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

Authors: Okolichany, Ronald | Padala, Prasad R. | Mooney, Scott

Article Type: Case Report

Abstract: Background: A 76-year-old male Veteran with a historical diagnosis of mild cognitive impairment was assessed at baseline and follow-up as part of two separate, ongoing studies. He was diagnosed with COVID-19 during the interim. Objective: To report potential effects on cognitive and functional abilities measured before and after contracting COVID-19. Methods: The patient was administered a series of cognitive tests and self-report procedures assessing cognitive, functional, and neuropsychiatric status. Results: Overall, no discernable pattern of cognitive changes between pre-COVID and post-COVID assessments were noted. Only mild increases in agitation, depression, and irritability were noted …on a self-report measure. However, this particular subject has relatively ideal psychosocial circumstances in comparison to the typical older adult Veteran male. It is hypothesized that improved psychosocial conditions will result in less negative cognitive and functional outcomes for older adults diagnosed with COVID-19. Conclusion: High levels of resilience, social support, and exercise, coupled with lower levels of perceived stress and loneliness may serve as protective factors against cognitive and functional decline in older adults who contract COVID-19. Show more

Keywords: Cognition, COVID-19, geriatrics, neuropsychology, Veterans

DOI: 10.3233/ADR-210055

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 115-120, 2022

Authors: Gleerup, Helena Sophia | Simonsen, Anja Hviid | Høgh, Peter

Article Type: Short Communication

Abstract: The added value of neurofilament light chain (NfL) to the existing diagnostic methods is unknown, although a plethora of studies have shown increased levels in cerebrospinal fluid (CSF) and blood in many neurodegenerative and neurological disorders. The added value of CSF NfL was determined in a mixed memory clinic cohort of consecutive patients for 136 patients with Alzheimer’s disease (AD) (n  = 69), mild cognitive impairment (n  = 24), non-AD (n  = 34), and also healthy controls (n  = 9). This study found no increase in the diagnostic accuracy of the etiological diagnoses but knowing the CSF NfL value led to increased diagnostic certainty …for the specialist in neurology. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, dementia, neurofilament light chain

DOI: 10.3233/ADR-210047

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 121-127, 2022

Authors: Rudge, Jonathan D’Arcy

Article Type: Research Article

Abstract: This paper proposes a new hypothesis for Alzheimer’s disease (AD)—the lipid invasion model. It argues that AD results from external influx of free fatty acids (FFAs) and lipid-rich lipoproteins into the brain, following disruption of the blood-brain barrier (BBB). The lipid invasion model explains how the influx of albumin-bound FFAs via a disrupted BBB induces bioenergetic changes and oxidative stress, stimulates microglia-driven neuroinflammation, and causes anterograde amnesia. It also explains how the influx of external lipoproteins, which are much larger and more lipid-rich, especially more cholesterol-rich, than those normally present in the brain, causes endosomal-lysosomal abnormalities and overproduction of the …peptide amyloid-β (Aβ). This leads to the formation of amyloid plaques and neurofibrillary tangles, the most well-known hallmarks of AD. The lipid invasion model argues that a key role of the BBB is protecting the brain from external lipid access. It shows how the BBB can be damaged by excess Aβ, as well as by most other known risk factors for AD, including aging, apolipoprotein E4 (APOE4 ), and lifestyle factors such as hypertension, smoking, obesity, diabetes, chronic sleep deprivation, stress, and head injury. The lipid invasion model gives a new rationale for what we already know about AD, explaining its many associated risk factors and neuropathologies, including some that are less well-accounted for in other explanations of AD. It offers new insights and suggests new ways to prevent, detect, and treat this destructive disease and potentially other neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, anesthesia, anterograde amnesia, apolipoproteins, blood-brain barrier, cholesterol, ethanol, lipids, lipoproteins, nonesterified fatty acids

DOI: 10.3233/ADR-210299

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 129-161, 2022

Authors: Wrigglesworth, Jo | Harding, Ian H. | Ward, Phillip | Woods, Robyn L. | Storey, Elsdon | Fitzgibbon, Bernadette | Egan, Gary | Murray, Anne | Shah, Raj C. | Trevaks, Ruth E. | Ward, Stephanie | McNeil, John J. | Ryan, Joanne | on behalf of the ASPREE investigator group

Article Type: Research Article

Abstract: Background: There is considerable variability in the rate at which we age biologically, and the brain is particularly susceptible to the effects of aging. Objective: We examined the test-retest reliability of brain age at one- and three-year intervals and identified characteristics that predict the longitudinal change in brain-predicted age difference (brain-PAD, defined by deviations of brain age from chronological age). Methods: T1-weighted magnetic resonance images were acquired at three timepoints from 497 community-dwelling adults (73.8±3.5 years at baseline, 48% were female). Brain age was estimated from whole brain volume, using a publicly available algorithm trained on …an independent dataset. Linear mixed models were used, adjusting for sex, age, and age2 . Results: Excellent retest reliability of brain age was observed over one and three years. We identified a significant sex difference in brain-PAD, where a faster rate of brain aging (worsening in brain age relative to chronological age) was observed in men, and this finding replicated in secondary analyses. The effect size, however, was relatively weak, equivalent to 0.16 years difference per year. A higher score in physical health related quality of life and verbal fluency were associated with a faster rate of brain aging, while depression was linked to a slower rate of brain aging, but these findings were not robust. Conclusion: Our study provides consistent evidence that older men have slightly faster brain atrophy than women. Given the sparsity of longitudinal research on brain age in older populations, future prospective studies are needed to confirm our findings. Show more

Keywords: Aging, biomarkers, cognition, depression, health status, neuroimaging, physical fitness, quality of life, sex, social class

DOI: 10.3233/ADR-220011

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 163-176, 2022

Authors: Moreira, Natália Chermont dos Santos | Lima, Jéssica Ellen Barbosa de Freitas | Marchiori, Marcelo Fiori | Carvalho, Ivone | Sakamoto-Hojo, Elza Tiemi

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a slowly progressive neurodegenerative disease conceptualized as a continuous process, ranging from mild cognitive impairment (MCI), to the mild, moderate, and severe clinical stages of AD dementia. AD is considered a complex multifactorial disease. Currently, the use of cholinesterase inhibitors (ChEI), such as tacrine, donepezil, rivastigmine, and galantamine, has been the main treatment for AD patients. Interestingly, there is evidence that ChEI also promotes neuroprotective effects, bringing some benefits to AD patients. The mechanisms by which the ChEI act have been investigated in AD. ChEI can modulate the PI3K/AKT pathway, which is an important signaling cascade …that is capable of causing a significant functional impact on neurons by activating cell survival pathways to promote neuroprotective effects. However, there is still a huge challenge in the field of neuroprotection, but in the context of unravelling the details of the PI3K/AKT pathway, a new scenario has emerged for the development of more efficient drugs that act on multiple protein targets. Thus, the mechanisms by which ChEI can promote neuroprotective effects and prospects for the development of new drug candidates for the treatment of AD are discussed in this review. Show more

Keywords: Acetylcholinesterase, butyrylcholinesterase, neurodegenerative diseases, neuroprotection, PI3K/AKT pathway

DOI: 10.3233/ADR-210061

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 177-193, 2022

Authors: Cai, Jingwen | Cai, Ming | Xia, Wenwen | Jiang, Lanlan | Song, Hang | Chen, Xiangtao

Article Type: Research Article

Abstract: Background: The number of people with diabetes is increasing, and many patients have significantly impaired cognitive function. For patients with diabetic encephalopathy (DE), simply lowering blood sugar does not improve learning and memory. Studies have shown that β-asarone can significantly improve cognitive impairment in patients with DE, but the specific mechanism of action is unclear. Objective: This experiment hopes to use a variety of experimental methods to clarify the protective effect and mechanism of β-asarone on brain neurons during the development of DE disease. Methods: A high-sugar and high-fat diet and streptozotocin injection-induced DE rat model …was used. β-asarone was administered for four weeks. The experiment used the Morris water maze test, biochemical index detection, and many methods to evaluate the neuroprotective effect of β-asarone on DE rats from various aspects and understand its mechanism. Results: β-asarone reduced neuronal cell damage and significantly improved the learning and memory ability of DE rats. In addition, β-asarone can reduce the oxidative stress response and amyloid-β accumulation in the brain of DE model rats and increase the content of brain-derived neurotrophic factor (BDNF) in the brain tissue, thereby reducing neuronal cell apoptosis and playing a protective role. Conclusion: β-asarone can reduce the accumulation of oxidative stress and amyloid-β in the brain, increase the content of BDNF, reduce the apoptosis of neuronal cells, and exert neuronal protection, thereby improving the learning and memory ability of DE model rats. Show more

Keywords: β-asarone, cognitive dysfunction, diabetic encephalopathy, neuronal cells

DOI: 10.3233/ADR-220001

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 195-206, 2022

Authors: Ho, Gilbert | Choo, Pei Chen | Waragai, Masaaki | Inoue, Satoshi | Masliah, Eliezer | Hashimoto, Makoto

Article Type: Article Commentary

Abstract:  Presuming that Alzheimer’s disease (AD) might represent an antagonistic pleiotropic phenomenon derived from the evolvability of multiple amyloidogenic proteins, targeting such proteins simultaneously could enhance therapeutic efficacy. Furthermore, considering that amyloid-β (Aβ) immunotherapies during reproductive life stage might adversely decrease Aβ evolvability in an offspring’s brain, the disease-modifying Aβ immunotherapies should be limited to post-reproductive time in lifespan. Thus, current Aβ immunotherapy strategies should be revised accordingly. Given that the “adiponectin paradox” might underlie both amyloidosis and cognitive dysfunction in aging brain, blocking activin signaling situated downstream of the adiponectin paradox might be an alternative strategy to prevent AD.

