) and knowledge about adverse events (76.09%versus 38.46%, respectively). Conclusions: A considerable percentage of physicians indicated NRT and off-label medication in MCI and dementia. In Argentina, there are many physicians who would indicate a MABs for AD, but many are not completely aware of its safety profile. Show more

Keywords: Alzheimer’s disease, drug therapy, epidemiology, health policy, monoclonal antibodies

DOI: 10.3233/ADR-240018

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 737-746, 2024

Authors: Brownell, Malcolm | Sehar, Ujala | Mukherjee, Upasana | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: Dementia is a major health concern in society, particularly in the aging population. It is alarmingly increasing in ethnic minorities such as Native Americans, African Americans, Hispanics/Latinos, and to some extent Asians. With increasing comorbidities of dementia such as diabetes, obesity, and hypertension, dementia rates are expected to increase in the next decade and beyond. Understanding and treating dementia, as well as determining how to prevent it, has become a healthcare priority across the globe for all races and genders. Awareness about dementia and its consequences such as healthcare costs, and caregiver burden are immediate needs to be addressed. Therefore, …it is high time for all of us to create awareness about dementia in society, particularly among Hispanics/Latinos, Native Americans, and African Americans. In the current article, we discuss the status of dementia, cultural, and racial impacts on dementia diagnosis and care, particularly in Hispanic populations, and possible steps to increase dementia awareness. We also discussed factors that need to be paid attention to, including, cultural & language barriers, low socioeconomic status, limited knowledge/education, religious/spiritual beliefs and not accepting modern medicine/healthcare facilities. Our article also covers both mental & physical health issues of caregivers who are living with patients with dementia, Alzheimer’s disease, and Alzheimer’s disease-related dementias. Most importantly, we discussed possible measures to create awareness about dementia, including empowering community advocacy, promoting healthy lifestyle choices, education on the impact of nutrition, encouraging community participation, and continued collaboration and evaluation of the success of dementia awareness. Show more

Keywords: Alzheimer’s disease, community participation, comorbidities, dementia, healthy brain aging, Hispanics, lifestyle choices

DOI: 10.3233/ADR-240043

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 747-764, 2024

Authors: Bai, Yamei | Tian, Meng | Chen, Yuqing | Song, Yulei | Zhang, Xueqing | Yin, Haiyan | Luo, Dan | Xu, Guihua

Article Type: Research Article

Abstract: Background: Individuals with mild cognitive impairment (MCI) frequently experience sleep disorders, which may elevate the risk of developing Alzheimer’s disease. Yet, sleep types in MCI patients and the factors influencing them have not been sufficiently investigated. Objective: The objective of this study was to explore potential sleep typing and its influencing factors in patients with MCI using latent class analysis. Methods: A cross-sectional survey was conducted in Jiangsu Province, China. Cognitive function in older adults was assessed using neuropsychological tests, including the Montreal Cognitive Assessment Scale-Beijing version (MoCA), the Mini-Mental State Examination (MMSE), the Activities of …Daily Living Scale (ADL), and the Clinical Dementia Rating Scale (CDR). Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). Latent class analysis based on PSQI scores and multinomial logistic regression analyses were employed to explore the influencing factors of sleep typing. Results: The study included a total of 611 patients with MCI. Latent class analysis identified three latent classes to categorize the sleep patterns of MCI patients: the good sleep type (56.6%), the insufficient sleep type (29.6%), and the difficulty falling asleep type (13.7%). Potential sleep typing is influenced by gender, chronic disease, physical exercise, social activity, brain exercise, smoking, frailty, subjective cognitive status, and global cognitive function. Conclusions: The findings of this study underscore the notable heterogeneity in the sleep patterns of patients with MCI. Future research may provide targeted prevention and interventions to address the characteristics and influencing factors of patients with different subtypes of sleep MCI. Show more

Keywords: Alzheimer’s disease, latent class analysis, mild cognitive impairment, risk factors, sleep

DOI: 10.3233/ADR-230192

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 765-776, 2024

Authors: Liang, Yulin | Doré, Vincent | Rowe, Christopher C. | Krishnadas, Natasha

Article Type: Systematic Review

Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia. While preclinical studies have shown benefits of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in targeting core AD pathology, clinical studies are limited. Objective: A systematic review was performed to evaluate GLP-1 RAs in AD for their potential to target core AD pathology and improve cognition. Methods: Searches were conducted via three different databases (PubMed, Embase, and Cochrane Library). Search terms included Medical Subject Headings (MeSH) terms: ‘glucagon-like peptide 1 receptor agonist’ and ‘Alzheimer’s disease’, as well as entry terms ‘GLP-1 RA’, ‘AD’, and three …types of GLP-1 RA: ‘liraglutide’, ‘exenatide’, and ‘lixisenatide’. Results: A total of 1,444 studies were screened. Six articles that met criteria were included (four randomized control trials [RCTs] and two protocol studies). Two RCTs with amyloid-β and tau biomarker endpoints did not observe an end of treatment difference between the placebo and treated groups. In three RCTs with cognitive endpoints, there was no end of treatment difference between placebo and treated groups. GLP-1 RA showed metabolic benefits, such as lower body mass index and improved glucose levels on oral glucose tolerance tests in treated groups. GLP-1 RA may mitigate the decline in cerebral glucose metabolism and show enhanced blood-brain glucose transport capacity using 18 F-FDG PET, however, more data is needed. Conclusions: GLP-1 RA therapy did not alter amyloid-β and tau biomarkers nor show improvements in cognition but showed potential metabolic and neuroprotective benefits. Show more

Keywords: Alzheimer’s disease, amyloid, cognition, glucagon-like peptide 1, tau protein

DOI: 10.3233/ADR-230181

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 777-789, 2024

Article Type: Correction

DOI: 10.3233/ADR-249002

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 791-792, 2024

Authors: Adhikari, Alisa | Nwosu, Adaora | Qian, Min | Hellegers, Caroline | Devanand, Davangere P. | Doraiswamy, P. Murali

Article Type: Research Article

Abstract: Background: There is a need for integration and comprehensive characterization of environmental determinants of Alzheimer’s disease. The Environmental Justice Index (EJI) is a new measure that consolidates multiple environmental health hazards. Objective: This analysis aims to explore how environmental vulnerabilities vary by race/ethnicity and whether they predict cognitive outcomes in a clinical trial of mild cognitive impairment (MCI). Methods: We used data from a clinical trial of 107 MCI participants (28% minorities). Using the EJI, we extracted 40 measures of neighborhood environmental and social vulnerability including air and water pollution, access to recreational …spaces, exposure to coal and lead mines, and area poverty. We also examined the relationship of the EJI to the Area Deprivation Index (ADI). Data was analyzed using regressions, correlations, and t -tests. Results: Environmental Burden Rank (EBR) across the sample (0.53±0.32) was near the 50th percentile nationally. When divided by race/ethnicity, environmental (p  = 0.025) and social (p  < 0.0001) vulnerabilities were significantly elevated for minorities, specifically for exposure to ozone, diesel particulate matter, carcinogenic air toxins, and proximity to treatment storage and disposal sites. ADI state decile was not correlated with the EBR. Neither EBR nor ADI were a significant predictor of cognitive decline. Conclusions: To our knowledge, this is the first study to link the EJI to an MCI trial. Despite limitations of a relatively small sample size, the study illustrates the potential of the EJI to provide deeper phenotyping of the exposome and diversity in clinical trial subjects. Show more

Keywords: Alzheimer’s disease, climate medicine, cognition, disparities, diversity, environment global warming, neurodegeneration, ozone, particulate matter

DOI: 10.3233/ADR-240020

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 793-804, 2024

Authors: Ho, Duc Sy Minh | Zaitsu, Takashi | Ihira, Hikaru | Iwasaki, Masanori | Yoshihara, Akihiro | Suzuki, Seitaro | Inoue, Manami | Yamagishi, Kazumasa | Yasuda, Nobufumi | Aida, Jun | Shinozaki, Tomohiro | Goto, Atsuhi | Tsugane, Shoichiro | Sawada, Norie

Article Type: Research Article

Abstract: Background: As infrequent social interaction is a potential risk of dementia, oral malodor may increase the risk of dementia, including Alzheimer’s disease. Objective: This study investigated the association between malodor and dementia. Methods: We used the Japan Public Health Center-based Prospective Study data obtained at Yokote City. A total of 1,493 individuals aged 56 to 75 years underwent a dental examination and self-reported survey from May 2005 to January 2006. Follow-up for the onset of dementia was conducted using long-term care insurance data from 2006 to 2016. Hazard ratios of oral malodor on …dementia were estimated by the Cox proportional hazards model. The inverse probability-weighted Cox model was used as a sensitivity analysis. Results: The study comprised 1493 participants (53.6% women) with a mean age of 65.6 (SD = 5.8) years old; at the end of the follow-up, 6.4% (n  = 96) developed dementia, and the percentage was 20.7 in severe malodor group. Throughout 15274.133 person-years of follow-up, the average incidence rate for the onset of dementia per 1000 person-years was 6.29. The highest incidence rate was seen in participants with severe malodor (22.4 per 1000 person-years). After adjusting for confounders, compared to those with no malodor, there was a 3.8 (95% confidence interval: 1.5 to 9.4) times greater hazard of developing dementia in participants with severe malodor. The inverse probability weighted Cox model confirmed the same trend with an adjusted marginal hazard ratio of 4.4 (1.2 to 16.4). CONCLUSIONS: A significant association between oral malodor and the onset of dementia exists. Show more

