Journal of Alzheimer's Disease - Volume 95, issue 3

Authors: Costa, Tommaso | Premi, Enrico | Liloia, Donato | Cauda, Franco | Manuello, Jordi

Article Type: Research Article

Abstract: Background: Clinical trials targeting Alzheimer’s disease (AD) aim to alleviate clinical symptoms and alter the course of this complex neurodegenerative disorder. However, the conventional approach of null hypothesis significance testing (NHST) commonly employed in such trials has inherent limitations in assessing clinical significance and capturing nuanced evidence of effectiveness on a continuous scale. Objective: In this study, we conducted a re-analysis of the phase III trial of lecanemab, a recently proposed humanized IgG1 monoclonal antibody with high affinity for Aβ soluble protofibrils, using a Bayesian approach with informed t-test priors. Methods: To achieve …this, we carefully selected trial data and derived effect size estimates for the primary endpoint, the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB). Subsequently, a series of Bayes Factor analyses were performed to compare evidence supporting the null hypothesis (no treatment effect) versus the alternative hypothesis (presence of an effect). Drawing on relevant literature and the lecanemab phase III trial, we incorporated different minimal clinically important difference (MCID) values for the primary endpoint CDR-SB as prior information. Results: Our findings, based on a standard prior, revealed anecdotal evidence favoring the null hypothesis. Additional robustness checks yielded consistent results. However, when employing informed priors, we observed varying evidence across different MCID values, ultimately indicating no support for the effectiveness of lecanemab over placebo. Conclusion: Our study underscores the value of Bayesian analysis in clinical trials while emphasizing the importance of incorporating MCID and effect size granularity to accurately assess treatment efficacy. Show more

Keywords: Alzheimer’s disease, Bayes Factor, Clarity AD, clinical trial, drug development, informed t priors

DOI: 10.3233/JAD-230589

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1059-1065, 2023

Authors: Di Gioia, Claudia | Santonico, Marco | Zompanti, Alessandro | Sabatini, Anna | Grasso, Simone | Ursini, Francesca | Pedone, Claudio | Galdi, Flavia | Antonelli Incalzi, Raffaele | Pennazza, Giorgio

Article Type: Research Article

Abstract: Background: Recent studies have shown that oxidative stress plays a relevant role in Alzheimer’s disease (AD), and in the pathogenesis of vascular dementia (VaD). New diagnostic methods look for biological samples with non-invasive sampling methods. Among these, saliva shows an increase in oxidative stress products, thus a corresponding reduction in antioxidant products were found in dementia cases compared to healthy controls. Compounds identified in saliva include some hydrocarbons whose production has been related to the presence of reactive oxygen species. Objective: The hypothesis is that the voltammetric analysis performed on saliva could be a useful test for diagnosing …dementia, potentially discriminating between AD and VaD. Methods: A single-center observational study was conducted on patients referred to the dementia clinic in the Neurology area and healthy controls recruited in the Orthopedics area of the Campus Bio-Medico Hospital in Rome. The study was aimed at evaluating the discriminative properties of salivary voltammetric analysis between healthy subjects and patients with dementia and, as a secondary outcome, between AD and VaD. A total of 69 subjects were enrolled, including 29 healthy controls, 20 patients with AD, and 20 patients with VaD. The degree of cognitive impairment was classified on the basis of the Mini-Mental State Examination score. Results: The results obtained are promising, with an accuracy of 79.7%, a sensitivity of 82.5%, and a specificity of 75.8%, in the discrimination of dementia versus controls. Conclusions: The methods tested demonstrate to be relevant in the discrimination between dementia and controls. A confirmatory study is already running. Show more

Keywords: Alzheimer’s disease, cyclic voltammetry, dementia, multivariate data analysis, saliva fingerprint, vascular dementia

DOI: 10.3233/JAD-230330

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1067-1075, 2023

Authors: Li, Jinghang | Mountz, Elizabeth J. | Mizuno, Akiko | Shah, Ashti M. | Weinstein, Andrea | Cohen, Ann D. | Klunk, William E. | Snitz, Beth E. | Aizenstein, Howard J. | Karim, Helmet T.