Keywords: Activin, adiponectin paradox, Alzheimer’s disease (AD), amyloid-β immunotherapy, antagonistic pleiotropy, evolvability, follistatin

DOI: 10.3233/ADR-210021

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 207-210, 2022

Authors: Fuller-Thomson, Esme | Nowaczynski, Aliya | MacNeil, Andie

Article Type: Research Article

Abstract: Background: Sensory impairments and cognitive impairment are increasing in scope due to the aging population. Objective: To investigate the association between hearing impairment, vision impairment, and dual sensory impairment with cognitive impairment among older adults. Methods: Secondary analysis of a combination of ten consecutive waves (2008–2017) of the nationally representative American Community Survey. The sample included 5.4 million community-dwelling and institutionalized older adults aged 65 and older. Bivariate and logistic regression models were conducted to examine the association hearing impairment, vision impairment, and dual sensory impairment with cognitive impairment. Results: After controlling for age, …race, education, and income, older adults with only hearing impairment had more than double the odds of cognitive impairment (OR = 2.66, 95% CI = 2.64, 2.68), while older adults with only vision impairment had more than triple the odds of cognitive impairment (OR = 3.63; 95% CI = 3.59, 3.67). For older adults with dual sensory impairment, the odds of cognitive impairment were eight-fold (OR = 8.16; 95% CI = 8.07, 8.25). Similar trends were apparent in each sex and age cohort. Conclusion: Hearing and vision impairment are both independently associated with cognitive impairment. However, dual sensory impairment is associated with substantially higher odds of cognitive impairment, even after controlling for sociodemographic characteristics. Practitioners working with older adults may consider treatment for sensory impairments and cognitive impairment concurrently. Future research is needed to determine if the association is causal, and to investigate the effectiveness of common methods of treatment for sensory impairment for reducing the prevalence of cognitive impairment. Show more

Keywords: Blindness, cognitive dysfunction, deafness, dementia, hearing disorders, hearing loss, vision disorders

DOI: 10.3233/ADR-220005

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 211-222, 2022

Authors: Carrarini, Claudia | De Rosa, Matteo Alessandro | Calisi, Dario | Digiovanni, Anna | Salute, Pierpaolo | Dono, Fedele | Evangelista, Giacomo | Consoli, Stefano | Russo, Mirella | Ferri, Laura | D’Ardes, Damiano | Mattoli, Maria Vittoria | Cipollone, Francesco | Onofrj, Marco | Bonanni, Laura

Article Type: Research Article

Abstract: Background: A 79-year-old woman was admitted to the Neurology Clinic of the University of Chieti-Pescara for a syncope. At admission, the occurrence of an acute stroke was ruled out. Her cognitive status was unimpaired. After three days from the hospitalization, the patient experienced an episode of mixed delirium. Objective: The present case report shows a case of delirium-onset dementia with Lewy bodies (DLB) with a specific electroencephalographic (EEG) pattern from its prodromal stage. Methods: Delirium was assessed by 4AT test. During the hospitalization, the patient underwent a quantitative EEG (QEEG) with spectral analysis. At six months …from the episode of delirium, she was tested by neuropsychological evaluation, QEEG, and 18 F-fluorodeoxyglucose PET/CT to assess the onset of a possible cognitive decline. Results: At baseline, the QEEG exam showed a dominant frequency (DF) in the pre-alpha band (7.5 Hz) with a dominant frequency variability (DFV) of 2 Hz. This pattern is typical of DLB at early stage. After six months, she reported attention deficits in association with cognitive fluctuation and REM sleep behavior disorder. The neurological examination revealed signs of parkinsonism. Cognitive status resulted to be impaired (MoCA = 15/30). QEEG recording confirmed the presence of a DLB-typical pattern (DF = 7.5 Hz, DFV = 2.5 Hz). The 18 F-FDG-PET/CT showed a moderate bilateral posterior hypometabolism (occipital and temporal cortex), with relative sparing of the posterior cingulate cortex compared to cuneus/precuneus (Cingulate Island sign ), and mild bilateral hypometabolism in frontal regions (suggestive of a DLB diagnosis). Conclusion: EEGs may represent supportive and validated biomarkers for delirium-onset prodromal DLB. Show more

Keywords: Delirium, dementia with Lewy bodies, EEG, prodromal dementia

DOI: 10.3233/ADR-220017

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 223-228, 2022

Authors: Zygouris, Stelios | Segkouli, Sofia | Triantafyllidis, Andreas | Giakoumis, Dimitrios | Tsolaki, Magdalini | Votis, Konstantinos | Tzovaras, Dimitrios

Article Type: Short Communication

Abstract: This study conducted a preliminary usability assessment of the Virtual Supermarket Test (VST), a serious game-based self-administered cognitive screening test for mild cognitive impairment (MCI). Twenty-four healthy older adults with subjective cognitive decline and 33 patients with MCI self-administered the VST and then completed the System Usability Scale (SUS). The average SUS score was 83.11 (SD = 14.6). The SUS score was unaffected by age, education, touch device familiarity, and diagnosis of MCI. SUS score correlated with VST performance (r  = –0.496, p  = 0.000). Results of this study indicate good usability of the VST.

Keywords: Age-related memory disorders, cognitive assessment screening instrument, computer games, dementia, mild cognitive impairment, neurocognitive tests, screening, self-evaluation

DOI: 10.3233/ADR-210064

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 229-234, 2022

Authors: Carotenuto, Anna | Fasanaro, Angiola Maria | Manzo, Valentino | Amenta, Francesco | Traini, Enea

Article Type: Research Article

Abstract: Background: Depressive symptoms are common in Alzheimer’s disease (AD) patients and are associated with an increased functional decline. Selective serotonin reuptake inhibitor antidepressants showed a limited efficacy. Objective: The purpose of this work was to evaluate if a higher brain cholinergic stimulation induced by the association between the acetylcholinesterase inhibitor donepezil and the cholinergic precursor choline alphoscerate has any effect on depression in AD patients. Methods: Patients were selected among those recruited in the ASCOMALVA (association between the cholinesterase inhibitor donepezil and the cholinergic precursor choline alphoscerate in AD) trial. Depressive symptoms were investigated in 90 …AD patients through the neuropsychiatric inventory at baseline and after 3, 6, 9, 12, 18, and 24 months of treatment. Patients were randomized in a group association therapy (45 subjects) receiving donepezil 10 mg plus choline alphoscerate 1,200 mg/day, and a group monotherapy (45 subjects) receiving donepezil 10 mg/day plus placebo. Based on the results of the MMSE at the recruitment patients were divided into 3 groups: severely impaired (score < 15); moderately impaired (score 19-16); mild-moderately impaired (score 24-20). Results: Depression symptoms were significantly lower (p  < 0.05) in patients treated with donepezil plus choline alphoscerate compared to patients treated with donepezil alone. Subjects of the group having mild to moderate cognitive impairment were those more sensitive to the association treatment. Conclusion: Depression symptoms of AD patients in the mild to moderate stage probably could to benefit of a stronger cholinergic stimulation induced by associating donepezil with the cholinergic precursor choline alphoscerate. Show more

Keywords: Alzheimer’s disease, association, choline alphoscerate, depression, donepezil

DOI: 10.3233/ADR-200269

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 235-243, 2022

Authors: Hu, Wen | Dai, Chun-Ling | Niu, Jiahui | Iqbal, Khalid

Article Type: Research Article

Abstract: Background: The triple transgenic mouse model of Alzheimer’s disease (3×Tg-AD) has gained popularity in Alzheimer’s research owing to the progressive development of both amyloid-β and tau pathologies in its brain. Prior handling-habituation, a necessary preparation procedure that reduces anxiety and stress in rodents, was seldom described in the literature involving these mice and needs to be addressed. Objective: We sought to determine whether 3×Tg-AD mice differ from B6;129 genetic control mice in terms of tameness and prior habituation to handling. Methods: We devised hand-staying and hand-boarding assays to evaluate tameness in 3×Tg-AD and B6;129 genetic …control mice at 2.5, 7, and 11.5 months of age, representing cognitively pre-symptomatic, early symptomatic and advanced symptomatic stages of the disease, respectively. We monitored the progress of handling-habituation across 8–15 daily handling sessions and assessed the animal behaviors in elevated plus maze. Results: We found that 3×Tg-AD mice were markedly tamer than age-matched control mice at the baseline. Whereas it took 2–3 days for 3×Tg-AD mice to reach the criteria for full tameness, it took an average of 7–9 days for young genetic control mice to do so. Prior handling-habituation enhanced risk assessment and coping strategy in mice in elevated plus maze. Completely handling-habituated mice exhibited comparable anxiety indices in the maze regardless of genotype and age. Conclusion: These findings collectively point to inherently heightened tameness and accelerated handling-habituation in 3×Tg-AD mice on a B6;129 genetic background. These traits should be carefully considered when behaviors are compared between 3×Tg-AD and the genetic control mice. Show more

Keywords: 3×Tg-AD, anxiety, mouse models of Alzheimer’s disease, prior handling-habituation, tameness

DOI: 10.3233/ADR-220007

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 245-255, 2022

Authors: Ahmed, Heba A. | Ishrat, Tauheed

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) has become a worldwide crisis with no effective therapeutic options. The medications currently available for AD are only palliative; their effect is temporary, and they are associated with unfavorable side effects. Even the newest medication aducanumab, granted accelerated FDA approval in 2021, failed to show cognitive benefits in clinical trials and continued approval requires verification in subsequent clinical trials. There is an urgent need for safe and effective therapies to preserve cognition and effectively manage AD. Generally, a new drug product takes several years for FDA approval and exceeds 2.5 billion dollars in research and development, …with most new drug products never even reaching the market. This has led to a recent shift for repurposing/repositioning existing FDA-approved medications, to new therapeutic indications. Objective: To investigate the effects of long-term treatment with candesartan, an FDA-approved angiotensin-II type-1 receptor blocker (ARB), on the development of cognitive impairment associated with premature aging. Methods: Candesartan was given at a dose of 1 mg/kg/d in an AD model of senescence-accelerated mouse prone-8 (SAMP8) and senescence-accelerated mouse resistant (SAMR1) mice. Oral treatment with candesartan or vehicle was started, in 2-month-old mice and administered continuously for 4-months. Results: Low-dose candesartan prevented the development of cognitive impairment, otherwise associated with accelerated aging, in SAMP8 mice, by reducing inflammation and nitro-oxidative stress. Candesartan did not affect the cognitive function of control SAMR1 mice. Conclusion: Early ARB treatment might be beneficial in preventing age-related cognitive deficits in AD-prone individuals. Show more

Keywords: Angiotensin receptor blocker, candesartan, cognitive impairment, oxidative stress, sporadic Alzheimer’s disease

DOI: 10.3233/ADR-220016

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 257-269, 2022

Authors: Tsamou, Maria | Roggen, Erwin L.