Keywords: Alzheimer’s disease, dementia, oral health, oral malodor

DOI: 10.3233/ADR-240015

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 805-816, 2024

Authors: Stein, Ryan G. | Ten Brinke, Lisanne F. | Boa Sorte Silva, Nárlon C. | Hsu, Chun Liang | Handy, Todd C. | Hsiung, Ging-Yuek R. | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: Slower walking is associated with changes in cortical volume and thickness. Computerized cognitive training (CCT) and exercise improve cortical volume and thickness and thus, may promote gait speed. Slowing of gait is predictive of Alzheimer’s disease. Objective: To examine: 1) the effect of CCT, with or without physical exercise, on cortical volume and thickness and; 2) the association of changes in cortical volume and thickness with changes in gait speed. Methods: A subset of 124 adults (n  = 53), aged 65–85 years, enrolled in an 8-week randomized controlled trial and completed T1-weighted MRI …and 4-meter walk at baseline and 8 weeks. Participants were randomized to: 1) active control (BAT; n  = 19); 2) CCT (n  = 17); or 3) CCT preceded by exercise (Ex-CCT; n  = 17). Change in cortical volume and thickness were assessed and compared across all groups using Freesurfer. RESULTS: BAT versus CCT increased left rostral middle frontal gyrus volume (p   = 0.027) and superior temporal gyrus thickness (p  = 0.039). Ex-CCT versus CCT increased left cuneus thickness (p  < 0.001) and right post central gyrus thickness (p  = 0.005), and volume (p  < 0.001). Ex-CCT versus BAT increased left (p  = 0.001) and right (p  = 0.020) superior parietal gyri thickness. There were no significant between-group differences in gait speed (p  > 0.175). Increased left superior parietal volume (p  = 0.036, r  = 0.340) and thickness (p  = 0.002, r  = 0.348), right post central volume (p  = .017, r  = 0.341) and thickness (p  = 0.001, r  = 0.348), left banks of superior temporal sulcus thickness (p  = 0.002, r  = 0.356), and left precuneus thickness (p  < 0.001, r  = 0.346) were associated with increased gait speed. CONCLUSIONS: CCT with physical exercise, but not CCT alone, improves cortical volume and thickness in older adults. These changes may contribute to the maintenance of gait speed in aging. Show more

Keywords: Alzheimer’s disease, clinical trial, cognitive training, exercise, gait, magnetic resonance imaging

DOI: 10.3233/ADR-230206

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 817-831, 2024

Authors: Ben Ayed, Ines | Ammar, Achraf | Aouichaoui, Chirine | Naija, Salma | Ben Amor, Sana | Glenn, Jordan M. | Chtourou, Hamdi | Jahrami, Haitham | Trabelsi, Khaled | Trabelsi, Yassine | El Massioui, Farid

Article Type: Research Article

Abstract: Background: The evidence supporting the effectiveness of combined interventions in Alzheimer’s disease (AD) patients remains inconclusive. Objective: The aim of this study was to evaluate the mid- and long-term effectiveness of physical training, alone or combined with cognitive games, on cognitive performance in patients with moderate AD. Methods: Seventy-nine AD patients (≈73% females, age of ≈70±1 years) were randomly divided into three groups: aerobic-based training (AT-group, n  = 27), aerobic-based training plus cognitive games (ACT-group, n  = 25), and a control group engaged in reading (CG, n  = 26), two sessions per week. Cognitive performance was evaluated at the …start, 4th week (W4), end of the 8th week (W8), and after a 4-week detraining period (W12), using problem-solving (Tower-of-Hanoi), selective attention (Stroop-test), and working memory (Digit-Span-test) assessments. Stress levels and quality of life were also evaluated. Results: Aerobic and combined training induced a positive effect on all cognitive functions tested at W4 (except problem-solving) and W8 (all p  < 0.001) with greater improvements in working-memory and problem-solving in ACT-group (p  < 0.05). Depression levels also decreased significantly, and quality of life improved at W8 (p  < 0.001) in both groups. After 4 weeks of detraining, the beneficial effect of AT and ACT was still observed. The CG did not show any significant improvements at all time points. Conclusions: Physical and cognitive interventions appear effective for improving cognitive-functions, quality-of-life, and reducing depression in AD patients. Combined training emerges as a more effective strategy to mitigate AD progression. Further research is necessary to validate these results and explore their potential for preventing early cognitive decline. Results: Aerobic and combined training induced a positive effect on all cognitive functions tested at W4 (except problem-solving) and W8 (all p  < 0.001) with greater improvements in working-memory and problem-solving in ACT-group (p  < 0.05). Depression levels also decreased significantly, and quality of life improved at W8 (p  < 0.001) in both groups. After 4 weeks of detraining, the beneficial effect of AT and ACT was still observed. The CG did not show any significant improvements at all time points. Conclusions: Physical and cognitive interventions appear effective for improving cognitive-functions, quality-of-life, and reducing depression in AD patients. Combined training emerges as a more effective strategy to mitigate AD progression. Further research is necessary to validate these results and explore their potential for preventing early cognitive decline. Show more

Keywords: Alzheimer’s disease, cognitive decline, combined intervention, dementia, low-cost intervention, problem-solving, selective attention, working memory

DOI: 10.3233/ADR-249003

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 833-845, 2024

Article Type: Correction

DOI: 10.3233/ADR-249000

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 847-848, 2024

Article Type: Correction

DOI: 10.3233/ADR-249001

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 849-850, 2024

Authors: Jang, Hyemin | Na, Duk L. | Kwon, Jay Cheol | Jung, Na-Yeon | Moon, Yeonsil | Lee, Jung Seok | Park, Kyung-Won | Lee, Ae Young | Cho, Hanna | Lee, Jae-Hong | Kim, Byeong C. | Park, Kee Hyung | Lee, Byung-Chul | Choi, Hojin | Kim, Jieun | Park, Mee Young

Article Type: Research Article

Abstract: Background: Predicting conversion to probable Alzheimer&s disease (AD) from amnestic mild cognitive impairment (aMCI) is difficult but important. A nomogram was developed previously for determining the risk of 3-year probable AD conversion in aMCI. Objective: To compare the probable AD conversion rates with cognitive and neurodegenerative changes for 2 years from high- and low risk aMCI groups classified using the nomogram. Methods: This prospective, multicenter, observational study was conducted in Korea. A total of patients were classified as high- or low-risk aMCI according to the nomogram and followed-up for 2 years to compare the annual conversion …rate to probable AD and brain structure changes between the two groups. Results: In total, 176 (high-risk, 85; low-risk, 91) and 160 (high-risk, 77; low-risk, 83) patients completed the 1-year and 2-year follow-up, respectively. The probable AD conversion rate was significantly higher in the high-risk (Year 1, 28.9%; Year 2, 46.1%) versus low-risk group (Year 1, 0.0%; Year 2, 4.9%, both p < 0.0001). Mean changes from baseline in Seoul Neuropsychological Screening Battery-Dementia Version, Clinical Dementia Rating-Sum of Box, and Korean version of the Instrumental Activities of Daily Living scores and cortical atrophy index at Years 1 and 2 were significantly greater in the high-risk group (p < 0.0001). Conclusions: The high-risk aMCI group, as determined by the nomogram, had a higher conversion rate to probable AD and faster cognitive decline and neurodegeneration change than the low-risk group. These real-world results have clinical implications that help clinicians in accurately predicting patient outcomes and facilitating early decision-making. Trial Registration: ClinicalTrials.gov (NCT03448445) Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, conversion rate, neurodegeneration, neuropsychometry, nomogram

DOI: 10.3233/ADR-230189

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 851-862, 2024

Authors: Choe, Yeong Sim | Kim, Regina E.Y. | Kim, Hye Weon | Kim, JeeYoung | Lee, Hyunji | Lee, Min Kyoung | Lee, Minho | Kim, Keun You | Kim, Se-Hong | Kim, Ji-hoon | Lee, Jun-Young | Kim, Eosu | Kim, Donghyeon | Lim, Hyun Kook

Article Type: Research Article

Abstract: Background: Application of visual scoring scales for regional atrophy in Alzheimer’s disease (AD) in clinical settings is limited by their high time cost and low intra/inter-rater agreement. Objective: To provide automated atrophy scoring using objective volume driven from deep-learning segmentation methods for AD subtype classification using magnetic resonance imaging (MRI). Methods: We enrolled 3,959 participants (1,732 cognitively normal [CN], 1594 with mild cognitive impairment [MCI], and 633 with AD). The occupancy indices for each regional volume were calculated by dividing each volume by the size of the lateral and inferior ventricular volumes. MR images …from 355 participants (119 CN, 119 MCI, and 117 AD) from three different centers were used for validation. Two neuroradiologists performed visual assessments of the medial temporal, posterior, and global cortical atrophy scores in the frontal lobe using T1-weighted MR images. Images were also analyzed using the deep learning-based segmentation software, Neurophet AQUA. Cutoff values for the three scores were determined using the data distribution according to age. The scoring results were compared for consistency and reliability. Results: Four volumetric-driven scoring results showed a high correlation with the visual scoring results for AD, MCI, and CN. The overall agreement with human raters was weak-to-moderate for atrophy scoring in CN participants, and good-to-almost perfect in AD and MCI participants. AD subtyping by automated scores also showed usefulness as a research tool. Conclusions: Determining AD subtypes using automated atrophy scoring for late-MCI and AD could be useful in clinical settings or multicenter studies with large datasets. Show more

Keywords: Alzheimer’s disease, atrophy, cognitive dysfunction, magnetic resonance imaging, visual scoring

DOI: 10.3233/ADR-230105

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 863-876, 2024

Authors: Garcia, Ricardo Isaiah | Khemka, Sachi | Roghani, Aryan Kia | Reddy, Ruhananhad P. | Pattoor, Vasanthkumar | Jacob, Michael | Reddy, Aananya | Sehar, Ujala | Reddy, P. Hemachandra

Article Type: Review Article

Abstract:  A caregiver is a constantly evolving role that an individual most likely undertakes at some point in their lifetime. With discoveries and research in increasing life expectancy, the prevalence of neurological-related diseases, such as Alzheimer’s disease (AD) and dementia, is certainly likely to require more caregivers. The demand for AD caregivers is escalating as the prevalence of the disease continues to rise. The projected rise in AD within the Hispanic population in the United States over the next few decades is expected to be the most significant among all ethnic groups. The Hispanic population faces unique dementia risks due to …cultural factors like language barriers, lower education, and limited healthcare access. Higher rates of conditions such as diabetes and cardiovascular disease further elevate dementia risk. Family dynamics and caregiving responsibilities also differ, affecting dementia management within Hispanic households. Addressing these distinct challenges requires culturally sensitive approaches to diagnosis, treatment, and support for Hispanic individuals and their family’s facing dementia. With AD and other dementia becoming more prevalent, this article will attempt to expand upon the status of caregivers concerning their economic, health, and cultural statuses. We will attempt to focus on the Hispanic caregivers that live in Texas and more specifically, West Texas due to the lack of current literature that applies to this area of Texas. Lastly, we discuss the ramifications of a multitude of factors that affect caregivers in Texas and attempt to provide tools that can be readily available for Hispanics and others alike. Show more

