Journal of Alzheimer's Disease Reports - Volume 5, issue 1

Authors: Wang, Ge | Li, Wei

Article Type: Research Article

Abstract: Background: It is inconclusive on how sex affects the risk of developing mild cognitive impairment (MCI) or dementia. Objective: To investigate how sex affects the risk of developing MCI or dementia. Methods: A secondary data analysis was performed on data collected from participants enrolled at Alzheimer’s Disease Research Centers funded by National Institute on Aging. There were two inclusion criteria: 1) participants were free of dementia at the baseline visit; 2) every participant must have at least one follow-up visit. A Cox proportional hazards model was used to investigate how sex affects the risk of developing …cognitive impairments. Results: During a follow-up period of more than 10 years, male participants had a slightly higher incidence than female participants for either MCI or dementia. Not surprisingly, a higher prevalence was observed in male than female participants for either MCI or dementia. However, male participants had a higher mortality rate than their female counterparts. Conclusion: The male sex is associated with a higher risk for developing cognitive impairments along the aging process. Show more

Keywords: Dementia, incidence, mild cognitive impairment, prevalence, sex

DOI: 10.3233/ADR-200275

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 1-6, 2021

Authors: Shin, Jisu | Yang, Seung-Hoon | Du, Young Eun | Park, Keunwan | Kim, DaWon | Shin, Daniel | Kim, Jungwoo | Kim, Seong-Hwan | Kim, Yun Kyung | Shin, Jongheon | Oh, Dong-Chan | Kim, YoungSoo

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by the aggregation of two pathological proteins, amyloid-β (Aβ) and tau, leading to neuronal and cognitive dysfunction. Clearance of either Aβ or tau aggregates by immunotherapy has become a potential therapy, as these aggregates are found in the brain ahead of the symptom onset. Given that Aβ and tau independently and cooperatively play critical roles in AD development, AD treatments might require therapeutic approaches to eliminate both aggregates together. Objective: We aimed to discover a chemical drug candidate from natural sources for direct dissociation of both insoluble Aβ and tau aggregates through …in vitro assessments. Methods: We isolated four borrelidin chemicals from a saltern-derived halophilic actinomycete strain of rare genus Nocardiopsis and simulated their docking interactions with Aβ fibrils. Then, anti-cytotoxic, anti-Aβ, and anti-tau effects of borrelidins were examined by MTT assays with HT22 hippocampal cell line, thioflavin T assays, and gel electrophoresis. Results: When HT22 cells were exposed to Aβ aggregates, the treatment of borrelidins alleviates the Aβ-induced toxicity. These anti-cytotoxic effects can be derived from the inhibitory functions of borrelidins against the Aβ aggregation as shown in thioflavin T and gel electrophoretic analyses. Among them, especially borrelidin, which exhibits the highest probability of docking, not only dissociates Aβ aggregates but also directly regulates tau aggregation. Conclusion: Borrelidin dissociates insoluble Aβ and tau aggregates together and our findings support the view that it is possible to develop an alternative chemical approach mimicking anti-Aβ or anti-tau immunotherapy for clearance of both aggregates. Show more

Keywords: Alzheimer’s disease, amyloid-β, borrelidin, natural products, tau

DOI: 10.3233/ADR-200247

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 7-13, 2021

Authors: Chávez-Fumagalli, Miguel A. | Shrivastava, Pallavi | Aguilar-Pineda, Jorge A. | Nieto-Montesinos, Rita | Del-Carpio, Gonzalo Davila | Peralta-Mestas, Antero | Caracela-Zeballos, Claudia | Valdez-Lazo, Guillermo | Fernandez-Macedo, Victor | Pino-Figueroa, Alejandro | Vera-Lopez, Karin J. | Lino Cardenas, Christian L.

Article Type: Research Article

Abstract: Background: The present systematic review and meta-analysis of diagnostic test accuracy summarizes the last three decades in advances on diagnosis of Alzheimer’s disease (AD) in developed and developing countries. Objective: To determine the accuracy of biomarkers in diagnostic tools in AD, for example, cerebrospinal fluid, positron emission tomography (PET), and magnetic resonance imaging (MRI), etc. Methods: The authors searched PubMed for published studies from 1990 to April 2020 on AD diagnostic biomarkers. 84 published studies were pooled and analyzed in this meta-analysis and diagnostic accuracy was compared by summary receiver operating characteristic statistics. Results: …Overall, 84 studies met the criteria and were included in a meta-analysis. For EEG, the sensitivity ranged from 67 to 98%, with a median of 80%, 95% CI [75, 91], tau-PET diagnosis sensitivity ranged from 76 to 97%, with a median of 94%, 95% CI [76, 97]; and MRI sensitivity ranged from 41 to 99%, with a median of 84%, 95% CI [81, 87]. Our results showed that tau-PET diagnosis had higher performance as compared to other diagnostic methods in this meta-analysis. Conclusion: Our findings showed an important discrepancy in diagnostic data for AD between developed and developing countries, which can impact global prevalence estimation and management of AD. Also, our analysis found a better performance for the tau-PET diagnostic over other methods to diagnose AD patients, but the expense of tau-PET scan seems to be the limiting factor in the diagnosis of AD in developing countries such as those found in Asia, Africa, and Latin America. Show more

Keywords: Alzheimer’s disease, diagnosis, meta-analysis, systematic review

DOI: 10.3233/ADR-200263

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 15-30, 2021

Authors: Stites, Shana D. | Largent, Emily A. | Johnson, Rebecca | Harkins, Kristin | Karlawish, Jason