Article Type: Review Article

Abstract: The adverse outcome pathway (AOP) concept was first proposed as a tool for chemical hazard assessment facilitating the regulatory decision-making in toxicology and was more recently recommended during the BioMed21 workshops as a tool for the characterization of crucial endpoints in the human disease development. This AOP framework represents mechanistically based approaches using existing data, more realistic and relevant to human biological systems. In principle, AOPs are described by molecular initiating events (MIEs) which induce key events (KEs) leading to adverse outcomes (AOs). In addition to the individual AOPs, the network of AOPs has been also suggested to beneficially support …the understanding and prediction of adverse effects in risk assessment. The AOP-based networks can capture the complexity of biological systems described by different AOPs, in which multiple AOs diverge from a single MIE or multiple MIEs trigger a cascade of KEs that converge to a single AO. Here, an AOP network incorporating a recently proposed tau-driven AOP toward memory loss (AOP429) related to sporadic (late-onset) Alzheimer’s disease is constructed. This proposed AOP network is an attempt to extract useful information for better comprehending the interactions among existing mechanistic data linked to memory loss as an early phase of sporadic Alzheimer’s disease pathology. Show more

Keywords: Adverse outcome pathway, AOP-wiki, memory loss, network

DOI: 10.3233/ADR-220015

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 271-296, 2022

Authors: Bohlken, Jens | Weber, Kerstin | Riedel Heller, Steffi | Michalowsky, Bernhard | Kostev, Karel

Article Type: Research Article

Abstract: Background: Little is known about the impact of COVID-19 on mild cognitive disorder. Objective: The aim of this retrospective cohort study was to investigate whether COVID-19 diagnosis is associated with subsequent mild cognitive disorder (MCD) compared to acute upper respiratory infections (AURI). Methods: This retrospective cohort study used data from the Disease Analyzer database (IQVIA) and included 67,046 patients with first-time symptomatic or asymptomatic COVID-19 diagnoses in 1,172 general practices in Germany between March 2020 and September 2021. Diagnoses were based on ICD-10 codes. Patients diagnosed with AURI were matched to 67,046 patients with COVID-19 using …propensity scores based on sex, age, index month, and comorbidities. The index date was the diagnosis date for either COVID-19 or AURI. Associations between the COVID-19 and MCD were studied using conditional Poisson regression models. Results: The incidence of MCD was 7.6 cases per 1,000 person-years in the COVID-19 group and 5.1 cases per 1,000 person-years in the AURI group (IRR = 1.49, 95% CI = 1.22–1.82). The incidence rate ratio decreased strongly with increasing age from 10.08 (95% CI = 4.00–24.42) in the age group≤50 to 1.03 (95% CI = 0.81–1.31) in the age group > 70. In addition, the association between COVID-19 and MCD was significant in women (IRR: 1.70, 95% CI: 1.34–2.16) but not in men (IRR: 1.08, 95% CI: 0.75–1.56). Conclusion The incidence of MCD was low but significantly higher in COVID-19 than in AURI patients, especially among younger patients. If a cognitive disorder is suspected, referral to a specialist is recommended. Show more

Keywords: COVID-19 pandemic, general practices, Germany, mild cognitive disorder, post-COVID

DOI: 10.3233/ADR-220020

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 297-305, 2022

Authors: Koppelmans, Vincent | Silvester, Benjamin | Duff, Kevin

Article Type: Systematic Review

Abstract: Background: Despite the prevalence of motor symptoms in mild cognitive impairment (MCI) and Alzheimer’s disease (AD), their underlying neural mechanisms have not been thoroughly studied. Objective: This review summarizes the neural underpinnings of motor deficits in MCI and AD. Methods: We searched PubMed up until August of 2021 and identified 37 articles on neuroimaging of motor function in MCI and AD. Study bias was evaluated based on sample size, availability of control samples, and definition of the study population in terms of diagnosis. Results: The majority of studies investigated gait, showing that slower gait …was associated with smaller hippocampal volume and prefrontal deactivation. Less prefrontal activation was also observed during cognitive-motor dual tasking, while more activation in cerebellar, cingulate, cuneal, somatosensory, and fusiform brain regions was observed when performing a hand squeezing task. Excessive subcortical white matter lesions in AD were associated with more signs of parkinsonism, poorer performance during a cognitive and motor dual task, and poorer functional mobility. Gait and cognitive dual-tasking was furthermore associated with cortical thickness of temporal lobe regions. Most non-gait motor measures were only reported in one study in relation to neural measures. Conclusion: Cross-sectional designs, lack of control groups, mixing amnestic- and non-amnestic MCI, disregard of sex differences, and small sample sizes limited the interpretation of several studies, which needs to be addressed in future research to progress the field. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, functional MRI, functional near-infrared spectroscopy, magnetic resonance imaging, mild cognitive impairment, motor function

DOI: 10.3233/ADR-210065

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 307-344, 2022

Authors: Padala, Sanjana P. | Yarns, Brandon C.

Article Type: Article Commentary

Abstract: Despite controversy about the efficacy and safety of aducanumab, the FDA’s fast-tracking of this medicine is truly historic. However, structural problems leading to socioeconomic disparities and systemic racism in science, healthcare, and society have left out under-represented populations. This perspective outlines the racial and socioeconomic health disparities in aducanumab treatment: 1) Disparities in the risk of Alzheimer’s disease (AD), 2) Limited participation from under-represented groups in AD trials raising concerns about the generalizability of the results, 3) Questionable applicability of the amyloid hypothesis in groups under-represented in AD research, and 4) Aducanumab’s initial sticker price that unfairly singled out those …with lower socioeconomic backgrounds. Potential solutions are discussed. Show more

Keywords: Aducanumab, Alzheimer’s disease, bioethics, ethics

DOI: 10.3233/ADR-220023

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 345-348, 2022

Authors: Patel, Vishvas N. | Chorawala, Mehul R. | Shah, Maitri B. | Shah, Kashvi C. | Dave, Bhavarth P. | Shah, Manal P. | Patel, Tanvi M.

Article Type: Review Article

Abstract: Type-2 diabetes mellitus (T2DM) is a chronic immuno-inflammatory and metabolic disease characterized by hyperglycemia and insulin resistance with corresponding hyperinsulinemia. On the other hand, Alzheimer’s disease (AD) is a neurodegenerative disease involving cognitive impairment, neuronal dysfunction, and memory loss. Several recently published literatures suggest a causal relationship between T2DM and AD. In this review, we have discussed several potential mechanisms underlying diabetes-induced cognitive impairment which include, abnormal insulin signaling, amyloid-β accumulation, oxidative stress, immuno-inflammation, mitochondrial dysfunction, advanced glycation end products, acetylcholinesterase and butyrylcholinesterase, advanced lipid peroxidation products, and apolipoprotein E. All these interconnected mechanisms may act either individually or synergistically …which eventually leads to neurodegeneration and AD. Show more

Keywords: Alzheimer’s disease, diabetes mellitus, hyperphosphorylation of tau, insulin resistance, neurodegeneration, oxidative stress

DOI: 10.3233/ADR-220021

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 349-357, 2022

Authors: Styck, Abigail C. | George, Daniel R.

Article Type: Research Article

Abstract: Background: Gardening has been shown to have positive effects on persons living with dementia, but no studies have explored the effects of gardening on sense of purpose. Objective: Explore how gardening may influence sense of purpose for people with dementia. Methods: Ten residents with dementia diagnoses living in a skilled care facility participated in hour-long gardening sessions twice weekly at outdoor raised beds over a two-month duration. One group (n  = 5) donated vegetables to a food pantry while the other (n  = 5) harvested produce for personal use. Semi-structured interviews with participants and their caregivers conducted post-intervention …were analyzed for themes. Results: Participants and caregivers reported biopsychosocial benefits of gardening, identifying four main themes: 1) Gardening outdoors provided specific physical benefits that improved quality of life; 2) Working on a project in a group setting improved mood and fostered a sense of community; 3) Gardening promoted reminiscence and reinforced a sense of self; 4) Gardening provided participants with a sense of purpose and pride. Conclusion: Gardening has biopsychosocial benefits for persons living with dementia, and there appears to be additive benefit linked to improved sense of purpose via charitable giving. Show more

Keywords: Arts, dementia, medical humanities, nature, psychosocial

DOI: 10.3233/ADR-220018

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 359-367, 2022

Authors: Volloch, Vladimir | Rits-Volloch, Sophia

Article Type: Research Article

Abstract: We posit that Alzheimer’s disease (AD) is driven by amyloid-β (Aβ) generated in the amyloid-β protein precursor (AβPP) independent pathway activated by AβPP-derived Aβ accumulated intraneuronally in a life-long process. This interpretation constitutes the Amyloid Cascade Hypothesis 2.0 (ACH2.0). It defines a tandem intraneuronal -Aβ (i Aβ)-anchored cascade occurrence: intraneuronally-accumulated, AβPP-derived i Aβ triggers relatively benign cascade that activates the AβPP-independent i Aβ-generating pathway, which, in turn, initiates the second, devastating cascade that includes tau pathology and leads to neuronal loss. The entire output of the AβPP-independent i Aβ-generating pathway is retained intraneuronally and perpetuates the pathway’s operation. This process …constitutes a self-propagating, autonomous engine that drives AD and ultimately kills its host cells. Once activated, the AD Engine is self-reliant and independent from Aβ production in the AβPP proteolytic pathway; operation of the former renders the latter irrelevant to the progression of AD by relegating its i Aβ contribution to insignificant, and brands its manipulation for therapeutic purposes, such as BACE (beta-site AβPP-cleaving enzyme) inhibition, as futile. In the proposed AD paradigm, the only valid direct therapeutic strategy is targeting the engine’s components, and the most effective feasible approach appears to be the activation of BACE1 and/or of its homolog BACE2, with the aim of exploiting their Aβ-cleaving activities. Such treatment would collapse the i Aβ population and ‘reset’ its levels below those required for the operation of the AD Engine. Any sufficiently selective i Aβ-depleting treatment would be equally effective. Remarkably, this approach opens the possibility of a short-duration, once-in-a-lifetime-only or very infrequent, preventive or curative therapy for AD; this therapy would be also effective for prevention and treatment of the ‘common’ pervasive aging-associated cognitive decline. The ACH2.0 clarifies all ACH-unresolved inconsistencies, explains the widespread ‘resilience to AD’ phenomenon, predicts occurrences of a category of AD-afflicted individuals without excessive Aβ plaque load and of a novel type of familial insusceptibility to AD; it also predicts the lifespan-dependent inevitability of AD in humans if untreated preventively. The article details strategy and methodology to generate an adequate AD model and validate the hypothesis; the proposed AD model may also serve as a research and drug development platform. Show more

Keywords: the Amyloid Cascade Hypothesis 2.0, intraneuronal Aβ (iAβ), AβPP-independent generation of iAβ, PKR and HRI kinases, integrated stress response, iAβ depletion therapy for AD, BACE activators as AD drugs

DOI: 10.3233/ADR-220031

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 369-399, 2022

Authors: Avey, Jaedon P. | Schaefer, Krista R. | Noonan, Carolyn J. | Muller, Clemma J. | Mosley, Michael | Galvin, James E.