Keywords: Alzheimer’s Association, Alzheimer’s disease, caregivers, culture, dementia, disparities, Hispanics, non-Hispanic whites, West Texas

DOI: 10.3233/ADR-240035

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 877-902, 2024

Authors: McKay, Mary | Gorai, Sukhamoy | Paidi, Ramesh K. | Mondal, Susanta | Pahan, Kalipada

Article Type: Research Article

Abstract: Background: Despite intense investigations, no effective treatment is yet available to reduce plaques and protect memory and learning in patients with Alzheimer’s disease (AD), the most common neurodegenerative disorder. Therefore, it is important to identify a non-toxic, but effective, treatment option for AD. Objective: Cinnamein, a nontoxic compound, is naturally available in Balsam of Peru and Tolu Balsam. We examined whether cinnamein treatment could decrease plaques and improve cognitive functions in 5XFAD mouse model of AD. Methods: We employed in silico analysis, time-resolved fluorescence energy transfer assay, thermal shift assay, primary neuron isolation, western …blot, immunostaining, immunohistochemistry, Barnes maze, T maze, and open field behavior. Results: Oral administration of cinnamein led to significant reduction in amyloid-β plaque deposits in the brain and protection of spatial learning and memory in 5XFAD mice. Peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor, is involved in plaque lowering and increase in hippocampal plasticity. While investigating underlying mechanisms, we found that cinnamein served as a ligand of PPARα. Accordingly, oral cinnamein upregulated the level of PPARα, but not PPARβ, in the hippocampus, and remained unable to decrease plaques from the hippocampus and improve memory and learning in 5XFAD mice lacking PPARα. While A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is one of the drivers of nonamyloidogenic pathway, transcription factor EB (TFEB) is considered as the master regulator of autophagy. Cinnamein treatment was found to upregulate both ADAM10 and TFEB in the brain of 5XFAD mice via PPARα. Conclusions: Our results suggest that this balsam component may have therapeutic importance in AD. Show more

Keywords: ADAM10, Alzheimer’s disease, cinnamein, cognitive function, plaque, PPARα , TFEB

DOI: 10.3233/ADR-230179

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 903-922, 2024

Authors: MohanaSundaram, ArunSundar | Patil, Bhushan | Praticò, Domenico

Article Type: Article Commentary

Abstract:  A recent article by El Haj et al. provided evidence that ChatGPT could be a potential tool that complements the clinical diagnosis of various stages of Alzheimer’s Disease (AD) as well as mild cognitive impairment (MCI). To reassess the accuracy and reproducibility of ChatGPT in the diagnosis of AD and MCI, we used the same prompt used by the authors. Surprisingly, we found that some of the responses of ChatGPT in the diagnoses of various stages of AD and MCI were different. In this commentary we discuss the possible reasons for these different results and propose strategies for future studies.

Keywords: Alzheimer’s disease, mild cognitive impairment, brain aging, diagnosis, artificial intelligence, ChatGPT

DOI: 10.3233/ADR-240069

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 923-925, 2024

Authors: Basta, Maria | Bouloukaki, Izolde | Skourti, Eleni | Zampetakis, Alexandros | Alexopoulou, Christina | Ganiaris, Andronikos | Aligizaki, Marina | Zaganas, Ioannis | Simos, ‘Panagiotis | Vgontzas, Alexandros

Article Type: Short Communication

Abstract:  We examined associations between objective sleep duration and cognitive status in older adults initially categorized as cognitively non-impaired (CNI, n  = 57) or diagnosed with mild cognitive impairment (MCI, n  = 53). On follow-up, 8 years later, all participants underwent neuropsychiatric/neuropsychological evaluation and 7-day 24-h actigraphy. On re-assessment 62.7% of participants were cognitively declined. Patients who developed dementia had significantly longer night total sleep time (TST) than persons with MCI who, in turn, had longer night TST than CNI participants. Objective long sleep duration is a marker of worse cognitive status in elderly with MCI/dementia and this association is very strong in …older adults. Show more

Keywords: Alzheimer’s disease, cognitive performance, dementia, long sleep duration, mild cognitive impairment, older adults

DOI: 10.3233/ADR-230203

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 927-934, 2024

Authors: Feng, Ziqian | Wang, Jiayu | Xu, Lisi | Wu, Jiajing | Li, Hongyi | Wang, Ziqi | Duan, Mingjun

Article Type: Research Article

Abstract: Background: Excessive daytime sleepiness (EDS) and caudate nucleus volume alterations have been linked to Alzheimer’s disease (AD), but their relationship remains unclear under the context of subjective cognitive decline (SCD). Objective: This study aimed to investigate the relationship between EDS and caudate nucleus volume in patients with SCD. Methods: The volume of entire brain was measured in 170 patients with SCD, including 37 patients with EDS and 133 non-EDS, from the Sino Longitudinal Study on Cognitive Decline (SILCODE). Participants underwent a comprehensive assessment battery, including neuropsychological and clinical evaluations, blood tests, genetic analysis for APOE …ɛ 4, and structural MRI scans analyzed using the fully automated segmentation tool, volBrain. Results: Patients with EDS had significantly increased volume in the total and left caudate nucleus compared to non-EDS. The most significant cognitive behavioral factor associated with caudate nucleus volume in the EDS was the Auditory Verbal Learning Test-recognition. Conclusions: These findings suggest that EDS may be associated with alterations in caudate nucleus volume, particularly in the left hemisphere, in the context of SCD. Further research is necessary to understand the underlying mechanisms of this relationship and its implications for clinical management. Show more

Keywords: Alzheimer’s disease, caudate nucleus, excessive daytime sleepiness, memory, subjective cognitive decline, volume

DOI: 10.3233/ADR-230101

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 935-944, 2024

Authors: Li, Cong | Qian, Haifeng | Feng, Lina | Li, Mingquan

Article Type: Research Article

Abstract: Background: There is now increasing evidence that type 2 diabetes mellitus (T2DM) is associated with Alzheimer’s disease (AD). However, it is unclear whether the two are causally related. Objective: To reveal the causal association between T2DM and AD, we performed a bidirectional Mendelian randomization (MR) analysis. Methods: Genetic instrumental variables were systematically screened, and inverse-variance weighting, MR—Egger regression, weighted median, simple mode, and weighted mode were applied to assess the pathogenic associations between the two diseases, and sensitivity analyses were used to further validate the robustness of the results. Results: The results of forward …MR analysis with T2DM as the exposure were [OR = 0.998, 95% CI (0.975∼1.021), p  = 0.857], and the results of reverse MR analysis with AD as the exposure were [OR = 0.966, 95% CI (0.934∼0.999), p  = 0.043]. The results showed no significant association between T2DM and AD at the gene level (p  < 0.025). Sensitivity analyses were consistent with the results of the main analysis, confirming the robustness of the study. Conclusions: T2DM and AD may not be genetically causally associated. Show more

Keywords: Alzheimer’s disease, causal association, Mendelian randomization, type 2 diabetes mellitus

DOI: 10.3233/ADR-240053

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 945-957, 2024

Authors: Abbate, Carlo | Gallucci, Alessia | Trimarchi, Pietro Davide | Piacquadio, Emanuela | Caramanti, Giulia | Parma, Anna | Fumagalli, Giorgio Giulio | Inglese, Silvia | Parisi, Paola Maria Rita | Tartarone, Federica | Giunco, Fabrizio

Article Type: Review Article

Abstract: We rediscovered a phenotype of AD known in the early 1900s as presbyophrenia, but then forgotten, and renamed as confabulation-misidentification phenotype. The phenotype includes diencephalic amnesia whose prototype is Korsakoff syndrome. The main features are anterograde and retrograde amnesia with marked disorientation and confabulation, executive impairments, reduced insight and attention deficits, misidentification, minor hallucination and other delusions, behavioral disturbances, and early anxiety. In this article, we summarize what we have discovered about the new phenotype and what is still missing to confirm this diencephalic variant of AD.

Keywords: Alzheimer’s disease, confabulation, diencephalic amnesia, Korsakoff syndrome, misidentification, presbyophrenia

DOI: 10.3233/ADR-230196

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 959-969, 2024

Authors: O’Caoimh, Rónán | Foley, Mary J. | Timmons, Suzanne | Molloy, D. William

Article Type: Research Article

Abstract: Background: The Montreal Cognitive Assessment (MoCA) is recommended by the Movement Disorder Society for cognitive testing in movement disorders including Parkinson’s disease (PD) and lewy body dementia. Few studies have compared cognitive screening instruments in these diseases, which overlap clinically. Objective: To compare the MoCA and Quick Mild Cognitive Impairment (Qmci) screen in this population. Methods: Patients attending memory and movement disorder clinics associated with a university hospital had the MoCA and Qmci screen performed and diagnostic accuracy compared with the area under the receiver operating characteristic curve (AUC). Duration and severity of movement …disorders was assessed using the Unified PD Rating Scale (UPDRS). Results: In total, 133 assessments were available, median age 74±5. Median education was 11±4 years and 65% were male. Median total UPDRS score was 37±26. Median Qmci screen was 51±27, median MoCA was 19±10. There were statistically significant differences in test scores between those with subjective symptoms but normal cognition, mild cognitive impairment (MCI) and dementia (p  < 0.001). The Qmci screen had significantly greater accuracy differentiating normal cognition from MCI versus the MoCA (AUC 0.90 versus 0.72, p  = 0.01). Both instruments had similar accuracy in identifying cognitive impairment and separating MCI from dementia. The median administration time for the Qmci screen and MoCA were 5.19 and 9.24 minutes (p  < 0.001), respectively. Conclusions: Both the MoCA and Qmci screen have good to excellent accuracy in a population with movement disorders experiencing cognitive symptoms. The Qmci screen was significantly more accurate for those with early symptoms and had a shorter administration time. Show more

Keywords: Alzheimer’s disease, cognitive assessment screening instrument, lewy body disease, Montreal Cognitive Assessment, movement disorders, Parkinson’s disease

DOI: 10.3233/ADR-230207

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 971-980, 2024

Authors: Chittimalli, Kishore | Adkins, Stephen | Arora, Sanjay | Singh, Jagdish | Jarajapu, Yagna P.R.