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) deposits asymmetrically early in Alzheimer’s disease (AD). This process is variable and has been associated with asymmetric hypometabolism. Objective: We investigated whether neural asymmetry during working memory and executive function processing was associated with AD genetic risk and markers of AD as well as other brain neuropathology biomarkers, cognitive function, and cognitive reserve in cognitively normal older adults. Methods: We analyzed data from 77 cognitively healthy, older adults who completed functional magnetic resonance imaging, positron emission tomography, and cognitive testing. We identified regions of significant activation and asymmetry during the Digital Symbol Substitution …Task (DSST). We examined associations between regions with significant hemispheric asymmetry (directional and absolute) and global cerebral Aβ, cerebral glucose metabolism, white matter hyperintensities, APOE ɛ4 allele status, DSST reaction time, age, sex, education, and cognitive function. Results: Asymmetry was not associated with several factors including cognitive function, Aβ, and white matter hyperintensities. The presence of at least one ɛ4 APOE allele in participants was associated with less asymmetric activation in the angular gyrus (right dominant activation). Greater education was associated with less asymmetric activation in mediodorsal thalamus (left dominant activation). Conclusions: Genetic risk of AD was associated with lower asymmetry in angular gyrus activation, while greater education was associated with lower asymmetry in mediodorsal thalamus activation. Changes in asymmetry may reflect components of compensation or cognitive reserve. Asymmetric neural recruitment during working memory may be related to maintenance of cognitive function in cognitively normal older adults. Show more

Keywords: Alzheimer’s disease, amyloid, asymmetry, functional brain activation, preclinical Alzheimer’s disease, working memory

DOI: 10.3233/JAD-230379

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1077-1089, 2023

Authors: Ramos, Claudia | Madrigal, Claudia | Aguirre-Acevedo, Daniel Camilo | Giraldo-Chica, Margarita | Acosta-Baena, Natalia | Aponte, Claudia | Aguillón, David | Gómez, Manuela | Espinosa, Alejandro | Madrigal, Lucia | Uribe, Claramonika | Saldarriaga, Amanda | Alzate, Diana | Ruiz, Alejandra | Andrade, Angela | Lopez, Hugo | Langbaum, Jessica B. | Sink, Kaycee M. | Reiman, Eric M. | Tariot, Pierre N. | Ríos-Romenets, Silvia | Lopera, Francisco

Article Type: Research Article

Abstract: Background: The SARS-CoV2 global pandemic impacted participants in the Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) clinical trial, who faced three stressors: 1) fear of developing dementia; 2) concerns about missing treatment; and 3) risk of SARS-CoV2 infection. Objective: To describe the frequency of psychological disorders among the participants of the API ADAD Colombia clinical study, treated by a holistic mental health team during the COVID-19 pandemic. The extent of use of mental health team services was explored considering different risk factors, and users and non-users of these services were compared. Methods: Participants had …free and optional access to psychology and psychiatry services, outside of the study protocol. Descriptive statistics was used to analyze the frequency of the mental health difficulties. A multivariable logistic regression model has been used to assess associations with using this program. Results: 66 participants were treated by the Mental Health Team from March 1, 2020, to December 31, 2020. Before and after the start of the pandemic, the most common psychological problems were anxiety (36.4% before, 63.6% after) and depression (34.8% before, 37.9% after). 70% of users assisted by psychology and 81.6% of those assisted by psychiatry felt that the services were useful for them. Female sex, depression, and anxiety before the pandemic were positively associated with being assisted by either psychology or psychiatry, while the association with hyperlipidemia was negative. Conclusions: A holistic mental health program, carried out in the context of a study, could mitigate psychopathology during pandemics such as COVID-19. Show more