Article Type: Research Article

Abstract: Background: Alaska Native and American Indian (AN/AI) people represent a rapidly aging population with disproportionate burdens of Alzheimer’s disease and related dementias (ADRD) risk factors. Objective: To characterize healthcare service use patterns and mortality in the years following ADRD diagnosis for patients in an Alaska Native Tribal health system. Methods: The study sample included all AN/AI patients aged 55 or older with an ADRD diagnosis who were seen between 2012–2018 (n  = 407). We used cluster analysis to identify distinct patterns of healthcare use for primary care, emergency and urgent care, inpatient hospital stays, and selected specialty …care. We compared demographic and clinical factors between clusters and used regression to compare mortality. Results: We identified five clusters of healthcare service use patterns after ADRD diagnosis: 1) people who use a low amount of all services (n  = 107), 2) people who use a high amount of all services (n  = 60), 3) people who use a high amount of primary and specialty care (n  = 105), 4) people who use a high amount of specialty care (n  = 65), and 5) people who use a high amount of emergency and urgent care (n  = 70). The cluster with the highest use had the greatest proportion of comorbidities and had a 2.3-fold increased risk of mortality compared to the cluster with the lowest healthcare service use. Conclusion: Results indicate that those receiving the most services had the greatest healthcare-related needs and increased mortality. Future research could isolate factors that predict service use following ADRD diagnosis and identify other differential health risks. Show more

Keywords: Alaska Native, Alzheimer’s disease, American Indian, cluster analysis, delivery of healthcare, dementia, geriatrics, health services

DOI: 10.3233/ADR-210062

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 401-410, 2022

Authors: Zuroff, Leah | Wisse, Laura EM | Glenn, Trevor | Xie, Sharon X. | Nasrallah, Ilya M. | Habes, Mohamad | Dubroff, Jacob | de Flores, Robin | Xie, Long | Yushkevich, Paul | Doshi, Jimit | Davatsikos, Christos | Shaw, Leslie M. | Tropea, Thomas F. | Chen-Plotkin, Alice S. | Wolk, David A | Das, Sandhitsu | Mechanic-Hamilton, Dawn

Article Type: Research Article

Abstract: Background: Episodic memory decline is a hallmark of Alzheimer’s disease (AD). Subjective memory complaints (SMCs) may represent one of the earliest signs of impending cognitive decline. The degree to which self- or partner-reported SMCs predict cognitive change remains unclear. Objective: We aimed to evaluate the relationship between self- and partner-reported SMCs, objective cognitive performance, AD biomarkers, and risk of future decline in a well-characterized longitudinal memory center cohort. We also evaluated whether study partner characteristics influence reports of SMCs. Methods: 758 participants and 690 study partners were recruited from the Penn Alzheimer’s Disease Research Center Clinical …Core. Participants included those with Normal Cognition, Mild Cognitive Impairment, and AD. SMCs were measured using the Prospective and Retrospective Memory Questionnaire (PRMQ), and were evaluated for their association with cognition, genetic, plasma, and neuroimaging biomarkers of AD, cognitive and functional decline, and diagnostic progression over an average of four years. Results: We found that partner-reported SMCs were more consistent with cognitive test performance and increasing symptom severity than self-reported SMCs. Partner-reported SMCs showed stronger correlations with AD-associated brain atrophy, plasma biomarkers of neurodegeneration, and longitudinal cognitive and functional decline. A 10-point increase on baseline PRMQ increased the annual risk of diagnostic progression by approximately 70%. Study partner demographics and relationship to participants influenced reports of SMCs in AD participants only. Conclusion: Partner-reported SMCs, using the PRMQ, have a stronger relationship with the neuroanatomic and cognitive changes associated with AD than patient-reported SMCs. Further work is needed to evaluate whether SMCs could be used to screen for future decline. Show more

Keywords: Alzheimer’s disease, brain atrophy, memory decline, mild cognitive impairment, proxy, self-report, subjective memory complaints

DOI: 10.3233/ADR-220013

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 411-430, 2022

Authors: Gallucci, Maurizio | Grassivaro, Francesca | Da Ronch, Chiara | Fiore, Vittorio | Bonifati, Domenico Marco | Bendini, Matteo | Zanusso, Gianluigi | Bonanni, Laura

Article Type: Research Article

Abstract: Background: An 82-year-old right-handed man, a retired teacher, reported the occurrence, three years earlier, of difficulties in moving his left arm and foot, tremor in his left hand, and gestures of the left upper limb that appeared to be independent of the patient’s will. Objective: We describe an unusual case of corticobasal syndrome (CBS) showing disease-associated biomarkers of dementia with Lewy bodies (DLB). Methods: Clinical, neuropsychological, imaging, and biomarker evaluations were conducted, including tau and amyloid-β levels in the cerebrospinal fluid (CSF) and a RT-QuIC assay for α-synuclein both in the CSF and olfactory mucosa (OM), …as well as a QEEG assessment. Results: The patient presented resting tremor, mild extrapyramidal hypertonus, mild bradykinesia on the left side, and severe apraxia on the left upper limb. Brain MRI showed a diffuse right hemisphere atrophy which was prominent in the posterior parietal and temporal cortices, and moderate in the frontal cortex and the precuneus area. 18 F-FDG PET imaging showed reduced glucose metabolism in the right lateral parietal, temporal, and frontal cortices with involvement of the right precuneus. The putamen did not appear to be pathological at DaTQUANT. Neuropsychological tests showed memory and visual-perceptual deficits. CSF tau and amyloid measurements did not show clear pathological values. RT-QuIC for α-synuclein in CSF and OM samples were positive. The QEEG analysis showed a pre-alpha dominant frequency in posterior derivations, typical of early stages of DLB. Conclusion: Although in the present patient the clinical diagnosis was of probable CBS, unexpectedly positive biomarkers for DLB suggested the co-presence of multiple pathologies. Show more

Keywords: α-synuclein, corticobasal syndrome, dementia with Lewy bodies, 18F-FDG-PET, magnetic resonance, neurodegenerative diseases, quantitative electroencephalography, real-time quaking-induced conversion, tauopathy, TREDEM

DOI: 10.3233/ADR-220026

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 431-442, 2022

Authors: Dai, Jiahui | Ports, Kayleen Deanna | Corrada, Maria M. | Odegaard, Andrew O. | O’Connell, Joan | Jiang, Luohua

Article Type: Research Article

Abstract: Background: When studying drug effects using observational data, time-related biases may exist and result in spurious associations. Numerous observational studies have investigated metformin and dementia risk, but have reported inconsistent findings, some of which might be caused by unaddressed time-related biases. Immortal time bias biases the results toward a “protective” effect, whereas time-lag and time-window biases can lead to either a “detrimental” or “protective” effect. Objective: To conduct a systematic review examining time-related biases in the literature on metformin and dementia. Methods: The electronic databases PubMed, Web of Science, and ProQuest were searched for the terms …“Metformin” AND (“dementia” OR “Alzheimer’s Disease” OR “cognitive impairment"). These databases were searched from inception through 09/24/2021. Only English language articles and human research were eligible. Results: Seventeen studies were identified: thirteen cohort studies, two case-control studies, and two nested case-control studies. Eleven (64.7%) studies reported a reduced risk of dementia associated with metformin use; two (11.8%) suggested metformin increased dementia risk, while four (23.5%) concluded no significant associations. Eight (61.5%) of thirteen cohort studies had immortal time bias or did not clearly address it. Fifteen (88.2%) of seventeen reviewed studies had time-lag bias or did not clearly address it. Two (50.0%) of four case-control studies did not explicitly address time-window bias. The studies that addressed most biases concluded no associations between metformin and dementia risk. Conclusion: None of the reviewed studies clearly addressed relevant time-related biases, illustrating time-related biases are common in observational studies investigating the impact of anti-diabetic medications on dementia risk. Show more

Keywords: Bias, case-control studies, cohort studies, dementia, metformin

DOI: 10.3233/ADR-220002

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 443-459, 2022

Authors: Sobregrau, Pau | Peri, Josep M. | Sánchez del Valle, Raquel | Molinuevo, Jose L. | Barra, Bernardo | Pintor, Luís

Article Type: Research Article

Abstract: Background: Predictive genetic tests are presently effective over several medical conditions, increasing the demand among patients and healthy individuals. Considering the psychological burden suspected familial dementia may carry on individuals, assessing personality, coping strategies, and mental health could aid clinicians in findings the appropriate time for delivering genetic test results and predict compliance regarding genetic counseling and expectations towards the genetic condition depending on the outcome. Objective: To describe the psychiatric, psychological, and coping characteristics of a sample of Spanish individuals at risk of familial dementia before genetic test results were given. Methods: We included 54 …first degree relatives of patients diagnosed with Alzheimer’s disease, lobar frontotemporal degeneration, or prion diseases. The NEO-FFI-R, COPE, and HADS tests evaluated personality, coping strategies, and psychological distress, respectively. Results: Anxiety and depression were below the cut-off point for mild severity. Conscientiousness and Agreeableness were the most preponderant personality factors, while Neuroticism was the least. Positive reinterpretation and Acceptance were the most frequent coping strategies, and Denial and Alcohol and drug use were the least used. Ongoing medical pathologies increased depression, while psychiatric disorders worsened psychological distress. Conclusion: Contrary to our expectations, PICOGEN candidates showed psychological distress and personality traits within normative ranges, and the use of problem-focused coping strategies prevailed over avoidance coping strategies. Nevertheless, clinicians should pay particular attention to individuals attending genetic counseling who are women, aged, and present an ongoing psychiatric disorder and psychiatric history at inclusion to ensure their mental health and adherence throughout the process. Show more

Keywords: Alzheimer’s disease, dementia, frontotemporal lobar degeneration, genetic counseling, genetic testing, neurodegenerative diseases,, prion diseases, psychiatry, psychology

DOI: 10.3233/ADR-210067

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 461-478, 2022

Authors: Butts, Alissa M. | Machulda, Mary M. | Martin, Peter | Przybelski, Scott A. | Duffy, Joseph R. | Graff-Radford, Jonathan | Knopman, David S. | Petersen, Ronald C. | Jack Jr., Clifford R. | Lowe, Val J. | Josephs, Keith A. | Whitwell, Jennifer L.

Article Type: Research Article

Abstract: Background: The hippocampus and temporal lobe are atrophic in typical amnestic Alzheimer’s disease (tAD) and are used as imaging biomarkers in treatment trials. However, a better understanding of how temporal structures differ across atypical AD phenotypes and relate to cognition is needed. Objective: Our goal was to compare temporal lobe regions between tAD and two atypical AD phenotypes (logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA)), and assess cognitive associations. Methods: We age and gender-matched 77 tAD participants to 50 LPA and 27 PCA participants, all of which were amyloid-positive. We used linear mixed-effects models …to compare FreeSurfer-derived hippocampal volumes and cortical thickness of entorhinal, inferior and middle temporal, and fusiform gyri, and to assess relationships between imaging and memory, naming, and visuospatial function across and within AD phenotype. Results: Hippocampal volume and entorhinal thickness were smaller bilaterally in tAD than LPA and PCA. PCA showed greater right inferior temporal and bilateral fusiform thinning and LPA showed greater left middle and inferior temporal and left fusiform thinning. Atypical AD phenotypes differed with greater right hemisphere thinning in PCA and greater left hemisphere thinning in LPA. Verbal and visual memory related most strongly to hippocampal volume; naming related to left temporal thickness; and visuospatial related to bilateral fusiform thickness. Fewer associations remained when examined within AD group. Conclusion: Atypical AD phenotypes are associated with greater thinning of lateral temporal structures, with relative sparing of medial temporal lobe, compared to tAD. These findings may have implications for future clinical trials in AD. Show more

Keywords: Alzheimer’s disease, atypical Alzheimer’s disease, cortical thickness, hippocampal volumes, logopenic progressive aphasia, memory, neuropsychological functioning, object naming, posterior cortical atrophy, visual spatial