Article Type: Research Article

Abstract: Background: The APP/PS1 mouse model recapitulates pathology of human Alzheimer’s disease (AD). While amyloid-β peptide deposition and neurodegeneration are features of AD, the pathology may involve inflammation and impaired vascular regeneration. Objective: This study evaluated inflammatory environments in the brain and bone marrow (BM), and the impact on brain microvascular density. Methods: BM and frontal cortex from male nine-month-old APP/PS1 or the control C57Bl6/j mice were studied. Vascular density and inflammatory cells were evaluated in the sections of frontal cortex by immunohistochemistry. Different subsets of hematopoietic stem/progenitor cells (BM) and monocyte-macrophages were characterized by flow cytometry …and by clonogenic assays. Myelopoietic or inflammatory factors were evaluated by real-time RT-PCR or by western blotting. Results: CD34+ or CD31+ vascular structures were lower (p  < 0.01, n  = 6) in the frontal cortex that was associated with decreased number of Lin− Sca-1+ cKit+ vasculogenic progenitor cells in the BM and circulation (p  < 0.02, n  = 6) compared to the control. Multipotent progenitor cells MPP4, common lymphoid, common myeloid and myeloid progenitor cells were higher in the APP/PS1-BM compared to the control, which agreed with increased numbers of monocytes and pro-inflammatory macrophages. The expression of pro-myelopoietic factors and alarmins was higher in the APP/PS1 BM-HSPCs or in the BM-supernatants compared to the control. Frontal cortices of APP/PS1 mice showed higher number of pro-inflammatory macrophages (CD11b+ F4/80+ or CD80+ ) and microglia (OX42+ Iba1+ ). Conclusions: These findings show that AD pathology in APP/PS1 mice is associated with upregulated myelopoiesis, which contributes to the brain inflammation and decreased vascularity. Show more

Keywords: Alarmins, Alzheimer’s disease, APP/PS1 mice, bone marrow, frontal cortex, inflammation, myelopoiesis

DOI: 10.3233/ADR-240024

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 981-998, 2024

Authors: Zhang, Weiyi | Fu, Weilun | Zhang, Yumei

Article Type: Research Article

Abstract: Background: Effect of stenosis of vertebrobasilar artery (VBA) on cognitive function is elusive. Objective: To investigate association of cerebral hypoperfusion and poor collaterals with vascular cognitive impairment (VCI) in severe VBA stenosis patients. Methods: We consecutively enrolled patients with severe VBA stenosis confirmed by digital subtraction angiography who underwent computed tomographic perfusion (CTP) and cognitive assessments. Patients were divided into poor or good collaterals groups according to the collateral circulation status, and were grouped into different perfusion groups according to CTP. Cognitive function was measured by Montreal Cognitive Assessment (MoCA), Clock Drawing Test, Stroop Color Word …Test, Trail Making Test, Digital Span Test, Auditory Verbal Learning Test, and Boston Naming Test scales. The association of cerebral perfusion and collaterals with VCI were explored. Results: Among 88 eligible patients, VCI occurred in 51 (57.9%) patients experienced. Poor collateral was present in 73 (83.0%) patients, and hypoperfusion in 64 (72.7%). Compared with normal perfusion patients, the odds ratio with 95% confidence interval for VCI was 12.5 (3.7–42.4) for overall hypoperfusion, 31.0 (7.1–135.5) for multiple site hypoperfusion, 3.3 (1.0–10.5) for poor collaterals, and 0.1 (0–0.6) for presence of posterior communicating artery (PcoA) compensated for posterior cerebral artery (PCA) and basilar artery (BA). Additionally, decreased scores of cognitive function tests occurred in patients with decompensated perfusion or poor collaterals. Conclusions: Hypoperfusion and poor collaterals were positively associated with cognitive impairment in patients with severe VBA. However, PcoA compensated for the PCA and BA had a protective role in cognitive impairment development. Show more

Keywords: Alzheimer’s disease, cerebral perfusion, collateral circulation, vascular cognitive impairment, vertebrobasilar artery stenosis

DOI: 10.3233/ADR-240007

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 999-1007, 2024

Authors: De Guia, Isaiah-Lorenzo | Eslick, Shaun | Naismith, Sharon L. | Kanduri, Swathi | Shah, Tejal M. | Martins, Ralph N.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common type of dementia, which is characterised by progressive memory loss and accumulation of hallmark markers amyloid-β (Aβ) and neurofibrillary tangles in the diseased brain. The current gold standard diagnostic methods have limitations of being invasive, costly, and not easily accessible. Thus, there is a need for new avenues, such as imaging the retina for early AD diagnosis. Sleep disruption is symptomatically frequent across preclinical and AD subjects. As circadian activity, such as the sleep-wake cycle, is linked to the retina, analysis of their association may be useful additions for achieving predictive AD diagnosis. …In this narrative review, we provide an overview of human retina studies concerning the deposition of Aβ, the role of the retina in sleep-wake cycle, the disruption of sleep in AD, and to gather evidence for the associations between Aβ, the retina, and sleep. Understanding the mechanisms behind the associations between Aβ, retina, and sleep could assist in the interpretation of retinal changes accurately in AD. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, retina, sleep

DOI: 10.3233/ADR-230150

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1009-1021, 2024

Authors: Caccamo, Martina | Urso, Daniele | Nanni, Alfredo Gabriele | Gnoni, Valentina | Giugno, Alessia | Vitulli, Alessandra | Vilella, Davide | Zecca, Chiara | Dell’Abate, Maria Teresa | Anastasia, Antonio | De Blasi, Roberto | Introna, Alessandro | Logroscino, Giancarlo

Article Type: Case Report

Abstract: The presence of parkinsonism features in primary progressive aphasia (PPA) is a subject of ongoing research. These features are usually more pronounced in the advanced stages of the disease, particularly in the non-fluent/agrammatic subtype, and are exceptionally rare in the logopenic variant (lvPPA). Here we report a case of a 63-year-old man presenting as language impairment, predominantly naming and word-finding difficulties, emerged alongside a left-sided internal tremor. Neurological examination revealed bilateral, left-side predominant rigidity, bradykinesia, and resting tremor. Notably, anosmia and constipation were present. Language assessments showed preserved single-word comprehension, object knowledge, and a minimal apraxia of speech, as well …as sentence repetition issues. Neuroimaging and biomarker analysis supported a diagnosis of primary progressive logopenic aphasia with amyloid pathology co-existing with prominent and early parkinsonism. This case underlines the intricate relationship between language disorders, parkinsonism, and amyloid pathology in lvPPA. Show more

Keywords: Alzheimer’s disease, amyloid, amyloid PET, logopenic variant, parkinsonism, primary progressive aphasia

DOI: 10.3233/ADR-230168

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1023-1030, 2024

Authors: Chen, Anqi | Wang, Yuquan | Hu, Yue-Qing

Article Type: Research Article

Abstract: Background: Many observational studies have investigated the link between the gut microbiota and Alzheimer’s disease (AD), but the causality remains uncertain. Objective: This study aimed to evaluate the causal impact of gut microbiota on AD. Methods: A two-sample Mendelian randomization (MR) study was conducted employing summary data. Summary statistics for AD were from the latest genome-wide association study (cases and proxy cases: 85,934; controls: 401,577). Summary data for gut microbiota were acquired from MiBioGen consortium. Causal effect estimations primarily relied on the inverse variance weighting method along with the sensitivity analyses for testing for pleiotropy and …heterogeneity. Additionally, reverse MR analyses were performed to examine potential reverse causality. Results: Seven gut microbiota were identified as associated with AD risk. Order Selenomonadales (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.03–1.24, p  = 0.01), Family Pasteurellaceae (OR 1.07, 95% CI 1.01–1.13, p  = 0.01), and Genus Methanobrevibacter (OR 1.07, 95% CI 1.00–1.13, p  = 0.04) were correlated with an elevated likelihood of AD, while Class Mollicutes (OR 0.87, 95% CI 0.79–0.95, p  = 0.00), Genus Ruminiclostridium9 (OR 0.87, 95% CI 0.78–0.97, p  = 0.01), Genus Clostridiuminnocuumgroup (OR 0.94, 95% CI 0.89–0.99, p  = 0.03), and Genus Eggerthella (OR 0.94, 95% CI 0.89–1.00, p  = 0.04) exerted beneficial impact in mitigating AD. No statistically significant reverse causality was found between AD and each of these seven specific gut microbiota species. Conclusions: This study unveiled a causal link between certain gut microbiota and AD, offering new insights for advancing clinical treatments. Show more

Keywords: Aging, Alzheimer’s disease, gut microbiota, Mendelian randomization, neuropsychiatric disorder

DOI: 10.3233/ADR-240071

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1031-1040, 2024

Authors: Sharif, Azaz Bin | Jahan, Ishrat | Hasan, A.B.M. Nahid

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a growing public health concern affecting millions of individuals worldwide. This disease burden is exacerbated in countries like Bangladesh, where public awareness and knowledge about the condition remains limited. Objective: This study aimed to assess the level of AD knowledge, awareness, and perceived threat among family caregivers of individuals with chronic physical conditions of Bangladesh. Methods: A descriptive cross-sectional study was conducted among the caregivers of patients selected via convenience sampling in six public hospitals between October 2022 and March 2023. The data was collected via face-to-face interviews employing a semi-structured …questionnaire that contained information about socio-demographic characteristics, personal experiences with AD, knowledge of AD, level of awareness regarding AD, and perceived threat toward AD. Results: The findings revealed a poor knowledge of AD among the study participants. Regarding AD awareness, 52.5% considered memory loss in older individuals abnormal, 26.2% attributed AD to causes like black magic, psychological distress, or bad eyes. Regarding perceived threat, 60.2% wanted to assess their AD risk, while 68.2% disagreed with the likelihood of developing the disease. Multiple linear regression analysis revealed that age, place of residence, education, and employment status significantly contribute to AD knowledge scores. Conclusions: This study highlights the urgent need for public education and awareness campaigns to address the knowledge gap and reduce stigmatization associated with AD in Bangladesh. Targeted efforts, particularly among older age groups and rural communities, can enhance understanding and improve the quality of care and support for AD patients and their caregivers. Show more

Keywords: Alzheimer’s disease, awareness, Bangladesh, knowledge, perceived threat

DOI: 10.3233/ADR-240055

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1041-1054, 2024

Authors: Singhrao, Sim K. | Consoli, Claudia | Dennison, Sarah R. | Kanagasingam, Shalini | Welbury, Richard