Keywords: Alzheimer’s disease, COVID-19, health services and institutions

DOI: 10.3233/JAD-220941

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1091-1106, 2023

Authors: Uchida, Yuto | Onda, Kengo | Hou, Zhipeng | Troncoso, Juan C. | Mori, Susumu | Oishi, Kenichi

Article Type: Research Article

Abstract: Background: Conventional neuroimaging biomarkers for the neurodegeneration of Alzheimer’s disease (AD) are not sensitive enough to detect neurodegenerative alterations during the preclinical stage of AD individuals. Objective: We examined whether neurodegeneration of the entorhinal-hippocampal pathway could be detected along the AD continuum using ultra-high-field diffusion tensor imaging and tractography for ex vivo brain tissues. Methods: Postmortem brain specimens from a cognitively unimpaired individual without AD pathological changes (non-AD), a cognitively unimpaired individual with AD pathological changes (preclinical AD), and a demented individual with AD pathological changes (AD dementia) were scanned with an …11.7T diffusion magnetic resonance imaging. Fractional anisotropy (FA) values of the entorhinal layer II and number of perforant path fibers counted by tractography were compared among the AD continuum. Following the imaging analyses, the status of myelinated fibers and neuronal cells were verified by subsequent serial histological examinations. Results: At 250μm (zipped to 125μm) isotropic resolution, the entorhinal layer II islands and the perforant path fibers could be identified in non-AD and preclinical AD, but not in AD dementia, followed by histological verification. The FA value of the entorhinal layer II was the highest among the entorhinal laminae in non-AD and preclinical AD, whereas the FA values in the entorhinal laminae were homogeneously low in AD dementia. The FA values and number of perforant path fibers decreased along the AD continuum (non-AD>preclinical AD > AD dementia). Conclusion: We successfully detected neurodegenerative alterations of the entorhinal-hippocampal pathway at the preclinical stage of the AD continuum. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, entorhinal cortex, fiber tractography, histology, magnetic resonance imaging, neurodegeneration

DOI: 10.3233/JAD-230452

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1107-1117, 2023

Authors: Serra, Laura | Bonarota, Sabrina | Di Domenico, Carlotta | Caruso, Giulia | Giulietti, Giovanni | Caltagirone, Carlo | Cercignani, Mara | Bozzali, Marco

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia worldwide. Currently there are no disease modifying treatments available. Detecting subjects with increased risk to develop dementia is essential for future clinical trials. Subjective cognitive decline (SCD) is a condition defining individuals who perceive a decrease in their own cognitive functioning in the absence of any detectable deficit on neuropsychological testing. SCD individuals show AD-related biomarkers abnormalities in cerebrospinal fluid. Objective: The aim of the present study was to assess brain functional connectivity (FC) changes in SCD individuals. Methods: 23 SCD and 33 healthy subjects …(HS) underwent an extensive neuropsychological assessment and 3T-MRI scanning including a T1-w volume and resting-state fMRI (RS-fMRI) to assess brain atrophy and brain FC. Results: No between-group differences in grey matter volumes were detected. SCD subjects compared to HS showed both increased and decreased FC in the executive and parietal networks. Associations between cognitive measures, mainly assessing working memory, and FC within brain networks were found both in SCD and HS separately. Conclusions: SCD individuals showed FC abnormalities in networks involving fronto-parietal areas that may account for their lower visuo-spatial working memory performances. Dysfunctions in executive-frontal networks may be responsible for the cognitive decline subjectively experienced by SCD individuals despite the normal scores observed by formal neuropsychological assessment. The present study contributes to consider SCD individuals in an early AD stage with an increased risk of developing the disease in the long term. Show more

Keywords: Alzheimer’s disease, brain functional connectivity, cognitive functions, magnetic resonance imaging, subjective cognitive decline

DOI: 10.3233/JAD-230536

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1119-1131, 2023

Authors: Ekenze, Oluchi | Pinheiro, Adlin | Demissie, Serkalem | Aparicio, Hugo J. | Charidimou, Andreas | Beiser, Alexa S. | Satizabal, Claudia L. | Kautz, Tiffany | DeCarli, Charles | Greenberg, Steven | Seshadri, Sudha | Romero, Jose R.