DOI: 10.3233/ADR-220010

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 479-491, 2022

Authors: Franczak, Stephanie | Pommy, Jessica | Minor, Greta | Zolliecoffer, Chandler | Bhalla, Manav | Agarwal, Mohit | Nencka, Andrew | Wang, Yang | Klein, Andrew | O’Neill, Darren | Henry, Jude | Umfleet, Glass

Article Type: Research Article

Abstract: Background: There are now clinically available automated MRI analysis software programs that compare brain volumes of patients to a normative sample and provide z -score data for various brain regions. These programs have yet to be validated in primary progressive aphasia (PPA). Objective: To address this gap in the literature, we examined Neuroreader™ z -scores in PPA, relative to visual MRI assessment. We predicted that Neuroreader™ 1) would be more sensitive for detecting left > right atrophy in the cortical lobar regions in logopenic variant PPA clinical phenotype (lvPPA), and 2) would distinguish lvPPA (n  = 11) from amnestic …mild cognitive impairment (aMCI; n  = 12). Methods: lvPPA or aMCI patients who underwent MRI with Neuroreader™ were included in this study. Two neuroradiologists rated 10 regions. Neuroreader™ lobar z-s cores for those 10 regions, as well as a hippocampal asymmetry metric, were included in analyses. Results: Cohen’s Kappa coefficients were significant in 10 of the 28 computations (k  = 0.351 to 0.593, p ≤0.029). Neuroradiologists agreed 0% of the time that left asymmetry was present across regions. No significant differences emerged between aMCI and lvPPA in Neuroreader™ z -scores across left or right frontal, temporal, or parietal regions (p s > 0.10). There were significantly lower z- scores in the left compared to right for the hippocampus, as well as parietal, occipital, and temporal cortices in lvPPA. Conclusion: Overall, our results indicated moderate to low interrater reliability, and raters never agreed that left asymmetry was present. While lower z -scores in the left hemisphere regions emerged in lvPPA, Neuroreader™ failed to differentiate lvPPA from aMCI. Show more

Keywords: Logopenic variant PPA, magnetic resonance imaging, mild cognitive impairment, neuroreader

DOI: 10.3233/ADR-220036

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 493-501, 2022

Authors: Giannouli, Vaitsa | Tsolaki, Magda

Article Type: Short Communication

Abstract: This study examines the connection between biological factors, social determinants, and behavioral and psychological symptoms of dementia (BPSD) and the estimations of financial capacity made by caregivers of mild AD patients in Greece. Financial capacity estimations negatively correlated with biological sex of the patients (female), but Neuropsychiatric Inventory (NPI) scores were statistically lower for older females. BPSD (measured with NPI) was found to negatively correlate with estimates of financial capacity. The existence of delusions-hallucinations was reported in all males. No correlations were found between financial capacity estimations, actual cognitive and financial capacity performance, and all other included biological and social …characteristics of the patients as well as their caregivers. Show more

Keywords: Behavioral and psychological symptoms of dementia, biological factors, caregivers, financial capacity estimations, social determinants

DOI: 10.3233/ADR-220037

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 503-507, 2022

Authors: Pirani, Alessandro | Nasreddine, Ziad | Neviani, Francesca | Fabbo, Andrea | Rocchi, Marco Bruno | Bertolotti, Marco | Tulipani, Cristina | Galassi, Matteo | Belvederi Murri, Martino | Neri, Mirco

Article Type: Research Article

Abstract: Background: The early detection of neurocognitive disorders, especially when mild, is a key issue of health care systems including the Italian Dementia National Plan. The Mini-Mental State Examination (MMSE), i.e., the reference screening tool for dementia in Italian Memory Clinics, has low sensitivity in detecting mild cognitive impairment (MCI) or mild dementia. Objective: Availability of a 10-minute screening test sensitive to MCI and mild dementia, such as the Montreal Cognitive Assessment (MoCA), is relevant in the field. This study presents initial validity and reliability data for the Italian version of MoCA 7.1 that is being collected as part …of a large ongoing longitudinal study to evaluate the rate of incident MCI and dementia in older adults. Methods: MoCA 7.1 and MMSE were administered to cognitive impaired patients (n  = 469; 214 with MCI, 255 with dementia; mean age: 75.5; 52% females,) and healthy older adults (n  = 123, mean age: 69.7, 64 % females). Results: Test-retest (0.945, p  < 0.001) and inter-rater (0.999, p  < 0.001) reliability of MoCA 7.1, assessed on randomly selected participants with normal cognition, MCI, dementia, were significant. MoCA 7.1 showed adequate sensitivity (95.3%) and specificity (84.5%) in detecting MCI compared to MMSE (sensitivity: 53.8%; specificity: 87.5%). The Area Under the Curve of MoCA 7.1 was significantly greater than that of MMSE (0.963 versus 0.742). MoCA 7.1 showed similar results in detecting both MCI and dementia. Conclusion: MoCA 7.1 is a reliable and useful tool that can aid in the diagnosis of MCI and dementia in the Italian population. Show more

Keywords: Brief cognitive screening test, dementia, early cognitive impairment detection, mild cognitive impairment, Montreal Cognitive Assessment, neurocognitive disorders

DOI: 10.3233/ADR-210053

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 509-520, 2022

Authors: Roe, Catherine M.

Article Type: Review Article

Abstract: Research on how preclinical and early symptomatic Alzheimer’s disease (AD) impacts driving behavior is in its infancy, with several important research areas yet to be explored. This paper identifies research gaps and suggests priorities for driving studies over the next few years among those at the earliest stages of AD. These priorities include how individual differences in demographic and biomarker measures of AD pathology, as well as differences in the in-vehicle and external driving environment, affect driving behavior. Understanding these differences is important to developing future interventions to increase driving safety among those at the earliest stages of AD.

Keywords: biomarkers, driving, early Alzheimer’s disease, mild cognitive impairment, preclinical Alzheimer’s disease

DOI: 10.3233/ADR-220024

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 521-528, 2022

Authors: Nägga, Katarina | Bränsvik, Vanja | Stomrud, Erik | Melander, Olle | Nilsson, Peter M. | Gustavsson, Anna-Märta | Hansson, Oskar

Article Type: Research Article

Abstract: Background: Register diagnoses, both hospital-based and from open clinic care, are often used in research studies in Sweden. The validity of such diagnoses has been debated and a validation assessment can improve the diagnostic accuracy for use in research studies. Objective: The aim of this study was to investigate the quality of register-derived dementia diagnoses in the Malmö Diet and Cancer population study (MDCS) and to validate these diagnoses using systematic criteria. Methods: MDCS is a population-based prospective study comprising 30,446 participants. Register diagnoses of dementia for the MDCS population were derived from the Swedish National …Patient Register (NPR) and validated through re-evaluation of available medical records by physicians. Results: In the MDCS cohort, 2,206 participants were diagnosed with dementia according to the NPR during a mean follow-up of 18.1 years. The general dementia diagnosis was valid in 96% of the cases, but 40% of the specific dementia diagnoses were changed during the process of reevaluation. The diagnostic validity varied between 25.2% and 82.9% for the different diagnoses. The results from the validity assessment per diagnostic category revealed that the validity of the NPR diagnoses was higher for the more specific diagnoses and lower for unspecified dementia. The major diagnostic shift during the re-evaluation was from unspecified dementia to more specific diagnoses. Conclusion: Validation of dementia diagnoses using medical records results in more precise diagnoses. Dementia diagnoses derived from registers should be validated in order to study associations between influential factors and different dementia diagnoses. Show more

Keywords: Alzheimer’s disease, dementia, register, risk factors, validation study

DOI: 10.3233/ADR-220003

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 529-538, 2022

Authors: Tarawneh, Hadeel Y. | Jayakody, Dona M.P. | Sohrabi, Hamid R. | Martins, Ralph N. | Mulders, Wilhelmina H.A.M.

Article Type: Review Article

Abstract: Evidence suggests that hearing loss (HL), even at mild levels, increases the long-term risk of cognitive decline and incident dementia. Hearing loss is one of the modifiable risk factors for dementia, with approximately 4 million of the 50 million cases of dementia worldwide possibly attributed to untreated HL. This paper describes four possible mechanisms that have been suggested for the relationship between age-related hearing loss (ARHL) and Alzheimer’s disease (AD), which is the most common form of dementia. The first mechanism suggests mitochondrial dysfunction and altered signal pathways due to aging as a possible link between ARHL and AD. The …second mechanism proposes that sensory degradation in hearing impaired people could explain the relationship between ARHL and AD. The occupation of cognitive resource (third) mechanism indicates that the association between ARHL and AD is a result of increased cognitive processing that is required to compensate for the degraded sensory input. The fourth mechanism is an expansion of the third mechanism, i.e., the function and structure interaction involves both cognitive resource occupation (neural activity) and AD pathology as the link between ARHL and AD. Exploring the specific mechanisms that provide the link between ARHL and AD has the potential to lead to innovative ideas for the diagnosis, prevention, and/or treatment of AD. This paper also provides insight into the current evidence for the use of hearing treatments as a possible treatment/prevention for AD, and if auditory assessments could provide an avenue for early detection of cognitive impairment associated with AD. Show more

Keywords: Age-related hearing loss, Alzheimer’s disease, cognitive function, hearing loss

DOI: 10.3233/ADR-220035

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 539-556, 2022

Authors: Lu, Lu-Ping | Chang, Wei-Hua | Huang, Jing-Jia | Tan, Peng | Tsai, Guochuan Emil

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease affecting many cellular pathways, including protein aggregation, mitochondrial dysfunction, oxidative stress (OS), and neuroinflammation. Currently, no effective treatment for AD exists. Objective: We aim to determine the effect of lithium benzoate (LiBen) in protecting neurons from amyloid-β (Aβ) or other neurotoxin insults. Methods: Primary rat cortical neurons co-treated with neurotoxins and LiBen were used to examine its effect in cell viability, reactive oxygen species (ROS) clearance, and mitochondrial functions by MTT, CellRox fluorescence staining, and seahorse assay. Then, Barnes maze and prepulse inhibition test were performed in …APP/PS1 mice that received chronic LiBen treatment to assess its effect on cognitive protection. Oral bioavailability of LiBen was also assessed by pharmacokinetic study in rat plasma. Results: In this study, we discovered that LiBen can attenuate cellular ROS level, improve mitochondrial function, increase cell viability against multiple different insults of mitochondrial dysfunction, Aβ accumulation, and neuroinflammation, and promote neurogenesis. We demonstrated that LiBen has advantages over lithium or sodium benzoate alone as LiBen displays superior neuroprotective efficacy and oral bioavailability than the other two agents when being applied either alone or in combination. Furthermore, chronic administration of LiBen showed protection for cognition as well as spatial memory and reduced the senile plaque deposition in brains of AD animal models. Conclusion: LiBen stands as a promising therapeutic agent for improving cognition and delaying the progression of AD. Show more

Keywords: Amyloid-β clearance, cognitive protection, dementia lithium benzoate, mitochondrial improvement, neurodegenerative diseases, reactive oxygenase species attenuation

DOI: 10.3233/ADR-220025

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 557-575, 2022

Authors: Kanagasingam, Shalini | von Ruhland, Christopher | Welbury, Richard | Chukkapalli, Sasanka S. | Singhrao, Sim K.