Article Type: Research Article

Abstract: Background: Glycogen synthase-3 kinase (GSK3) is one of the major contributors of tau hyperphosphorylation linked to neurofibrillary tangles in Alzheimer’s disease (AD). Objective: To determine a mechanism of GSK-3β activation by two periodontal bacteria consistently confirmed in AD autopsied brains. Methods: Porphyromonas gingivalis FDC381 and Actinomyces naeslundii ATCC10301 conditioned media were collected. IMR-32 cells were challenged for 48 h with the conditioned media alongside P. gingivalis (ATCC33277) ultrapurified lipopolysaccharide (LPS) designated Pg.LPS under established cell culture conditions either alone or combined. Gene expression and protein analyses for GSK-3β were carried out. Results: …qPCR demonstrated that GSK-3β gene was overexpressed in IMR-32 cells treated with Pg.LPS with a 2.09-fold change (p  = 0.0005), while A. naeslundii treated cells demonstrated 1.41-fold change (p  = 0.004). Western blotting of the cells challenged with Pg.LPS (p  = 0.01) and A. naeslundii conditioned medium (p  = 0.001) demonstrated the 37 kDa band for each treatment with variable intensity across the medium control. Immunohistochemistry with the GSK-3β of the IMR-32 cells challenged with Pg.LPS and A. naeslundii alone demonstrated cytoplasmic and nuclear localization. Conclusions: Exposure to various bacterial factors upregulated the gene expression of GSK-3β. Western blotting for GSK-3β confirmed the presence of the cleaved fragment by Pg.LPS (37 kDa band p  = 0.01) and A. naeslundii conditioned medium (37 kDa band p  = 0.001). Immunostaining demonstrated both cytoplasmic and nuclear localization of GSK-3β. Therefore, Pg.LPS and an unknown factor from the A. naeslundii conditioned medium mediated GSK-3β activation via its transcriptionally active, cleaved, fragment. These virulence factors in the body appear to be detrimental to brain health. Show more

Keywords: Actinomyces naeslundii, Alzheimer’s disease, glycogen synthase-3 kinase, inflammation, LPS, Porphyromonas gingivalis

DOI: 10.3233/ADR-240066

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1055-1067, 2024

Authors: Kunkler, Michelle Celine | Falkenreck, Julia Maria | Ophey, Anja | Dencker, Katharina | Friese, Andrea | Jahr, Petra | Kalbe, Elke | Nelles, Gereon | Polidori, M. Cristina

Article Type: Research Article

Abstract: Background: Age-related neuronal changes impact cognitive integrity, which is a major contributor to health and quality of life. The best strategy to prevent cognitive decline and Alzheimer’s disease is still debated. Objective: To investigate the long-term effects of the eight-week multicomponent training program BrainProtect® on cognitive abilities compared to general health counseling (GHC) in cognitively healthy adults in Germany. Methods: Healthy adults (age ≥50 years) previously randomized to either GHC (n  = 72) or BrainProtect (intervention group, IG, n  = 60) for eight-weeks (once weekly, 90 minutes, group-based) underwent a comprehensive neuropsychological test battery and health-related quality …of life (HRQoL) evaluation 3- and 12-months after intervention end. Results: Dropout rates were n  = 8 after 3 months and n  = 19 after 12 months. No significant long-term effect of BrainProtect was observed for the primary endpoint Consortium to Establish a Registry for Alzheimer’s Disease (CERAD-Plus) total score. Logical reasoning was significantly improved (p  = 0.024) 12 months after completion of the training program in IG participants compared to the GHC group independent of sex, age, education, diet, and physical activity. In IG participants, thinking flexibility (p  = 0.019) and confrontational naming (p  = 0.010) were improved 3 months after completing the intervention compared to the GHC group, however, after conservative Bonferroni adjustment, significance was lost. Conclusions: BrainProtect® independently improved logical reasoning compared to GHC up to 12 months after cognitive training’s end in healthy adults. To uncover the long-term clinical significance of multicomponent cognitive training in healthy adults, studies with larger sample size and frequent follow up visits are necessary. Show more

Keywords: Alzheimer’s disease, cognitive integrity, cognitive training, dementia prevention, long-term effects

DOI: 10.3233/ADR-230199

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1069-1087, 2024

Authors: Renard, Dimitri | Sangare, Birama | Youssouf, Ansma | Thouvenot, Eric

Article Type: Short Communication

Abstract:  Alzheimer’s disease and cerebral amyloid angiopathy (CAA) are often associated. Amyloid accumulation within leptomeningeal and small/median-sized cerebral blood vessels in CAA results in vessel fragility, leading to spontaneous leptomeningeal bleeding, lobar intracerebral hemorrhage (ICH) and cerebral microbleeds. CAA is also associated with non-traumatic subdural hematoma. The role of CAA-related vessel fragility in hemorrhagic complications after trauma, brain surgery, and intracranial drain insertion in CAA is unknown. We present two sporadic CAA patients with intracranial drain-related ICH, probably due to different underlying mechanisms, related to indirect and direct CAA-associated vessel fragility.

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, decompressive craniectomy, intracranial drain, intracerebral hemorrhage

DOI: 10.3233/ADR-240086

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1089-1092, 2024

Authors: Hu, Wenyi | Chu, Tiancheng | Liao, Huan | Wang, Wei | Ha, Jason | Kiburg, Katerina | Zhang, Xiayin | Shang, Xianwen | Huang, Yu | Zhang, Xueli | Tang, Shulin | Hu, Yijun | Yu, Honghua | Yang, Xiaohong | He, Mingguang | Zhu, Zhuoting

Article Type: Research Article

Abstract: Background: Previous studies found that visual impairment (VI) is associated with higher risk of cognitive impairment, but the molecular basis of these conditions is unknown. Objective: We aim to compare the metabolite associations of VI and cognitive impairment. Methods: The study population with comprehensive measurements was derived from the UK Biobank study. Visual acuity worse than 0.3 logMAR units were defined as VI. Failure in one or more of the four cognitive tests was defined as cognitive impairment. A panel of 249 metabolites was measured using a nuclear magnetic resonance metabolites profiling platform. Logistic regression models …were applied to compare metabolite associations with VI and cognitive impairment. Results: 23,775 participants with complete data on visual acuity, cognitive tests and metabolomics, and without a history of neurological disorders at baseline were included. After adjusting for confounding factors, VI was significantly associated with cognitive impairment (odds ratio[OR] = 1.49, 95% confidence interval [CI]: 1.27–1.74, p  < 0.001). After multiple testing correction (p  < 9×10–4 ), five metabolites including the ratio of omega-6 to omega-3 fatty acids (FAs) (OR = 1.18[1.10–1.27]), ratio of omega-3 to total FAs (OR = 0.84[0.77–0.91]), ratio of docosahexaenoic acid (DHA) to total FAs (OR = 0.86[0.80–0.94]), DHA (OR = 0.85[0.78–0.92]), and omega-3 FAs (OR = 0.84[0.77–0.91]) were uniquely associated with VI. Glycoprotein acetyls (OR = 1.06[1.03–1.10]) and alanine (OR = 0.95[0.92–0.98]) were exclusively associated with cognitive impairment. Albumin was identified as the common metabolite shared by the two phenotypes (OR = 0.90[0.85–0.95] for VI, and 0.95[0.92–0.98]) for cognitive impairment). Conclusions: We identified distinct and overlapping metabolites associated with VI and cognitive impairment, unveiling their distinct metabolic profiles and potential common pathophysiology. Show more

Keywords: Alzheimer’s disease, cognitive impairment, metabolomics, visual impairment

DOI: 10.3233/ADR-230154

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1093-1104, 2024

Authors: Nanni, Alfredo Gabriele | Urso, Daniele | Caccamo, Martina | Gnoni, Valentina | Giugno, Alessia | Zecca, Chiara | Dell’Abate, Maria Teresa | Vilella, Davide | De Blasi, Roberto | Logroscino, Giancarlo

Article Type: Case Report

Abstract: This report presents a challenging case of Creutzfeldt-Jakob Disease (CJD), a rare and rapidly progressing neurological disorder. The patient exhibited diverse and progressive neuro-psychiatric symptoms, including memory impairment, behavioral changes, and hallucinations associated with cacosmia. The diagnosis of CJD is complicated due to its variable clinical presentation, limited awareness, and the need for tissue pathology confirmation. Diagnostic tests, particularly brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis, played crucial roles in the evaluation. The MRI revealed characteristic cortical ribboning patterns. CSF analysis initially suggested Alzheimer’s disease pathology continuum. Repeated Real-time-quaking-induced assay testing (RT-QuIC) confirmed the diagnosis despite an …initial negative result. This case underscores the significance of contemplating CJD in individuals exhibiting rapidly progressive dementia, even in the presence of atypical clinical features. Furthermore, it emphasizes the importance of recognizing that an initial negative result from the RT-QuIC test should not preclude consideration of CJD, particularly when characteristic MRI findings are present. Show more

Keywords: Alzheimer’s disease, amyloid pathology, cacosmia, Creutzfeldt-Jacob Disease, prion disease, RT-QuIC Test

DOI: 10.3233/ADR-230173

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1105-1110, 2024

Authors: Gordon, Marc L. | Christen, Erica | Keehlisen, Lynda | Gong, Michelle | Lam, Fung | Giliberto, Luca | Gomar, Jesus J. | Koppel, Jeremy

Article Type: Short Communication

Abstract: We conducted a small, open-label, pilot study of daratumumab to explore target engagement, safety, and potential efficacy in patients with mild to moderate Alzheimer’s disease. Daratumumab SC 1800 mg was given subcutaneously weekly for 8 weeks, then every 2 weeks for 16 weeks. Flow cytometry to measure the CD38+ proportion of CD8 + CD4- T cells and cognitive assessments were performed at baseline, day 176, and day 246. Daratumumab significantly reduced CD38 + CD8 + CD4- T cells after 24 weeks and this effect persisted 11 weeks thereafter. There was no hematological toxicity or unexpected adverse events. Responder analysis showed no improvement on cognitive outcome measures.

