Journal of Alzheimer's Disease Reports - Volume 6, issue 1

Authors: Willis, Brian A. | Lowe, Stephen L. | Monk, Scott A. | Cocke, Patrick J. | Aluise, Christopher D. | Boggs, Leonard N. | Borders, Anthony R. | Brier, Richard A. | Dean, Robert A. | Green, Steven J. | James, Douglas E. | Jhee, Stanford S. | Lin, Qun | Lo, Albert C. | May, Patrick C. | Watson, Brian M. | Winneroski, Leonard L. | Yang, Zhixiang | Zimmer, Jennifer A. | McKinzie, David L. | Mergott, Dustin J.

Article Type: Research Article

Abstract: Background: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer’s disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors. Objective: To determine whether the high in vitro potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans. Methods: The effect of LY3202626 versus vehicle on amyloid-β (Aβ) levels was evaluated in a series of in vitro assays, as well as in …in vivo and multi-part clinical pharmacology studies. Aβ levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey’s post hoc test and clinical data used summary statistics. Results: LY3202626 exhibited significant human BACE1 inhibition, with an IC50 of 0.615±0.101 nM in a fluorescence resonance energy transfer assay and an EC50 of 0.275±0.176 nM for lowering Aβ1–40 and 0.228±0.244 nM for Aβ1–42 in PDAPP neuronal cultures. In dogs, CSF Aβ1hboxx concentrations were significantly reduced by ∼80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF Aβ1–42 was reduced by 73.1±7.96 % following administration of 6 mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans. Conclusion: LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development. Show more

Keywords: Amyloid-β, BACE1 inhibitor, pharmacodynamics, pharmacokinetics, translational studies

DOI: 10.3233/ADR-210037

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 1-15, 2022

Authors: Grigoletti-Lima, Gabriel Boer | Lopes, Marcelo Gustavo | Franco, Ana Tereza Barufi | Damico, Aparecida Marcela | Boer, Patrìcia Aline | Rocha Gontijo, José Antonio

Article Type: Research Article

Abstract: Background: Maternal undernutrition has been associated with psychiatric and neurological disorders characterized by learning and memory impairment. Objective: Considering the lack of evidence, we aimed to analyze the effects of gestational protein restriction on learning and memory function associated with hippocampal cell numbers and neurodegenerative protein content later in life. Methods: Experiments were conducted in gestational low- (LP, 6% casein) or regular-protein (NP, 17% casein) diet intake offspring. Behavioral tests, isolated hippocampal isotropic fractionator cell studies, immunoblotting, and survival lifetime were observed. Results: The birthweight of LP males is significantly reduced relative to NP …male progeny, and hippocampal mass increased in 88-week-old LP compared to age-matched NP offspring. The results showed an increased proximity measure in 87-week-old LP compared to NP offspring. Also, LP rats exhibited anxiety-like behaviors compared to NP rats at 48 and 86-wk of life. The estimated neuron number was unaltered in LP rats; however, non-neuron cell numbers increased compared to NP progeny. Here, we showed unprecedented hippocampal deposition of brain-derived neurotrophic factor, amyloid-β peptide (Aβ), and tau protein in 88-week-old LP relative to age-matched NP offspring. Conclusion: To date, no predicted studies showed changes in hippocampal morphological structure in maternal protein-restricted elderly offspring. The current data suggest that gestational protein restriction may accelerate hippocampal function loss, impacting learning/memory performance, and supposedly developing diseases similar to Alzheimer’s disease (AD) in elderly offspring. Thus, we propose that maternal protein restriction could be an elegant and novel method for constructing an AD-like model in adult male offspring. Show more

Keywords: Keywords: Alzheimer’s disease, amyloid-β peptide, behavior and memory, fetal programming, hippocampus, maternal protein restriction, tau protein

DOI: 10.3233/ADR-210297

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 17-30, 2022

Authors: Eldem, Ece | Barve, Aatmika | Sallin, Olivier | Foucras, Sandrine | Annoni, Jean-Marie | Schmid, Adrien W. | Alberi Auber, Lavinia