Article Type: Research Article

Abstract: Background: Cleavage of the amyloid-β protein precursor (AβPP) mediated by host secretase enzymes, releases several fragments including amyloid-β (Aβ40 and Aβ42 ). Objective: To determine if Porphyromonas gingivalis conditioned medium cleaved AβPP to release Aβ40 and Aβ42 . Methods: The SH-SY5Y cell line was challenged, in vitro , with P. gingivalis (Pg381) conditioned medium in the presence/absence of cytokines. The cells and their supernatants were assessed for AβPP cleavage fragments by immunoblotting and transmission electron microscopy. Results: Western blotting of the cell lysates with the anti-AβPP C-terminal antibody demonstrated variable …molecular weight bands corresponding to full length and fragmented AβPP in lanes treated with the following factors: Tryptic soy broth (TSB), Pg381, IL-6, Pg381 + IL-1β, and Pg381 + TNF-α. The low molecular weight bands corresponding to the C99 dimerized fragment were observed in the Pg381 and interlukin-6 (IL-6) treated groups and were significantly more intense in the presence of Pg381 with either IL-6 or TNF-α. Bands corresponding to the dimerized C83 fragment were observed with cells treated with TNF-α alone and with Pg381 combined with IL-1β or IL-6 or TNF-α. The anti-Aβ antibody detected statistically significant Aβ40 and Aβ42 , levels when these two Aβ species were pooled across test samples and compared to the untreated group. Electron microscopic examination of the supernatants demonstrated insoluble Aβ40 and Aβ42 . Conclusion: These observations strongly imply that AβPP is an infection responsive protein cleaved via the amyloidogenic pathway on exposure to conditioned medium and in the presence of pro-inflammatory mediators. Show more

Keywords: Amyloid-β, amyloid-βprotein precursor, Porphyromonas gingivalis conditioned medium

DOI: 10.3233/ADR-220029

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 577-587, 2022

Authors: Ochi, Shinichiro | Mori, Takaaki | Iga, Jun-ichi | Ueno, Shu-ichi

Article Type: Research Article

Abstract: Background: Dementia in patients with late-life mood disorders is clinically important. Objective: We aimed to investigate the prevalence of dementia in patients with late-life major depressive disorder (MDD) or bipolar disorder (BD) and to clarify the clinical characteristics associated with the diagnosis of dementia. Methods: The prevalence of dementia at hospital discharge and the clinical characteristics at hospitalization who are diagnosed with MDD or BD over 65 years of age, from the medical records of 684 patients who had been admitted from 2015 to 2020 were investigated. Results: A total of 66 patients with …MDD (n  = 50) and BD (n  = 16) were analyzed. The prevalence of dementia was significantly higher in MDD than in BD (24.0% versus 0%; p  = 0.026). The mean age at onset of MDD was significantly older in the MDD with dementia group than in the MDD without (76.9±6.3 years versus 62.2±14.0 years; p  < 0.001). The rate of first depressive episode at this admission was significantly higher in the MDD with dementia group (91.7% versus 30.3%; p  < 0.001). The diagnosis of dementia was significantly associated with lower scores for “insomnia early” (p  = 0.019) and higher scores for “insight” (p  = 0.049) on the 17-item Hamilton Depression Rating (HAMD-17) subscales and lower scores for “recall” (p  = 0.003) on the MMSE subscales. Conclusion: The older age of first onset of depression, “insomnia early”, “insight” and “recall” may be useful indicators for a diagnosis of dementia in late-life depression. Show more

Keywords: Bipolar disorder, dementia, hospitalization, late-life depression, prevalence

DOI: 10.3233/ADR-220052

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 589-598, 2022

Authors: Bourgade, Karine | Frost, Eric H. | Dupuis, Gilles | Witkowski, Jacek M. | Laurent, Benoit | Calmettes, Charles | Ramassamy, Charles | Desroches, Mathieu | Rodrigues, Serafim | Fülöp Jr., Tamás

Article Type: Research Article

Abstract: Background: Unravelling the mystery of Alzheimer’s disease (AD) requires urgent resolution given the worldwide increase of the aging population. There is a growing concern that the current leading AD hypothesis, the amyloid cascade hypothesis, does not stand up to validation with respect to emerging new data. Indeed, several paradoxes are being discussed in the literature, for instance, both the deposition of the amyloid-β peptide (Aβ) and the intracellular neurofibrillary tangles could occur within the brain without any cognitive pathology. Thus, these paradoxes suggest that something more fundamental is at play in the onset of the disease and other key and …related pathomechanisms must be investigated. Objective: The present study follows our previous investigations on the infectious hypothesis, which posits that some pathogens are linked to late onset AD. Our studies also build upon the finding that Aβ is a powerful antimicrobial agent, produced by neurons in response to viral infection, capable of inhibiting pathogens as observed in in vitro experiments. Herein, we ask what are the molecular mechanisms in play when Aβ neutralizes infectious pathogens? Methods: To answer this question, we probed at nanoscale lengths with FRET (Förster Resonance Energy Transfer), the interaction between Aβ peptides and glycoprotein B (responsible of virus-cell binding) within the HSV-1 virion Results: The experiments show an energy transfer between Aβ peptides and glycoprotein B when membrane is intact. No energy transfer occurs after membrane disruption or treatment with blocking antibody. Conclusion: We concluded that Aβ insert into viral membrane, close to glycoprotein B, and participate in virus neutralization. Show more

Keywords: Alzheimer’s disease, amyloid-beta, FRET, HSV-1, glycoprotein B, interaction

DOI: 10.3233/ADR-220061

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 599-606, 2022

Authors: Durrani, Romella | Badhwar, Amanpreet | Bhangu, Jaspreet | Ganesh, Aravind | Black, Sandra E. | Barber, Philip A. | Frayne, Richard | Field, Thalia S. | Hachinski, Vladimir | Sahlas, Demetrios | Mai, Lauren M. | Sharma, Mukul | Swartz, Richard H. | Smith, Eric E.

Article Type: Research Article

Abstract: Background: Cognitive reserve may protect against the effects of brain pathology, but few studies have looked at whether cognitive reserve modifies the adverse effects of vascular brain pathology. Objective: We determined if cognitive reserve attenuates the associations of vascular brain lesions with worse cognition in persons with subjective concerns or mild impairment. Methods: We analyzed 200 participants aged 50–90 years from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. Cognition was measured using the Montreal Cognitive Assessment and a neuropsychological test battery. High vascular lesion burden was defined as two or more supratentorial infarcts or …beginning confluent or confluent white matter hyperintensity. Cognitive reserve proxies included education, occupational attainment, marital status, social activities, physical activity, household income, and multilingualism. Results: Mean age was 72.8 years and 48% were female; 73.5% had mild cognitive impairment and 26.5% had subjective concerns. Professional/managerial occupations, annual household income≥$60,000 per year, not being married/common law, and high physical activity were independently associated with higher cognition. Higher vascular lesion burden was associated with lower executive function, but the association was not modified by cognitive reserve. Conclusion: Markers of cognitive reserve are associated with higher cognition. Vascular lesion burden is associated with lower executive function. However, cognitive reserve does not mitigate the effects of vascular lesion burden on executive function. Public health efforts should focus on preventing vascular brain injury as well as promoting lifestyle factors related to cognitive reserve, as cognitive reserve alone may not mitigate the effects of vascular brain injury. Show more

Keywords: Brain vascular disorders, cerebral small vessel disease, cerebrovascular disease, cognitive dysfunction, cognitive reserve, infarct, white matter disease

DOI: 10.3233/ADR-220054

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 607-616, 2022

Authors: Platen, Moritz | Hoffmann, Wolfgang | Rädke, Anika | Scharf, Annelie | Mohr, Wiebke | Mühlichen, Franka | Michalowsky, Bernhard

Article Type: Research Article

Abstract: Background: Collaborative care models for people living with dementia (PwD) have been developed and evaluated, demonstrating safety, efficacy, and cost-effectiveness. However, these studies are based on heterogeneous study populations and primary care settings, limiting the generalizability of the results. Therefore, this study aims to implement and evaluate collaborative care across various healthcare settings and patient populations. Objective: To describe the study design of this multicenter implementation trial. Methods: This single-arm, multicenter, longitudinal implementation study will be conducted in five different healthcare settings, including 1) physicians’ networks, 2) dementia networks, 3) counselling centers, 4) hospitals, and 5) …ambulatory care services. Eligibility criteria are: having a formal dementia diagnosis or having been screened positive for dementia and living community-dwelling. The staff of each healthcare setting identifies patients, informs them about the study, and invites them to participate. Participants will receive a baseline assessment followed by collaborative individualized dementia care management, comprising proven safe, effective, and cost-effective modules. Over six months, specially-qualified nurses will assess patients’ unmet needs, transfer them to individualized care plans, and address them, cooperating with various healthcare providers. A follow-up assessment is conducted six months after baseline. Approximately 60–100 PwD per setting per year are expected to participate. Differences across settings will be assessed regarding acceptability, demand, implementation success and barriers, efficacy, and cost-effectiveness. Results: We expect that acceptability, demand, implementation success and barriers, efficacy, and cost-effectiveness will vary by patients’ sociodemographic and clinical characteristics and unmet needs in each setting. Conclusion: The results will provide evidence highlighting differences in the implementation of collaborative care in various healthcare settings and demonstrating the settings with the highest need, best conditions for a successful implementation, and highest (cost-)effectiveness, as well as the population group that benefits most from collaborative care. Trial registration: German Clinical Trials Register: DRKS00025074. Registered 16 April 2021-retrospectively registered. Show more

Keywords: Alzheimer’s disease, collaborative care, dementia, dementia care management, healthcare settings, implementation

DOI: 10.3233/ADR-220045

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 617-626, 2022

Authors: Singh, Baljinder | Lavezo, Jonathan | Gavito-Higueroa, Jose | Ahmed, Faiza | Narasimhan, Sathya | Brar, Simrandeep | Cruz-Flores, Salvador | Kraus, Jacqueline

Article Type: Review Article

Abstract: Cerebral amyloid angiopathy (CAA) is a common untreatable cause of lobar hemorrhages and cognitive decline in the older population. Subset of patients present with its inflammatory subtype with rapid decline in cognitive functions and neurological deficits. Most commonly the underlying pathophysiology of this disease is deposition of insoluble amyloid protein into blood vessel walls which results in vessel fragility leading to local neurotoxicity which may eventually leads to lobar hemorrhages and cognitive decline. The term “Amyloid Spell” encompasses transient focal neurological deficits which is commonly misdiagnosed as seizures or transient ischemic attack in the emergency department. Radiologic findings in these …patients may reveal microbleeds, cortical superficial siderosis, white matter hyperintensities, and cerebral edema which support the clinical diagnosis which could be otherwise challenging. CAA diagnostic criteria require CT (Edinburgh Criteria) or MRI imaging, or neuropathology. The diagnosis can be suspected without imaging or neuropathology but cannot be confirmed. This review article provides a critical outlook on different types of presentations, updated diagnostic criteria and management of CAA patients illustrating underlying mechanisms associated with neuronal injury secondary to amyloid deposition. Show more