Keywords: Alzheimer’s disease, CD38, daratumumab, energy metabolism, NAD, neuroinflammation

DOI: 10.3233/ADR-240089

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1111-1114, 2024

Authors: Kaltsa, Maria | Tsolaki, Anthoula | Lazarou, Ioulietta | Mittas, Ilias | Papageorgiou, Mairi | Papadopoulou, Despina | Tsimpli, Ianthi Maria | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: Earlier research focuses primarily on the cognitive changes due to Alzheimer’s disease (AD); however, little is known with regard to changes in language competence across the lifespan. Objective: The present study aims to investigate the decline of language skills at the grammatical and syntactic levels due to changes in cognitive function. Methods: We administered the Litmus Sentence Repetition Task (SRT) to 150 native speakers of Greek who fall into five groups: 1) young healthy speakers, 2) cognitively intact elder healthy speakers, 3) speakers with subjective cognitive impairment (SCI), 4) speakers with mild cognitive impairment (MCI); …and 5) speakers with AD dementia at the mild/moderate stages. All participants underwent a physical and neurological examination and cognitive screening with a standardized neuropsychological battery to assess cognitive status comprehensively and evaluate aspects like working memory, executive function, attention and memory to appropriately classify them. Results: The data analysis revealed that the SRT had high discriminatory value in the development of AD; specifically, both accuracy and grammaticality indices were related to cognitive decline. Additionally, syntax significantly affected the performance of speakers with structures such as clitics being particularly challenging and in most structures the performance of speakers with MCI drops significantly compared to speakers with SCI. Conclusions: Linguistic indices revealed subtle early signs of cognitive decline that can be helpful in the early detection of AD, thus facilitating the clinical process offering support to language-based assessment tools such as sentence repetition, a non-invasive type of assessment to evaluate symptoms of AD. Show more

Keywords: Alzheimer’s disease, grammar, healthy aging, language competence, mild cognitive impairment, sentence repetition, subjective cognitive impairment, syntax

DOI: 10.3233/ADR-230204

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1115-1132, 2024

Authors: Khan, Hafiz | Farhana, Fardous | Mostafa, Fahad | Rafiq, Aamrin | Nizia, Effat Walia | Razzaq, Refaya | Atique, Rumana | Dauenhauer, Megan | Zabin, Zawah | Palle, Komaraiah | Reddy, P. Hemachandra

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is related to one or more chronic illnesses, which may develop cognitive decline and dementia. Cognitive impairment is increasing, and public health officials must address risk factors for AD to improve the health of rural West Texas communities. Objective: The purpose of this study was to explore the sociodemographic and chronic disease risk factors related to cognitive impairment among elderly adults living in Cochran, Parmer, and Bailey counties in rural West Texas. Methods: Statistical methods such as Pearson’s chi-squared, proportion tests, univariate binary logistic regression, and a multivariable logistic regression were utilized …to analyze data. SPSS software was used to detect the significant relationship between cognitive impairment and risk factors. Results: Summary statistics were obtained for sociodemographic and chronic diseases by using cross-tabulation analysis and comparing the county respondents with proportion tests. A univariate binary logistic regression method was utilized and found that age group 60–69, anxiety, depression, diabetes, hypertension, and cardiovascular disease were significantly associated with cognitive impairment. Using a multivariable logistic regression approach, it was found that Bailey County (age group 60–69) had a higher likelihood (p  = 0.002) of cognitive impairment than Parmer (p  = 0.067) and Cochran counties (p  = 0.064). The risk of females (p  = 0.033) in Parmer County was 78.3% lower compared to males in developing AD. Conclusions: Identifying significant risk factors for cognitive impairment are important in addressing issues of geographic variations and integrating such factors may guide relevant policy interventions to reduce cognitive impairment incidence in rural communities within West Texas. Show more

Keywords: Alzheimer’s disease, chronic diseases, cognitive impairment, FRONTIER database, risk factors, rural West Texas, sociodemographic variables

DOI: 10.3233/ADR-240092

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1133-1151, 2024

Authors: Ehteshamzad, Sharareh

Article Type: Systematic Review

Abstract: Background: As the prevalence of Alzheimer’s disease (AD) grows with an aging population, the need for early diagnosis has led to increased focus on electroencephalography (EEG) as a non-invasive diagnostic tool. Objective: This review assesses advancements in EEG analysis, including the application of machine learning, for detecting AD from 2000 to 2023. Methods: Following PRISMA guidelines, a search across major databases resulted in 25 studies that met the inclusion criteria, focusing on EEG’s application in AD diagnosis and the use of novel signal processing and machine learning techniques. Results: Progress in EEG analysis has …shown promise for early AD identification, with techniques like Hjorth parameters and signal compressibility enhancing detection capabilities. Machine learning has improved the precision of differential diagnosis between AD and mild cognitive impairment. However, challenges in standardizing EEG methodologies and data privacy remain. Conclusions: EEG stands out as a valuable tool for early AD detection, with the potential to integrate into multimodal diagnostic approaches. Future research should aim to standardize EEG procedures and explore collaborative, privacy-preserving research methods. Show more

Keywords: Alzheimer’s disease, cognitive decline, diagnostic advancements, electroencephalography, machine learning, mild cognitive impairment, neurodiagnostic, neurophysiological biomarkers

DOI: 10.3233/ADR-230159

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1153-1169, 2024

Authors: Islam, Md Ariful | Kshirsagar, Sudhir | Reddy, Arubala P. | Sehar, Ujala | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: Several decades of research on cell and animal models contributed tremendously to understanding human diseases. Particularly, research on rodents and non-human primates revealed that animal research is a major and important component in biomedical research in learning complex pathophysiological processes. Further, animal research helped us to understand human diseases, such as Alzheimer’s disease. In addition, animal research has also helped us to test hundreds of drugs and develop treatments for human use. Researchers can gain a better understanding of key biological and physiological processes in humans by comparing them to laboratory animals. Based on their relevance and resemblance to people, …or even usual living conditions, scientists rationalize the use of particular animal models in their studies. It is suggested that in the National Institutes of Health and other agencies-funded research, animal models should be carefully selected to study the biology and pathophysiology of human health and diseases such as Alzheimer’s disease and other dementias. However, it is critical to use a minimum number of animals for human research. Further, it is also noted that the use and reuse of behavioral,  molecular, and biochemical data from wild-type (WT) control mice with mutant lines of disease models, as long as the genetic background is the same in both WT and disease mice. On the other hand, anonymous readers have challenged the use and reuse of WT mice data for comparison. In the current article, we discuss the minimum utility of animals, covering the 3Rs, Replacement, Reduction, and Refinement, and also discuss the use and reuse of behavioral, molecular, and biochemical data. Show more

Keywords: Alzheimer’s disease, animal research, replacement, reduction and refinement, wild-type mice

DOI: 10.3233/ADR-240126

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1171-1184, 2024

Authors: Wang, Ying | Song, Xinhua | Wang, Rui | Xu, Xinzi | Du, Yaming | Chen, Guohua | Mei, Junhua

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) currently lacks effective disease-modifying treatments. Recent research suggests that ferroptosis could be a potential therapeutic target. Mendelian randomization (MR) is a widely used method for identifying novel therapeutic targets. Objective: Employ genetic information to evaluate the causal impact of ferroptosis-related genes on the risk of AD. Methods: 564 ferroptosis-related genes were obtained from FerrDb. We derived genetic instrumental variables for these genes using four brain quantitative trait loci (QTL) and two blood QTL datasets. Summary-data-based Mendelian randomization (SMR) and two-sample MR methods were applied to estimate the causal effects of ferroptosis-related genes …on AD. Using extern transcriptomic datasets and triple-transgenic mouse model of AD (3xTg-AD) to further validate the gene targets identified by the MR analysis. Results: We identified 17 potential AD risk gene targets from GTEx, 13 from PsychENCODE, and 22 from BrainMeta (SMR p  < 0.05 and HEIDI test p  > 0.05). Six overlapping ferroptosis-related genes associated with AD were identified, which could serve as potential therapeutic targets (PEX10, CDC25A, EGFR, DLD, LIG3, and TRIB3 ). Additionally, we further pinpointed risk genes or proteins at the blood tissue and pQTL levels. Notably, EGFR demonstrated significant dysregulation in the extern transcriptomic datasets and 3xTg-AD models. Conclusions: This study provides genetic evidence supporting the potential therapeutic benefits of targeting the six druggable genes for AD treatment, especially for EGFR (validated by transcriptome and 3xTg-AD), which could be useful for prioritizing AD drug development in the field of ferroptosis. Show more

Keywords: Alzheimer’s disease, ferroptosis, Mendelian randomization, 3xTg-AD

DOI: 10.3233/ADR-240062

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1185-1197, 2024

Authors: Low, Serena | Moh, Angela | Goh, Kiat Sern | Khoo, Jonathon | Ang, Keven | Liu, Allen Yan Lun | Tang, Wern Ee | Lim, Ziliang | Subramaniam, Tavintharan | Sum, Chee Fang | Lim, Su Chi

Article Type: Research Article

Abstract: Background: Decline in renal function impairs systemic clearance of amyloid-β which characterizes Alzheimer’s disease while albuminuria is associated with blood-brain barrier disruption due to endothelial damage. Arterial stiffness adversely affects the brain with high pulsatile flow damaging cerebral micro-vessels. Objective: To examine association between a novel kidney disease index (KDI), which is a composite index of estimated glomerular filtration (eGFR) and urinary albumin-to-creatinine ratio (uACR), and cognitive function with potential mediation by arterial stiffness. Methods: This was a longitudinal multi-center study of participants with type 2 diabetes (T2D) aged 45 years and above. We assessed cognitive …function with Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Pulse wave velocity (PWV), an index of arterial stiffness, was measured using applanation tonometry method. KDI was calculated as geometric mean of 1/eGFR and natural logarithmically-transformed (ln)(ACR*100). Results: There were 1,303 participants with mean age 61.3±8.0 years. LnKDI was associated with lower baseline RBANS total score with adjusted coefficient –2.83 (95% CI –4.30 to –1.35; p  < 0.001). 590 participants were followed over up to 8.6 years. LnKDI was associated with lower follow-up RBANS score in total, immediate memory, visuo-spatial/construction and attention domains with corresponding adjusted coefficients –2.35 (95% CI –4.50 to –0.20; p  = 0.032), –2.93 (95% CI –5.84 to –0.02; p  = 0.049), –3.26 (95% CI –6.25 to –0.27; p  = 0.033) and –4.88 (95% CI –7.95 to –1.82; p  = 0.002). PWV accounted for 19.5% of association between and follow-up RBANS total score. Conclusions: KDI was associated with lower cognitive function globally, and in immediate memory, visuo-spatial/construction and attention domains. Arterial stiffness mediated the association between KDI and cognitive decline in patients with T2D. Show more