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) remains to date an incurable disease with a long asymptomatic phase. Early diagnosis in peripheral biofluids has emerged as key for identifying subjects at risk and developing therapeutics and preventative approaches. Objective: We apply proteomics discovery to identify salivary diagnostic biomarkers for AD, which are suitable for self-sampling and longitudinal biomonitoring during aging. Methods: 57 participants were recruited for the study and were categorized into Cognitively normal (CNh) (n  = 19), mild cognitive impaired (MCI) (n  = 21), and Alzheimer’s disease (AD) (n  = 17). On a subset of subjects, 3 CNh and 3 mild …AD, shot-gun filter aided sample preparation (FASP) proteomics and liquid chromatography mass spectroscopy (LC-MS/MS) was employed in saliva and cerebrospinal fluid (CSF) to identify neural-derived proteins. The protein level of salivary Transthyretin (TTR) was validated using western blot analysis across groups. Results: We found that 19.8% of the proteins in saliva are shared with CSF. When we compared the saliva and CSF proteome, 24 hits were decreased with only one protein expressed more. Among the differentially expressed proteins, TTR with reported function in amyloid misfolding, shows a significant drop in AD samples, confirmed by western blot showing a 0.5-fold reduction in MCI and AD compared to CNh. Conclusion: A reduction in salivary TTR appears with the onset of cognitive symptoms. More in general, the proteomic profiling of saliva shows a plethora of biomarkers worth pursuing as non-invasive hallmarks of dementia in the preclinical stage. Show more

Keywords: Alzheimer’s disease, amyloid-β, cerebrospinal fluid, LC-MS/MS, saliva, tau, transthyretin

DOI: 10.3233/ADR-210056

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 31-41, 2022

Authors: Bufalini, John | Eslinger, Paul | Lehman, Erik | George, Daniel R.

Article Type: Research Article

Abstract: Background: Given the challenges of developing disease-modifying treatments for Alzheimer’s disease and related disorders, non-pharmacological interventions represent an increasingly promising approach in long-term care settings. Music-based interventions have been effective in improving the quality of life by influencing biopsychosocial factors that play a role in the progression of illnesses such as depression and anxiety. However, approaches have tended to focus exclusively on the person with dementia rather than integrating caregivers. Objective: This study aimed to determine the impact of a music-based intervention on the quality of life of persons with dementia and their caregivers. Methods: A …mixed-methods study was conducted with seven dyads consisting of residents (aged 76–92) with diagnoses of dementia and their caregivers (aged 53–84) at a skilled nursing facility in Pennsylvania. Eight music intervention sessions were completed in the presence of the resident and caregiver using personalized playlists created for the dyad. Pre- and post-intervention questionnaires were administered during each session, and observational data for both residents and caregivers were collected. Results: Caregivers reported feeling less overwhelmed after the intervention with a mean difference of –0.24±0.14, p  = 0.016. Mean difference in the other 5 responses showed that listening to music had a beneficial impact for resident/caregiver dyads. Observations of interpersonal behavior supported the benefit of the intervention for these dyads. Conclusion: Quantitative analysis of a personalized music intervention for residents/caregivers showed positive trends in increasing personal connection, and qualitative data identified greater appreciation of the relationship and increased bonding. Show more

Keywords: Arts, caregivers, dementia, memory disorder, music

DOI: 10.3233/ADR-210043

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 43-48, 2022

Authors: Cimino, Nicolas | Kang, Min Suk | Honig, Lawrence S. | Rutherford, Bret R.

Article Type: Research Article

Abstract: Background: Posttraumatic stress disorder (PTSD) is associated with cognitive decline and risk for dementia, but the neuropathology involved is unclear. Objective: The aim of this study was to determine whether PTSD is associated with increased levels of Alzheimer’s disease (AD) blood-based biomarkers. Methods: Individuals aged 50 years and older with PTSD were compared to trauma-exposed healthy controls (TEHCs) at baseline on serum measures of amyloid-β (Aβ ) 42 and 40 levels, the Aβ 42 /Aβ 40 ratio, and total tau. Serum was analyzed using ultrasensitive Simoa Human Neurology 3-Plex A assay (N3PA). Linear regressions …modeling each AD biomarker as a function of group were used to investigate between-group differences, controlling for age, sex, and educational attainment (years). Results: TEHC participants (N  = 26) were 53.8% male with mean age 66.8±10.7, whereas PTSD participants (N  = 44) were 47.7% male and aged 62.5±9.1 years. No between-group differences were noted on demographic characteristics or cognitive performance measured with the NIH Toolbox Cognition Battery. There were no significant between-group differences in serum Aβ 40 (TEHC 105.8±51.6 versus PTSD 93.2±56.1, p  = 0.46), Aβ 42 (TEHC 8.1±4.6 versus PTSD 7.8±4.6, p  = 0.63), Aβ 42 /Aβ 40 (TEHC 0.08±0.03 versus PTSD 0.09±0.03, p  = 0.27), or total tau (TEHC 0.5±0.3 versus PTSD 0.5±0.4, p  = 0.77). Likewise, there were no significant interaction effects of amyloid or tau serum concentrations and PTSD group status on cognitive functioning. Conclusion: Findings from cognitive assessments and serum analyses do not support PTSD-induced neurodegeneration of the Alzheimer’s type as a pathway linking PTSD to increased incidence of dementia in older adults. Show more