Article Type: Research Article

Abstract: Background: Neurofilament light chain (NfL) is a marker of neuronal injury. Perivascular spaces (PVS) visible on magnetic resonance imaging (MRI) represent cerebral small vessel disease (CSVD) but their role as markers of neuronal injury needs further clarification. Objective: To relate PVS burden according to brain topography and plasma NfL. Methods: Framingham Heart Study (FHS) participants with brain MRI and NfL measurements were included. PVS were rated in the basal ganglia (BG) and centrum semiovale (CSO) using validated methods and categorized based on counts. A mixed region variable representing high burden PVS in either BG or CSO …was assessed. Multivariable linear regression analyses were used to relate PVS burden to log-transformed NfL levels in models adjusted for age, sex, FHS cohort, time between MRI and clinic exam, and image view (model 1), vascular risk factors (model 2), and white matter hyperintensity volume, covert brain infarcts, and cerebral microbleeds (model 3). Results: Among 1,457 participants (68.1±8.5 years, 45% males), NfL levels increased with higher PVS burden. Multivariable analysis showed an association of high PVS burden strictly in BG with NfL (β= 0.117, 95% CI 0.014–0.221; p  = 0.027), but attenuated in model 3. The associations were mainly in participants≥65 years (β= 0.122, 95% CI 0.015–0.229, p  = 0.026), women (β= 0.156, 95% CI 0.024–0.288, p  = 0.021), and APOE ɛ4 non-carriers (β= 0.140, 95% CI 0.017–0.263, p  = 0.026). Conclusions: The association of strictly BG high PVS burden with NfL suggests a role for PVS as markers of neuroaxonal injury, but our results are hypothesis generating and require further replication. Show more

Keywords: Alzheimer’s disease, basal ganglia, cerebral small vessel disease, MRI visible perivascular spaces, neurofilament light chain, neuroaxonal injury

DOI: 10.3233/JAD-221260

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1133-1145, 2023

Authors: Hua, Simin | Peters, Brandilyn A. | Lee, Susie | Fitzgerald, Kathryn | Wang, Zheng | Sollecito, Christopher C. | Grassi, Evan | Wiek, Fanua | St Peter, Lauren | D’Souza, Gypsyamber | Weber, Kathleen M. | Kaplan, Robert C. | Gustafson, Deborah | Sharma, Anjali | Burk, Robert D. | Rubin, Leah H. | Qi, Qibin

Article Type: Research Article

Abstract: Background: Altered gut microbiota has been associated with cognitive dysfunction and Alzheimer’s disease, but little is known among people living with HIV. Objective: To examine associations between gut microbiota and cognitive impairment among women with or without HIV. Methods: This is a cross-sectional study of 446 women (302 HIV+) who had completed a neuropsychological test battery and stool sample collected within 1 year. Gut microbiota composition was quantified using 16SV4 rRNA gene sequencing and microbial functional pathways were predicted using PICRUSt. Cognitive domains included attention, executive function, learning, memory, fluency, processing speed, and motor function. Cognitive …impairment was defined as two or more domains with T scores < 1 SD below mean. ANCOM-II was used to identify taxa and functional pathways associated with cognitive impairment, and the associations were further examined by multivariable logistic regression. Results: In overall sample, adjusting for multiple covariates including HIV status, we found that higher abundance of Methanobrevibacter, Odoribacter, Pyramidobacter, Eubacterium, Ruminococcus , and Gemmiger , and lower abundance of Veillonella were associated with cognitive impairment. The associations between these taxa and cognitive impairment were more profound in HIV+ women compared to HIV- women. Most associations with bacterial taxa were observed for learning and memory. We found accompanying microbial functional differences associated with cognitive impairment, including twelve enriched pathways and three depleted pathways. Conclusions: In women with or without HIV infection, this study identified multiple altered gut bacterial taxa and functional pathways associated with cognitive impairment, supporting the potential role of gut microbiota in cognitive dysfunction and Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, cognitive impairment, gut microbiome, HIV, human, women