Keywords: Alzheimer’s disease, cognitive function, kidney disease index, type 2 diabetes

DOI: 10.3233/ADR-240067

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1199-1210, 2024

Authors: Yang, Yiwen | Tong, Ming | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), one of the most prevalent causes of dementia, is mainly sporadic in occurrence but driven by aging and other cofactors. Studies suggest that excessive alcohol consumption may increase AD risk. Objective: Our study examined the degree to which short-term moderate ethanol exposure leads to molecular pathological changes of AD-type neurodegeneration. Methods: Long Evans male and female rats were fed for 2 weeks with isocaloric liquid diets containing 24% or 0% caloric ethanol (n  = 8/group). The frontal lobes were used to measure immunoreactivity to AD biomarkers, insulin-related endocrine metabolic molecules, and proinflammatory cytokines/chemokines …by duplex or multiplex enzyme-linked immunosorbent assays (ELISAs). Results: Ethanol significantly increased frontal lobe levels of phospho-tau, but reduced Aβ, ghrelin, glucagon, leptin, PAI, IL-2, and IFN-γ . Conclusions: Short-term effects of chronic ethanol feeding produced neuroendocrine molecular pathologic changes reflective of metabolic dysregulation, together with abnormalities that likely contribute to impairments in neuroplasticity. The findings suggest that chronic alcohol consumption rapidly establishes a platform for impairments in energy metabolism that occur in both the early stages of AD and alcohol-related brain degeneration. Show more

Keywords: Alzheimer’s disease, alcohol, amyloid, cytokines, metabolism, neurodegeneration, neuroendocrine, rat model, tau

DOI: 10.3233/ADR-240026

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1211-1228, 2024

Authors: Xiong, Min | You, Hongji | Liao, Wang | Mai, Yingren | Luo, Xiaoming | Liu, Yipei | Jiang, Sheng-nan

Article Type: Research Article

Abstract: Background: 18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography (PET) is valuable in Alzheimer’s disease (AD) workup. Objective: To explore the effectiveness of 18 F-FDG PET in differentiating and staging AD and associations between brain glucose metabolism and cognitive functions and vascular risk factors. Methods: 107 participates including 19 mild cognitive impairment (MCI), 38 mild AD, 24 moderate AD, 15 moderate-severe AD, and 11 frontotemporal dementia (FTD) were enrolled. Visual and voxel-based analysis procedures were utilized. Cognitive conditions, including 6 cognitive function scores and 7 single-domain cognitive performances, and vascular risk factors linked to hypertension, hyperlipidemia, diabetes, …and obesity were correlated with glucose metabolism in AD dementia using age as a covariate. Results: 18 F-FDG PET effectively differentiated AD from FTD and also differentiated MCI from AD subtypes with significantly different hypometabolism (except for mild AD) (height threshold p  < 0.001, all puncorr  < 0.05, the same below). The cognitive function scores, notably Mini-Mental State Examination and Montreal Cognitive Assessment, correlated significantly with regional glucose metabolism in AD participants (all p  < 0.05), whereas the single-domain cognitive performance and vascular risk factors were significantly associated with regional glucose metabolism in MCI patients (all p  < 0.05). Conclusions: This study underlines the vital role of 18 F-FDG PET in identifying and staging AD. Brain glucose metabolism is associated with cognitive status in AD dementia and vascular risk factors in MCI, indicating that 18 F-FDG PET might be promising for predicting cognitive decline and serve as a visual framework for investigating underlying mechanism of vascular risk factors influencing the conversion from MCI to AD. Show more

Keywords: Alzheimer’s disease, cognitive function, 18Fluorodeoxyglucose, metabolism, mild cognitive impairment, positron emission tomography, risk factor

DOI: 10.3233/ADR-240104

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1229-1240, 2024

Authors: Gohil, Namra Vinay | Gandara, Fabio Fuentes | Gohil, Harshal | Gurajala, Swathi | Innocent, David Chinaecherem | Tesfaye, Tadele | Praticò, Domenico

Article Type: Systematic Review

Abstract: Background: Antibiotic resistance is a global health concern, and its prevalence among older adults and Alzheimer’s disease (AD) patients is gaining attention. Understanding the extent of antibiotic resistance in these populations is critical for designing targeted interventions. Objective: The objective of this systematic review and meta-analysis was to determine the prevalence of antibiotic resistance in older adults and AD patients with a focus on quantitative studies in order to provide comprehensive insights into the current landscape. Methods: To identify relevant studies, we conducted a thorough search of the PubMed, Scopus, CINAHL, and Web of Science databases. …Only studies involving adults and AD patients, published in English, and reporting quantitative data on antibiotic resistance prevalence were considered. The Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool was used to assess quality. The data was summarized by using Revman 5.4.1. Results: A total of six studies met the final criteria for selection and results from the meta-analysis found a pooled prevalence odds ratio of OR = 1.27 (95% CI: [0.99, 1.63], Z  = 1.87, p  = 0.06). The studies showed significant heterogeneity (I2 = 100%, p  < 0.00001), emphasizing the need for cautious interpretation. Conclusions: The findings indicate a potential trend of increased antibiotic resistance in older adults and AD patients, though statistical significance was not achieved for both. The significant heterogeneity highlights the complexity of resistance patterns in these populations, necessitating additional research for tailored interventions. Show more

Keywords: Alzheimer’s disease, antibiotic resistance, meta-analysis, older adults, prevalence, systematic review

DOI: 10.3233/ADR-240057

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1241-1251, 2024

Authors: Coemans, Silke | De Aguiar, Vânia | Paquier, Philippe | Tsapkini, Kyrana | Engelborghs, Sebastiaan | Struys, Esli | Keulen, Stefanie

Article Type: Case Report

Abstract: Background: Primary progressive aphasia (PPA) is a language-based dementia, causing progressive decline of language functions. Transcranial direct current stimulation (tDCS) can augment effects of speech-and language therapy (SLT). However, this has not been investigated in bilingual patients with PPA. Objective: We evaluated the case of Mr. G., a French (native language, L1)/Dutch (second language, L2)-speaking 59-year-old male, with logopenic PPA, associated with Alzheimer’s disease pathology. We aimed to characterize his patterns of language decline and evaluate the effects of tDCS applied to the right posterolateral cerebellum on his language abilities and executive control circuits. Methods: In …a within-subject controlled design, Mr. G received 9 sessions of sham and anodal tDCS combined with semantic and phonological SLT in L2. Changes were evaluated with an oral naming task in L2, the Boston Naming Task and subtests of the Bilingual Aphasia Test in in L2 and L1, the Stroop Test and Attention Network Test, before and after each phase of stimulation (sham/tDCS) and at 2-month follow-up. Results: After anodal tDCS, but not after sham, results improved significantly on oral naming in L2, with generalization to untrained tasks and cross-language transfer (CLT) to L1: picture naming in both languages, syntactic comprehension and repetition in L2, and response times in the incongruent condition of the Attention Network Test, indicating increased inhibitory control. Conclusions: Our preliminary results are the first to indicate that tDCS applied to the cerebellum may be a valuable tool to enhance the effects of SLT in bilingual patients with logopenic PPA. Show more

Keywords: Alzheimer’s disease, bilingualism, cerebellum, executive functions, primary progressive aphasia, transcranial direct current stimulation

DOI: 10.3233/ADR-240034

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1253-1273, 2024

Authors: Fernandes, Mariana | Chiaravalloti, Agostino | Cassetta, Emanuele | Placidi, Fabio | Mercuri, Nicola Biagio | Liguori, Claudio

Article Type: Research Article

Abstract: Background: Although disturbed sleep is frequent in patients with mild cognitive impairment (MCI) and dementia due to Alzheimer’s disease (AD), the association between sleep and tau pathology is unclear. Objective: This case series focused on measuring the sleep-wake rhythm over 7 days through actigraphy in patients diagnosed with MCI due to AD. Further, the association between sleep-wake cycle and tau deposition measured through positron emission tomography (PET) was explored. Methods: This case series included 6 MCI due to AD patients (2 women and 4 men, mean age 73.17±5.53 years), who completed neuropsychological testing, 7-day actigraphy, and …tau PET imaging with radiolabeled compounds aimed to estimate the density and distribution of aggregated tau neurofibrillary tangles in the brain. Results: The case series indicated that patients with MCI due to AD who exhibited greater tau deposition in the frontal, parietal, and limbic regions, as well as in the precuneus and olfactory regions, also showed increased sleep fragmentation, as measured through actigraphy. Conclusion: The findings from this case series suggest a potential link between tau deposition in key brain regions associated with AD and both sleep fragmentation and sleep-wake cycle dysregulation in a small sample of patients with MCI due to AD. These preliminary results warrant further investigation in larger, more comprehensive studies to confirm and expand upon these findings. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, positron emission tomography, sleep, sleep-wake cycle, tau

DOI: 10.3233/ADR-230187

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1275-1283, 2024

Authors: Bai, Dong | Fan, Junting | Li, Mengyue | Dong, Cuixia | Gao, Yiming | Fu, Min | Liu, Qianfeng | Liu, Huan

Article Type: Research Article

Abstract: Background: Our previously randomized controlled trial (RCT) showed daily oral folic acid (FA), docosahexaenoic acid (DHA) and their combined treatment for 6 months could significantly improve cognitive function in mild cognitive impairment (MCI) individuals. Objective: This study aimed to evaluate whether this benefit seen in the treatment group would sustain after stopping intervention when patients returned to a real-world. Methods: RCT (ChiCTR-IOR-16008351) was conducted in Tianjin, China. 160 MCI elders aged ≥60 years were randomly divided into four groups: FA + DHA, FA, DHA, and control. 138 MCI elders who completed the 6-month interventional trial underwent another 6-month …follow-up without receiving nutritional therapy. Cognitive performance was measured at 6 and 12 months. Blood amyloid-β peptide (Aβ) and homocysteine (Hcy) related biomarkers were measured at baseline and 6 months. Results: In comparison to the end of nutritional therapy, all intervention groups had considerably lower full-scale IQ, arithmetic, and image completion scores during the follow-up period, while the combined intervention and DHA groups had significantly lower picture arrangement scores. Furthermore, after 6-month treatment with FA and FA + DHA, plasma Aβ40 , Aβ42 , and Hcy levels were significantly decreased. However, these biomarker levels at the start of follow-up were positively correlated with the degree of cognitive function change during follow-up period. Conclusions: FA and DHA supplementation enhance cognitive performance in MCI elderly following a six-month intervention by reducing Hcy or Aβ levels. However, their effects on improving cognitive decline are likely to diminish when the intervention is discontinued. Show more