Keywords: Amyloid beta-related angiitis, amyloid spells, cerebral amyloid angiopathy, cerebral amyloid angiopathy-related inflammation, transient focal neurologic deficits

DOI: 10.3233/ADR-220055

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 627-639, 2022

Authors: Michalowsky, Bernhard | Platen, Moritz | Bohlken, Jens | Kostev, Karel

Article Type: Research Article

Abstract: Background: Previous studies revealed that low-value medication (LvM), drugs that provide little or no benefit but have the potential to cause harm, are associated with hospitalizations in dementia. Recommended medications, referred to as high-value medication (HvM), can be used alternately. However, the effect of LvM and HvM on hospitalizations is uncertain. Objective: To determine the prevalence of LvM and HvM in hospitalized and non-hospitalized patients living with dementia (PwD) and the odds for hospital referrals in PwD receiving LvM or HvM. Methods: The analysis was based on 47,446 PwD who visited a general practitioner practice between …2017 and 2019. Different guidelines were used to elicit LvM and HvM, resulting in 185 LvM and HvM related recommendations. Of these, 117 recommendations (83 for LvM, 34 for HvM) were categorized into thirteen therapy classes. The association of hospital referrals issued by general practitioners and receiving LvM or HvM was assessed using multiple logistic regression models. Results: 20.4% of PWD received LvM. Most frequently prescribed LvM were non-recommended sedatives and hypnotics, analgesics, and antidepressants. Recommended HvM were 3.4 (69.9%) more frequently prescribed than LvM. Most commonly prescribed HvM were recommended antihypertensives, antiplatelet agents, and antiarrhythmics. Both receiving LvM and receiving HvM were associated with higher odds for hospital referrals. When receiving LvM were compared to HvM, no significant differences could be found in hospital referrals. Conclusion: LvM is highly prevalent but did not cause more likely hospital referrals than HvM. Further research should focus on acute hospitalizations, not only on planned hospital referrals. Show more

Keywords: Alzheimer’s disease, health-related quality of life, hospitalization, low-value care, patient-centered outcomes

DOI: 10.3233/ADR-220004

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 641-650, 2022

Authors: Kim, Eun-Joo | Na, Duk L. | Kim, Hee-Jin | Park, Kyung Won | Lee, Jae-Hong | Roh, Jee Hoon | Kwon, Jay C. | Yoon, Soo Jin | Jung, Na-Yeon | Jeong, Jee Hyang | Jang, Jae-Won | Kim, Hee-Jin | Park, Kee Hyung | Choi, Seong Hye | Kim, SangYun | Park, Young Ho | Kim, Byeong C. | Youn, Young Chul | Ki, Chang-Seok | Kim, Seung Hyun | Seo, Sang Won | Kim, Young-Eun

Article Type: Research Article

Abstract: Background: Frontotemporal dementia (FTD) syndrome is a genetically heterogeneous group of diseases. Pathogenic variants in the chromosome 9 open reading frame 72 (C9orf72 ), microtubule-associated protein tau (MAPT ), and progranulin (GRN ) genes are mainly associated with genetic FTD in Caucasian populations. Objective: To understand the genetic background of Korean patients with FTD syndrome. Methods: We searched for pathogenic variants of 52 genes related to FTD, amyotrophic lateral sclerosis, familial Alzheimer’s disease, and other dementias, and hexanucleotide repeats of the C9orf72 gene in 72 Korean patients with FTD using whole exome sequencing and the …repeat-primed polymerase chain reaction, respectively. Results: One likely pathogenic variant, p.G706R of MAPT , in a patient with behavioral variant FTD (bvFTD) and 13 variants of uncertain significance (VUSs) in nine patients with FTD were identified. Of these VUSs, M232R of the PRNP gene, whose role in pathogenicity is controversial, was also found in two patients with bvFTD. Conclusions: These results indicate that known pathogenic variants of the three main FTD genes (MAPT , GRN , and C9orf72 ) in Western countries are rare in Korean FTD patients. Show more

Keywords: Frontotemporal dementia, MAPT, next-generation sequencing, PRNP

DOI: 10.3233/ADR-220030

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 651-662, 2022

Authors: Taslima, Ferdous | Abdelhamid, Mona | Zhou, Chunyu | Chen, Yuxin | Jung, Cha-Gyun | Michikawa, Makoto

Article Type: Research Article

Abstract: Background: Tooth loss is closely associated with Alzheimer’s disease (AD). Previously, we reported that tooth loss induced memory impairment in amyloid precursor protein knock-in mice by decreasing neuronal activity and synaptic protein levels and increasing glial activation, neuroinflammation, and pyramidal neuronal cell loss without altering amyloid-β levels in the hippocampus. However, the effects of tooth loss in young wild-type mice have not been explored yet. Objective: We investigated the effects of tooth loss on memory impairment, neuronal activity, synaptic protein levels, glial activation, and pyramidal neuronal cell loss in young wild-type mice. Methods: Two-month-old wild-type mice …were randomly divided into control and tooth loss groups. In the tooth loss group, maxillary molar teeth on both sides were extracted, whereas no teeth were extracted in the control group. Two months after tooth extraction, we performed a novel object recognition test to evaluate memory function. Glial activation, neuronal activity, synaptic protein levels, and the number of pyramidal neurons were evaluated using immunofluorescence staining, immunohistochemistry, and western blotting. Results: The tooth loss group exhibited memory impairment and decreased neuronal activity and the levels of synaptic proteins in both the hippocampus and cortex. Moreover, tooth loss increased the activation of phosphorylated c-Jun N-terminal kinase (JNK), heat shock protein 90 (HSP90), and glial activation and reduced the number of pyramidal neurons in the hippocampus. Conclusion: Tooth loss in the young wild-type mice will attenuate neuronal activity, decrease synaptic protein levels, and induce pyramidal neuronal loss, and eventually lead to memory impairment. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, glial activation, neuronal cell loss, tooth loss, wild-type mice

DOI: 10.3233/ADR-220053

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 663-675, 2022

Authors: Vallés-Saiz, Laura | Ruiz-Gabarre, Daniel | García-Escudero, Vega | Perry, George | Avila, Jesús | Hernández, Félix

Article Type: Research Article

Abstract: Background: An increase in tau protein is believed to be necessary for tau aggregation. However, whether this is due to increased expression of the endogenous tau promoter or protein accumulation due to proteostasis failure remains uncertain. Objective: To analyze the expression of GFP protein under endogenous tau promoter across different ages and within different brain areas. Methods: We have measured direct expression of Mapt gene promotor by western blot and immunofluorescence, by means of a commercial tau knock-out mice generated by integrating GFP-encoding cDNA into exon 1 of the Mapt gene. Besides, we have …analyzed the MAPT gene expression in human samples. Results: Mapt expression is similar in the cortex, hippocampus, and cerebellum in mice and in human samples although some differences exist between dentate gyrus and CA1 hippocampal areas in mice. Besides, we have analyzed the murine Mapt gene expression during aging (at 2, 6, 12, and 18 moths) and no differences in endogenous tau promoter expression were observed. Conclusion: Our results suggest that Mapt promoter activity is similar in the brain areas studied and, therefore, tau accumulation due to aging is likely due to proteostasis failure rather than occurring at the transcriptional level. Show more

Keywords: Aging, neurodegeneration, promotor expression, tau

DOI: 10.3233/ADR-220051

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 677-684, 2022

Authors: See, Yi Na | Khor, Pee Fen | Koh, Hui Ying | Leung, Phuong | Del-Pino-Casado, Rafael | Orgeta, Vasiliki

Article Type: Systematic Review

Abstract: Background: Anger is commonly experienced by family caregivers of people living with dementia yet its effect on caregivers’ physical health remains unknown. Objective: The primary aim of this study was to systematically review current evidence on the effects of anger and hostility on caregivers’ physical health. Methods: We searched Medline, EMBASE, PubMed, and PsycINFO up to January 2022. Two review authors independently extracted data on study characteristics, study quality, and effect sizes of associations of anger and hostility with caregiver health outcomes. Results: We found eight studies examining the effects of anger and hostility …on caregivers’ physical health reporting on a total of 937 participants, of which four were cross-sectional and four were longitudinal. Overall findings indicated that higher levels of anger and hostility exerted a negative effect on caregivers’ physical health. Higher anger control was longitudinally associated with increased weight gain (β = 1.13, p  < 0.001), whereas higher anger out predicted higher glucose dysregulation at long-term follow-up (r  = 0.27, p  < 0.05). Higher levels of caregiver hostility were associated with increased risk of chronic low-grade inflammation long-term (r  = 0.18, p  < 0.05), and increased risk of cognitive decline over time (r  = –0.16, p  < 0.05). Conclusion: Our review provides the first systematic synthesis of the evidence demonstrating the harmful effects of anger and hostility on dementia caregivers’ health and highlights the need for preventative interventions to support family caregivers experiencing high levels of anger. Show more

Keywords: Anger, dementia caregivers, disease, hostility, physical health

DOI: 10.3233/ADR-220040

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 685-698, 2022

Authors: Kandiah, Nagaendran | Choi, Seong Hye | Hu, Chaur-Jong | Ishii, Kenji | Kasuga, Kensaku | Mok, Vincent C.T.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) poses a substantial healthcare burden in the rapidly aging Asian population. Early diagnosis of AD, by means of biomarkers, can lead to interventions that might alter the course of the disease. The amyloid, tau, and neurodegeneration (AT[N]) framework, which classifies biomarkers by their core pathophysiological features, is a biomarker measure of amyloid plaques and neurofibrillary tangles. Our current AD biomarker armamentarium, comprising neuroimaging biomarkers and cerebrospinal fluid biomarkers, while clinically useful, may be invasive and expensive and hence not readily available to patients. Several studies have also investigated the use of blood-based measures of established core markers …for detection of AD, such as amyloid-β and phosphorylated tau. Furthermore, novel non-invasive peripheral biomarkers and digital biomarkers could potentially expand access to early AD diagnosis to patients in Asia. Despite the multiplicity of established and potential biomarkers in AD, a regional framework for their optimal use to guide early AD diagnosis remains lacking. A group of experts from five regions in Asia gathered at a meeting in March 2021 to review the current evidence on biomarkers in AD diagnosis and discuss best practice around their use, with the goal of developing practical guidance that can be implemented easily by clinicians in Asia to support the early diagnosis of AD. This article summarizes recent key evidence on AD biomarkers and consolidates the experts’ insights into the current and future use of these biomarkers for the screening and early diagnosis of AD in Asia. Show more