DOI: 10.3233/JAD-230117

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1147-1161, 2023

Authors: Makri, Marina | Gkioka, Mara | Moraitou, Despina | Fidani, Liana | Tegos, Thomas | Tsolaki, Magdalini

Article Type: Research Article

Abstract: Background: Pre-symptomatic screening methods for detecting a higher risk of Alzheimer’s disease (AD) are gaining popularity; thus, more people are seeking these tests. However, to date, not much is known about the attitudes toward pre-symptomatic AD screening. Objective: The goal of this study is to examine the psychometric properties of a tool for assessing the attitudes, barriers, and motivations to pre-symptomatic AD screening. Methods: This is a cross-sectional study performed on 208 Greek participants (189 students and 19 caregivers) provided with an online questionnaire. Psychometric properties were assessed through the examination of its construct validity (principal …component analysis) and internal consistency. Results: Exploratory factor analysis revealed the presence of four factors. The first factor is labeled as “Perceived harms of testing” (10 items), the second “Acceptance of testing” (5 items), the third “Perceived benefits of testing” (6 items), and the fourth factor “Need for knowledge” (4 items). The reliability (internal consistency) of each factor separately was acceptable to good (0.70–0.87) while the internal consistency of the overall questionnaire (25 items) was good (Cronbach’s α =0.82). Conclusion: PRE-ADS is a valid questionnaire that might help in the research of peoples’ attitudes related to the pros and cons of pre-symptomatic screening for AD, and the development of effective counseling programs and prevention strategies. However, future research is required in the target population. Show more

Keywords: Alzheimer’s disease, attitudes, benefits, perceived harms, pre-symptomatic testing, psychometrics, screening, screening acceptance, validation

DOI: 10.3233/JAD-220954

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1163-1174, 2023

Authors: Li, Zhigang | Wu, Hao | Ji, Yong | Shi, Zhihong | Liu, Shuai | Bao, Xinran | Shan, Peng | Hu, Dean | Li, Meimei

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease. The detection of early-stage AD is particularly desirable because it would allow early intervention. However, a minimally invasive, low-cost, and accurate discrimination or diagnostic method for AD is especially difficult in the earliest stage of AD. Objective: The aim of this research is to discover blood plasma spectral digital biomarkers of AD, develop a novel intelligent method for the discrimination of AD and accelerate the translation of Fourier transform infrared (FTIR) spectral-based disease discrimination methods from the laboratory to clinical practice. Methods: Since vibration spectroscopy can …provide the structure and chemical composition information of biological samples at the molecular level, we investigated the potential of FTIR spectral biomarkers of blood plasma to differentiate between AD patients and healthy controls. Combined with machine learning technology, we designed a hierarchical discrimination system that provides reagent-free and accurate AD discrimination based on blood plasma spectral digital biomarkers of AD. Results: Accurate segregation between AD patients and healthy controls was achieved with 89.3% sensitivity and 85.7% specificity for early-stage AD patients, 92.8% sensitivity and 87.5% specificity for middle-stage AD patients, and 100% sensitivity and 100% specificity for late-stage AD patients. Conclusions: Our results show that blood plasma spectral digital biomarkers hold great promise as discrimination markers of AD, indicating the potential for the development of an inexpensive, reagent-free, and less laborious clinical test. As a result, our research outcome will accelerate the clinical application of spectral digital biomarkers and machine learning. Show more

Keywords: Alzheimer’s disease, blood plasma, discrimination, machine learning, reagent-free, spectral digital biomarkers

DOI: 10.3233/JAD-230248

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1175-1188, 2023