Keywords: Alzheimer’s disease, amyloid-β-related biomarkers, docosahexaenoic acid, folic acid, mild cognitive impairment, one carbon metabolism, real world study

DOI: 10.3233/ADR-240033

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1285-1295, 2024

Authors: Lesage, Myriam | Cinalioglu, Karin | Chan, Sabrina | Kumar, Sanjeev | Rajji, Tarek | Melichercik, Ashley | Desjardins, Carmen | Friedland, Jess | Burhan, Amer | Colman, Sarah | Chu, Li | Davies, Simon | Derkach, Peter | Elmi, Sarah | Gerretsen, Philip | Graff-Guerrero, Ariel | Hussain, Maria | Ismail, Zahinoor | Kim, Donna | Krisman, Linda | Moghabghab, Rola | Mulsant, Benoit H. | Pollock, Bruce G. | Rostas, Aviva | Van Bussel, Lisa | Rej, Soham

Article Type: Short Communication

Abstract:  Agitation, a common dementia symptom often arising from untreated pain, lacks comprehensive research on its connection with opioids prescribed for long-term pain. This study investigated the relationship between opioid use and agitation in dementia patients. Participants (n  = 188) were categorized into opioid, acetaminophen PRN, or no-pain medication groups. Despite higher reported pain levels in the opioid group, no significant differences in agitation were observed among the groups. In conclusion, opioid use for pain management in older adults with dementia did not significantly impact agitation, emphasizing the ongoing importance of proper pain management in improving dementia care and addressing agitation in …this population. Show more

Keywords: Agitation, Alzheimer’s disease, dementia, opioid, pain management

DOI: 10.3233/ADR-240025

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1297-1300, 2024

Authors: Wang, Xiwu | Ye, Teng | Huang, Ziye | Zhou, Wenjun | Zhang, Jie

Article Type: Research Article

Abstract: Background: Although individualized models using demographic, MRI, and biological markers have recently been applied in mild cognitive impairment (MCI), a similar study is lacking for patients with early Alzheimer’s disease (AD) with biomarker evidence of abnormal amyloid in the brain. Objective: We aimed to develop prognostic models for individualized prediction of cognitive change in early AD. Methods: A total of 421 individuals with early AD (MCI or mild dementia due to AD) having biomarker evidence of abnormal amyloid in the brain were included in the current study. The primary cognitive outcome was the slope of change …in Alzheimer’s Disease Assessment Scale-cognitive subscale-13 (ADAS-Cog-13) over a period of up to 5 years. Results: A model combining demographics, baseline cognition, neurodegenerative markers, and CSF AD biomarkers provided the best predictive performance, achieving an overfitting-corrected R2 of 0.59 (bootstrapping validation). A nomogram was created to enable clinicians or trialists to easily and visually estimate the individualized magnitude of cognitive change in the context of patient characteristics. Simulated clinical trials suggested that the inclusion of our nomogram into the enrichment strategy would lead to a substantial reduction of sample size in a trial of early AD. Conclusions: Our findings may be of great clinical relevance to identify individuals with early AD who are likely to experience fast cognitive deterioration in clinical practice and in clinical trials. Show more

Keywords: Alzheimer’s disease, cognitive decline, individualized prediction, mild cognitive impairment, nomogram

DOI: 10.3233/ADR-240049

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1301-1315, 2024

Authors: Luo, Qian | Crivelli, Simone M. | Zong, Shenghua | Giovagnoni, Caterina | van Kruining, Daan | Mané-Damas, Marina | den Hoedt, Sandra | Berkes, Dusan | De Vries, Helga E. | Mulder, Monique T. | Walter, Jochen | Waelkens, Etienne | Derua, Rita | Swinnen, Johannes V. | Dehairs, Jonas | Losen, Mario | Martinez-Martinez, Pilar

Article Type: Research Article

Abstract: Background: During Alzheimer’s disease (AD) progression, there is a decline in the bioactive sphingolipid sphingosine-1-phosphate (S1P). Previous research showed that FTY720, an S1P mimetic, prevented cognitive decline and reduced ceramide levels in transgenic mice with familial AD carrying the human APOE4 gene (E4FAD) at 6–7 months of age. Objective: The objective of this study is to explore the protective effects of FTY720 at late-stage AD. Methods: Male mice aged 9.5 to 10.5 months were orally administered FTY720 (0.1 mg/kg) via oral gavage for 6 weeks. A pre-test of water maze was used for evaluating the pathological status. …After 4 weeks of administration, memory, locomotion, and anxiety were assessed. Cortex samples were analyzed for amyloid-β (Aβ) and sphingolipid levels. Results: Compared with APOE3 mice, APOE4, E3FAD and E4FAD mice exhibited significant memory deficits. After 6 weeks administration, FTY720 did not alleviate memory deficits in EFAD mice. Lipid analysis revealed that S1P was significantly reduced in EFAD mice (E3FAD or E4FAD) compared to controls (APOE3 and APOE4). Ceramide level alterations were predominantly dependent on APOE isoforms rather than AD transgenes. Interestingly, Cer (d18 : 1/22 : 1) was elevated in APOE4 mice compared to APOE3, and FTY720 reduced it. Conclusions: E4FAD and APOE4 mice exhibited significant spatial memory deficits and higher ceramide concentrations compared to APOE3 mice. FTY720 did not reverse memory deficits in E4FAD and APOE4 mice but reduced specific ceramide species. This study provides insights into the association between sphingolipids and APOE4 in advanced AD stages, exploring potential therapeutic targeting of sphingolipid metabolism. Show more

Keywords: Alzheimer’s disease, APOE4, ceramide, FTY720, sphingolipid

DOI: 10.3233/ADR-230053

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1317-1327, 2024

Authors: Dong, Qiwei | Li, Yuanjing | Song, Yiming | Zhang, Yu | Han, Xiaodong | Ren, Yifei | Wang, Jiafeng | Han, Xiaojuan | Du, Yifeng

Article Type: Research Article

Abstract: Background: Cognitive reserve (CR) may be beneficial to the physical function of the elderly. Objective: We aimed to examine the association of CR proxies and composite CR capacity with physical function in older adults while considering age and sex. Methods: This population-based cross-sectional study included 4,714 participants living in rural China (age≥60 years) who were dementia-free. Structural equation modeling was used to generate a composite CR score by integrating early-life education, midlife occupational complexity, and late-life mental activity and social support. The Short Physical Performance Battery (SPPB) measured physical function. Data were analyzed using linear regression …models. Results: Greater educational attainment and mental activity were associated with higher composite SPPB scores and those of its three subtests (p  < 0.05). Skilled occupations were associated with higher SPPB, chair stand, and walking speed scores, while greater social support was associated with higher scores for SPPB and chair stand (p  < 0.05). Each 1-point increase in composite CR score (range: –0.77 to 1.03) was linearly associated with a multivariable-adjusted β-coefficient of 0.74 (95% confidence interval (CI): 0.58–0.89) for total SPPB score, 0.16 (0.10–0.22) for balance test, 0.40 (0.32–0.48) for chair stand, and 0.17 (0.12–0.23) for walking speed. The association between higher composite CR and total SPPB scores was more prominent in those≥75 years than those aged 60–74 years (p  < 0.01). There was no statistical interaction of composite CR score and sex in physical function. Conclusions: High CR is associated with better physical function, especially among older adults (≥75 years). Show more

Keywords: Alzheimer’s disease, cognitive reserve, physical fitness, population-based study

DOI: 10.3233/ADR-240064

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1329-1338, 2024

Authors: Malaty, Giovanni R. | Decourt, Boris | Shill, Holly A. | Sabbagh, Marwan N.

Article Type: Research Article

Abstract: Background: Plasma biomarker assays provide an opportunity to reassess whether Alzheimer’s disease, Parkinson’s disease dementia (PDD), and dementia with Lewy bodies (DLB) plasma biomarkers are diagnostically useful. Objective: We hypothesized that immunomagnetic reduction (IMR) of plasma biomarkers could differentiate between patients with PDD and DLB and healthy patients when combined with established clinical testing measures. Methods: Plasma samples from 61 participants (12 PDD, 12 DLB, 37 controls) were analyzed using IMR to quantify amyloid-β 42 (Aβ42 ), total tau (t-tau), phosphorylated tau at threonine 181 (p-tau181), and α-synuclein (α-syn). Receiver operating characteristic curve (ROC) analysis was …used to obtain sensitivity, specificity, and area under the ROC curve. Biomarker results were combined with clinical measures from the Unified Parkinson’s Disease Rating Scale (UPDRS), Montreal Cognitive Assessment, and Hoehn-Yahr stage to optimize diagnostic test performance. Results: Participants with PDD had higher α-syn than those with DLB and healthy participants and were distinguishable by their biomarker products Aβ42 ×p-tau181 and Aβ42 ×α-syn. Patients with DLB had higher p-tau181 than those with PDD and healthy participants and were distinguishable by their concentrations of α-syn×p-tau181. Plasma α-syn plus UPDRS versus either test alone increased sensitivity, specificity, and AUC when healthy patients were compared with those with PDD and DLB. Combined clinical examination scores and plasma biomarker products demonstrated utility in differentiating PDD from DLB when p-tau181 was combined with UPDRS, α-syn was combined with UPDRS, and α-syn×p-tau181 was combined with UPDRS. Conclusions: In this pilot study, IMR plasma p-tau181 and α-syn may discriminate between PDD and DLB when used in conjunction with clinical testing. Show more

Keywords: Alzheimer’s disease, α-synuclein, dementia with Lewy bodies, immunomagnetic reduction assay, Parkinson’s disease dementia, p-tau181, Unified Parkinson’s Disease Rating Scale

DOI: 10.3233/ADR-240110

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1361-1371, 2024