Keywords: Alzheimer’s disease, Asia, AT(N), biomarkers, dementia, early diagnosis

DOI: 10.3233/ADR-220059

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 699-710, 2022

Authors: Weigert, Hannah | Stuckenschneider, Tim | Pickert, Lena | Rossi, Andrea | Meyer, Anna M. | Nelles, Gereon | Schulz, Ralf-Joachim | Stahl, Wilhelm | Schneider, Stefan | Polidori, M. Cristina

Article Type: Research Article

Abstract: Background: Preventive lifestyle strategies have shown promise to slow down or prevent age-related cognitive decline. However, evidence on the reciprocal longitudinal relationships between nutrition biomarkers and cognitive and physical performance is lacking. Studying nutritional, cognitive, and physical profiles over time may help to overcome this knowledge gap. Objective: To investigate the relationship of plasma levels of the robust nutritional- and antioxidant defense-related biomarkers carotenoids and tocopherols with both indicators of cognitive and physical performance in persons with mild cognitive impairment (MCI) participating in a structured exercise program. Methods: Data from 40 participants with MCI of the …NeuroExercise study were analyzed. Participants had undergone a blood withdrawal for the analysis of plasma concentrations of six carotenoids, two tocopherols and retinol prior to and after one-year of structured exercise. All participants had undergone a broad spectrum of cognitive and physical performance tests. Results: Significant associations between lipophilic micronutrients and cognitive/physical measures were observed that were previously found to play a role in cognitive and physical frailty. In particular, lutein, zeaxanthin, and lycopene are confirmed as robust, reliable, and stable indicators of nutritional defense. Importantly, these micronutrients were associated with cognitive measures prior to the physical training program and to a more prominent extent with indicators of motoric function after the physical exercise program. Conclusion: Specific profiles of lipophilic micronutrients are associated to cognitive performance measures and, especially after a structured exercise program, to indicators of physical performance. Show more

Keywords: Carotenoids, cognitive performance, micronutrients, mild cognitive impairment, neuropsychological tests, nutrition, physical activity

DOI: 10.3233/ADR-220039

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 711-722, 2022

Authors: Velázquez, Esther | Le Baut Ayuso, Yannick | Blázquez, Enrique | Ruiz-Albusac, Juan Miguel

Article Type: Research Article

Abstract: Background: Glucagon-like peptide-2 (GLP-2) is an intestinal trophic factor that induces astrocyte proliferation through its own receptor (GLP-2R), but the control of its expression is not well known. Objective: To study the effects of glucose and of different mitogenic agents on the control of GLP-2R expression in cultured rat astrocytes. Methods: GLP-2R mRNA content was measured by quantitative RT-PCR. Results: GLP-2R expression was higher in proliferating than in resting cells. The expression was dependent of glucose concentration both in the absence and in the presence of GLP-2. In the presence of a high glucose …concentration, GLP-2, PDGF, and PDGF plus GLP-2 presented opposite effects depending on the incubation time. However, insulin, IGF-1, and EGF alone, and plus GLP-2 had no effect. IGF-2, but not IGF-2 plus GLP-2, increased the expression. On the contrary, NGF decreased the GLP-2R expression, but NGF plus GLP-2 increased it even until values similar to those obtained with GLP-2 alone. Interestingly, in the presence of a low glucose concentration, leptin and NPY produced a significant reduction of GLP-2R expression. Conclusion: Astrocytes are distributed throughout the brain, where GLP-2 appears to have important functions. Since these cells express the GLP-2R, the results of this study could be considered of interest to advance the knowledge of the role of GLP-2 signaling in the CNS, which should lead a better understanding of the events that occur under normal and pathophysiological conditions. Show more

Keywords: Astrocytes, GLP-2, GLP-2 receptor, glucose, growth factors, insulin, leptin, NPY

DOI: 10.3233/ADR-220043

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 723-732, 2022

Authors: Arthur, Paul | Li, Chih-Ying

Article Type: Short Communication

Abstract: Persons living with dementia and their caregivers are among society’s most vulnerable, a condition exacerbated by the COVID-19 pandemic. This national survey was conducted with dementia caregivers in the US. Primary outcomes targeted pandemic-related changes in cognitive, behavioral, and motors systems. 113 dementia caregivers from 30 US states completed the survey. The impact of the COVID-19 pandemic on persons living with dementia and their caregivers is substantial in comparison to society at large. A marked public health and preventative role signals opportunity for practitioners to fill the void and prepare for future public health emergencies.

Keywords: Alzheimer’s disease, behaviors, caregiving, COVID-19, dementia, neuropsychiatric symptoms, pandemic, public health emergency

DOI: 10.3233/ADR-220085

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 733-737, 2022

Authors: Santiago-Mujika, Estibaliz | Luthi-Carter, Ruth | Giorgini, Flaviano | Mukaetova-Ladinska, Elizabeta B.

Article Type: Research Article

Abstract: Background: Vascular dementia (VaD) and Alzheimer’s disease (AD) are the two most common forms of dementia. Although these two types of dementia have different etiologies, they share some similarities in their pathophysiology, such as neuronal loss and decreased levels of tau protein. We hypothesize that these can have an impact upon the molecular changes in tubulin, precede the neuronal cell loss, and lead to changes in cytoskeletal associated proteins, as documented in both VaD and AD. Objective: We characterized different isotypes of tubulin together with their posttranslational modifications, as well as several microtubule associated proteins (MAPs), such as …tau protein, MAP2 and MAP6, all together known as the tubulin code. Methods: We performed western blotting in human brain homogenates of controls and AD and VaD subjects. Results: We report that the levels of different tubulin isotypes differ depending on the dementia type and the brain area being studied: whereas α-tubulin is increased in the temporal lobe of VaD patients, it is decreased in the frontal lobe of AD patients. In VaD patients, the frontal lobe had a decrease in tyrosinated tubulin, which was accompanied by a decrease in tau protein and a tendency for lower levels of MAP2. Conclusion: Our findings highlight distinct changes in the tubulin code in VaD and AD, suggesting a therapeutic opportunity for different dementia subtypes in the future. Show more

Keywords: Alzheimer’s disease, human brain samples, posttranslational modifications, tubulin, vascular dementia

DOI: 10.3233/ADR-220068

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 739-748, 2022

Authors: Mozdbar, Sima | Petersen, Melissa | Zhang, Fan | Johnson, Leigh | Tolman, Alex | Nyalakonda, Ramyashree | Gutierrez, Alejandra | O’Bryant, Sid

Article Type: Research Article

Abstract: Background: Despite the diagnostic accuracy of advanced neurodiagnostic procedures, the detection of Alzheimer’s disease (AD) remains poor in primary care. There is an urgent need for screening tools to aid in the detection of early AD. Objective: This study examines the predictive ability of structural retinal biomarkers in detecting cognitive impairment in a primary care setting. Methods: Participants were recruited from Alzheimer’s Disease in Primary Care (ADPC) study. As part of the ADPC Retinal Biomarker Study (ADPC RBS), visual acuity, an ocular history questionnaire, eye pressure, optical coherence tomography (OCT) imaging, and fundus …imaging was performed. Results: Data were examined on n  = 91 participants. The top biomarkers for predicting cognitive impairment included the inferior quadrant of the outer retinal layers, all four quadrants of the peripapillary retinal nerve fiber layer, and the inferior quadrant of the macular retinal nerve fiber layer. Conclusion: The current data provides strong support for continued investigation into structural retinal biomarkers, particularly the retinal nerve fiber layer, as screening tools for AD. Show more

Keywords: Alzheimer’s disease, cognitive impairment, optical coherence tomography, retinal biomarkers

DOI: 10.3233/ADR-220070

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 749-755, 2022

Authors: Kanagasingam, Shalini | von Ruhland, Christopher | Welbury, Richard | Singhrao, Sim K.

Article Type: Research Article

Abstract: Background: Oral infection has been implicated in the possible etiology of Alzheimer’s disease. Objective: To detect amyloid-β (Aβ) within microbial biofilms. Methods: Freshly extracted teeth (N  = 87) with periodontal disease were separated into Group A (N  = 11), with primary root canal infection and Group B (N  = 21) with failed endodontic treatment identified by the presence of, gutta percha root filling. Biofilm characteristics were observed by scanning electron microscopy (SEM). Demineralized paraffin wax embedded tooth sections and mineralized calculus biofilm were immunostained with the anti-Aβ antibody. The gutta perchas were processed either for on-section acrylic resin tissue …immunocolloidal gold silver staining (IGSS) using the anti-Aβ antibody or in Araldite resin for ultrastructure. Results: SEM demonstrated calculus and gutta percha in situ harboring a polymicrobial biofilm featuring extracellular polymeric substance (EPS) and water channels. Immunohistochemistry on rehydrated paraffin wax tooth sections from Group A, demonstrated Aβ staining on external (calculus and plaque) and all intracanal infected regions. In Group B, the gutta percha biofilm IGSS gave an inconclusive result for Aβ. Transmission electron microscopy of selected teeth with infected intra-canals (Group A) and 20% of gutta percha biofilm (Group B) EPS contained electron dense fibrils of variable sizes, some of which were typical of human Aβ fibrils. Conclusion: This study detected both soluble and insoluble Aβ fibrils within the EPS of periodontal and endodontic natural biofilm, strongly suggesting its role as an antimicrobial peptide in combatting local infection, with potential risk for cross-seeding into the brain for AD development. Show more

Keywords: Amyloid-β fibrils, biofilm, extracellular polymeric substance, periodontal bacteria, root canal

DOI: 10.3233/ADR-220076

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 757-773, 2022

Authors: El Haj, Mohamad | Boudoukha, Abdel Halim | Moustafa, Ahmed A. | Gallouj, Karim | Altintas, Emin

Article Type: Research Article

Abstract: Background: Within the concept of the self, a distinction can be made between ideal self (i.e., what would like to become) and feared self (i.e., what would not like to become in the future). Objective: We investigated ideal self and feared self in patients with mild Alzheimer’s disease (AD). We have also measured these self-related processes in relation to depression and anxiety. Methods: We invited 31 patients with mild AD and 35 control participants to decide whether they would consider the statement (e.g., I will be healthy) as a representation that they would like to acquire …(i.e., ideal self) or to avoid (i.e., feared self). Results: Analysis demonstrated that more participants assigned the “I will be healthy” statement to ideal self than to feared self, and this tendency was observed in both AD participants and controls. Less depression and anxiety were observed in participants who have assigned the “I will be healthy” statement to their ideal self compared to those who assigned this statement to their feared self, and this was observed in both AD participant and control groups. Conclusion: Our study demonstrates that AD patients tend to endorse positive health traits and to integrate these traits into their ideal self. AD patients tend to endorse health-related images that are associated with hopes when projecting into their future self. This positive projection into the self may create a motivational force (e.g., aspirations and hopes) to embody the “healthy” self that AD patients desire to be. Show more

Keywords: Alzheimer’s disease, feared self, health, ideal self, self

DOI: 10.3233/ADR-220041

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 775-781, 2022