Keywords: Alzheimer’s disease, dementia, posttraumatic stress disorder, trauma

DOI: 10.3233/ADR-210048

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 49-56, 2022

Authors: Gosselin, Penny | Guan, Dylan X. | Chen, Hung-Yu | Pichora-Fuller, M. Kathleen | Phillips, Natalie | Faris, Peter | Smith, Eric E. | Ismail, Zahinoor

Article Type: Research Article

Abstract: Background: Hearing loss and mild behavioral impairment (MBI), both non-cognitive markers of dementia, can be early warning signs of incident cognitive decline. Objective: We investigated the relationship between these markers and reported the influence of sex, using non-dementia participants (n  = 219; 107 females) from the Canadian Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND). Methods: Hearing was assessed with the 10-item Hearing Handicap for the Elderly–Screening (HHIE-S) questionnaire, a speech-in-noise test, screening audiometry, and hearing aid use. MBI symptoms were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Multivariable linear regressions examined the association between hearing and MBI …symptom severity and multiple logistic regressions examined the association between hearing and MBI domains. Results: HHIE-S score was significantly associated with greater global MBI symptom burden, and symptoms in the apathy and affective dysregulation domains. Objective measures of audiometric hearing loss and speech-in-noise testing as well as hearing aid use were not associated with global MBI symptom severity or the presence of MBI domain-specific symptoms. Males were older, had more audiometric and speech-in-noise hearing loss, higher rates of hearing-aid use, and showed more MBI symptoms than females, especially apathy. Conclusion: The HHIE-S, a subjective self-report measure that captures emotional and social aspects of hearing disability, was associated with informant-reported global MBI symptom burden, and more specifically the domains of affective dysregulation and apathy. These domains can be potential drivers of depression and social isolation. Hearing and behavior change can be assessed with non-invasive measures, adding value to a comprehensive dementia risk assessment. Show more

Keywords: Aging, apathy, dementia, depression, hearing loss, neurobehavioral manifestations, sex characteristics

DOI: 10.3233/ADR-210045

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 57-66, 2022

Authors: Gillie, Monica | Ali, Diab | Vadlamuri, Diamler | Carstarphen, Kathy Jo

Article Type: Research Article

Abstract: Background: Telehealth has evolved as a solution to COVID-19 isolation precautions and remote care with well-established health, socioeconomic, and practical benefits. However, there are many gaps in the current literature regarding telehealth use among older, low health literate, and resource-limited populations. There are ethical considerations that warrant understanding this digital divide. Objective: The objective of this review is to propose the Telehealth Literacy Screening Tool (TLST) for use in older adults and support the future inclusion of telehealth literacy as an important social determinant of health (SDOH). Methods: Initially a four-week outreach was performed that targeted …older adults and low-health literate patients at the MedVantage Clinic (MVC) within Ochsner Health (OH) to identify common barriers to patient engagement with the OH Epic MyChart telehealth platform. Themes from those barriers directed a meta-synthetic review of the methods and ethical considerations of current, validated technological and telehealth literacy screening tools. Those findings were reported based on the standards of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. Results: Based on the barriers identified during our MVC patient outreach, PRISMA-reported review of telehealth literacy screening research, and evaluation of the MyChart platform and the technological resources required for its use; we developed a multidimensional questionnaire for telehealth literacy screening of older adults. Conclusion: The TLST is designed to identify patients in need of additional interventions for successful connection to telehealth services. This is an important step towards addressing the ethical obligation to decrease disparities in telehealth literacy for vulnerable populations and identifying telehealth literacy as a SDOH. Show more

Keywords: Dementia, eHealth, health literacy, literacy, older adults, screening tool, telehealth, telemedicine

DOI: 10.3233/ADR-210024

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 67-72, 2022

Authors: Niyasti, Parham | Saberi, Alia | Hatamyain, Hamidreza | Ajamian, Farzam | Ghorbani Shirkouhi, Samaneh | Mirzanejad, Laleh | Andalib, Sasan

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia. AD is also the leading cause of morbidity and mortality due to dementia worldwide. It has been shown that AD is associated with type 2 diabetes mellitus (T2DM) and brain insulin resistance. Rs1801278 is a polymorphism in insulin receptor substrate-1 (IRS-1 ) gene which changes the amino acid Arg972. This polymorphism has been found to be associated with susceptibility to AD in some populations. Objective: In the present study, our aim was to investigate the association of Arg972 IRS-1 (rs1801278) gene polymorphism and late-onset Alzheimer’s disease …(LOAD) in an Iranian population. Methods: In this case-control study, 150 patients with LOAD and 150 unrelated healthy controls were recruited. Polymerase chain reaction (PCR) was performed to amplify a DNA segment of 263 base-pair (bp) length containing the single nucleotide polymorphism (SNP). The PCR product was then incubated with MvaI restriction enzyme to undergo enzymatic cleavage. Electrophoresis was thereafter carried out using agarose gel and DNA safe stain. The gel was ultimately visualized under a UV trans-illuminator. Allelic and genotypic frequencies were then compared. Results: A allele (mutant) of the gene was significantly associated with the risk of AD after adjustment for sex and age (p  = 0.04, adjusted OR:1.77, 95% CI:1.00–3.11). Only AA genotype (mutant homozygote) was significantly associated with the risk of AD after adjustment for sex and age (p  = 0.01, adjusted OR:2.39, 95% CI:1.22–4.66). Conclusion: SNP rs1801278 is significantly associated with the risk of developing AD in the studied Iranian population. Show more

Keywords: Alzheimer’s disease, insulin receptor substrate-1, polymorphism, rs1801278

DOI: 10.3233/ADR-210060

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 73-80, 2022

Authors: Silva, Priscilla Chantal Duarte | de Oliveira, Larissa Leite Vieira | Teixeira, Ricardo Luiz Perez | Brito, Max Leandro de Araújo | Filippe, Anna Rita Tomich Magalhães

Article Type: Systematic Review

Abstract: Background: In Alzheimer’s disease, in addition to memory, attention has been given to cognitive testing due to its interface and connection with memory. Objective: The aim of this study is to take a global view of executive functions and place the concept within the theoretical framework of Alzheimer’s disease dementia, verifying their role in the cognitive functioning of the human mind, as well as how they are compromised in this pathology. Methods: An initial search was carried out in databases such as PubMed, ScienceDirect, and Web of Science. The guiding question presented at the end of …the introduction was elaborated from the PICO/PIO/PEO strategy. The selected articles, therefore, answered the guiding question, were made available in full, and published in the period from 2000 to 2020. Studies without specific methodology and which correlated with other diseases or other types of dementia were excluded. To meet the objective, an integrative literature review was adopted. Results: The results indicate that, although the tests to verify the performance of cognitive functions have their limitations, they bring some evidence that they have been compromised, especially when analyzed periodically during the development of dementia. Conclusion: It is concluded that there is an interference of executive functions in function of Alzheimer’s and that memory and attention are the most evident in this type of dementia. Show more

Keywords: Alzheimer’s disease, cognition, executive functions, integrative literature review, PICO strategy

DOI: 10.3233/ADR-210059

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 81-99, 2022

Authors: Schütze, Sandra | Döpke, Anika | Kellert, Benedikt | Seele, Jana | Ballüer, Melissa | Bunkowski, Stephanie | Kreutzfeldt, Mario | Brück, Wolfgang | Nau, Roland

Article Type: Research Article

Abstract: Background: In patients with Alzheimer’s disease (AD), bacterial infections are often associated with a cognitive decline. Animal models of genuine acute infections with viable bacteria which induce deterioration of neurodegenerative diseases are missing. Objective: We assessed the effect of an intracerebral infection with E. coli in a mouse model of AD. Methods: 13-month-old Tg2576 +/- mice and transgene negative littermates (Tg2576 -/-) received an intracerebral injection with E. coli K1 or saline followed by treatment with ceftriaxone starting 41 h post infection (p.i.) for 5 days. For 4 weeks, mice were monitored for clinical status, weight, …motor functions, and neuropsychological status using the Morris water maze. ELISAs, stainings, and immunohistochemistry in brains were performed at the end of the experiment. Results: Mortality of the infection was approximately 20%. After 4 weeks, spatial learning of infected Tg2576 +/- mice was compromised compared to non-infected Tg2576 +/- mice (p  < 0.05). E. coli infection did not influence spatial learning in Tg2576 -/- mice, or spatial memory in both Tg2576 +/- and -/- mice within 4 weeks p.i.. Necrosis of hippocampal neurons was induced in infected compared to non-infected Tg2576 +/- mice 4 weeks p.i., whereas brain concentrations of Aβ1–40 , Aβ1–42 , and phosphoTau as well as axonal damage and microglia density were not altered. Conclusion: Here, we proved in principle that a genuine acute bacterial infection can worsen cognitive functions of AD mice. Mouse models of subacute systemic infections are needed to develop new strategies for the treatment of bacterial infections in patients with AD in order to minimize their cognitive decline. Show more

Keywords: Alzheimer’s disease, amyloid-β, cognitive functions, delirium, E. coli, intracerebral infection, neurodegenerative disease, spatial learning, spatial memory, water maze

DOI: 10.3233/ADR-210049

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 101-114, 2022