Article Type: Research Article

Abstract: Background: As a result of caring for a person with dementia, caregivers of persons with Alzheimer’s disease (AD) may be uniquely aware of public stigma for persons with AD. Objective: The purpose of this study was to compare self-identified caregivers and non-caregivers’ expectations of public stigma experienced by persons living with dementia. Methods: Analysis of data from a survey of 910 adults (median age = 49 years) who read a vignette about a man with mild stage dementia. Multivariable ordered logistic regression was used to examine how AD caregiver status associated with responses on a modified Family …Stigma in Alzheimer’s Disease Scale (FS-ADS). Results: 9%(n  = 82) of respondents self-identified as a current or former primary caregiver of a person with AD, about the same as the national estimate of informal caregivers (8.8%). Compared to non-caregivers, AD caregivers were more likely to report stronger reactions on all seven domains of the FS-ADS (all p  <  0.05). As compared to AD caregivers with less factual knowledge about caregiving, AD caregivers with more knowledge expected the person with dementia to experience less social distance (p  <  0.05). In addition, female AD caregivers reported fewer negative aesthetic attributions than male AD caregivers (p  <  0.05). Conclusion: Compared to non-caregivers, respondents who self-identified as an AD caregiver gave responses that suggest they perceived more stigma of dementia among members of the public. Their reactions were attenuated by AD knowledge and being female. The findings have key implications for interventions to reduce AD stigma. Show more

Keywords: Alzheimer’s disease, caregivers, public survey, stigma

DOI: 10.3233/ADR-200206

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 31-39, 2021

Authors: Andrews, Murray | Ross, Ryan | Malhotra, Atul | Ancoli-Israel, Sonia | Brewer, James B. | Banks, Sarah J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The increasing prevalence of Alzheimer’s disease (AD) and lack of effective medications has led to a need to identify modifiable risk factors as targets for interventions. Objective: In this cross-sectional study, we sought to determine whether worse sleep quality is associated with increased pathological tau, and whether this relationship is affected by amyloid pathology. Methods: 66 male participants underwent Florbetapir (AV45) positron emission tomography (PET) and Flortaucipir (FTP) PET and completed the Pittsburgh Sleep Quality Index questionnaire (PSQI) as part of the Department of Defense Alzheimer’s Disease Neuroimaging Initiative, a multicenter study collecting data from …Vietnam War veterans, some of whom have a history of post-traumatic stress disorder, or non-penetrating traumatic brain injury. AV45 PET was used to determine the presence of significant amyloid pathology. We used regression models to determine the effects of amyloid pathology and PSQI on tau deposition in brain regions associated with Braak stages. Results: Among the 66 participants, 14 individuals were amyloid positive (21%) and 52 were amyloid negative (79%). In regions associated with Braak stages III-IV, there was a significant interaction of amyloid status on PSQI (β= 0.04, p  = 0.003) with higher PSQI correlating with higher FTP SUVr in amyloid-positive individuals only (β= 0.031, p  = 0.005). Conclusion: Our study found that an AD profile of tau deposition was associated with an interaction between self-reported sleep quality and amyloid pathology such that worse self-reported sleep was related to higher tau in regions usually associated with AD progression, but only in individuals with high cerebral amyloid deposition. Show more

Keywords: Amyloid, mild cognitive impairment, positron emission tomography, preclinical AD, sleep, tau

DOI: 10.3233/ADR-200245

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 41-48, 2021

Authors: Lehrer, Steven | Rheinstein, Peter H.

Article Type: Research Article

Abstract: Background: Cognitive problems are common in breast cancer patients. The apolipoprotein E4 (APOE4 ) gene, a risk factor for Alzheimer’s disease (AD), may be associated with cancer-related cognitive decline. Objective: To further evaluate the effects of the APOE4 allele, we studied a cohort of patients from the UK Biobank (UKB) who had breast cancer; some also had AD. Methods: Our analysis included all subjects with invasive breast cancer. Single nucleotide polymorphism (SNP) data for rs 429358 and rs 7412 was used to determine APOE genotypes. Cognitive function as numeric memory was assessed with an …online test (UKB data field 20240). Results: We analyzed data from 2,876 women with breast cancer. Of the breast cancer subjects, 585 (20%) carried the APOE4 allele. Numeric memory scores were significantly lower in APOE4 carriers and APOE4 homozygotes than non-carriers (p  = 0.046). 34 breast cancer subjects (1.1%) had AD. There was no significant difference in survival among genotypes ɛ 3/ɛ 3, ɛ 3/ɛ 4, and ɛ 4/ɛ 4. Conclusion: UKB data suggest that cognitive problems in women with breast cancer are, for the most part, mild, compared with other sequelae of the disease. AD, the worst cognitive problem, is relatively rare (1.1%) and, when it occurs, APOE genotype has little impact on survival. Show more

Keywords: APOE , chemobrain, dementia, heterozygote

DOI: 10.3233/ADR-200266

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 49-53, 2021

Authors: Falck, Ryan S. | Crockett, Rachel A. | Davis, Jennifer C. | Khan, Karim M. | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: Poor sleep is common among older adults at risk for dementia and may be due to circadian dysregulation. Light is the most important external stimulus to the circadian clock and bright light therapy (BLT) has been used for >20 years to help realign circadian rhythms. However, the ability of field methods (e.g., actigraphy) to accurately determine the type and intensity of light is unknown. Objective: We examined the ability of the MotionWatch8 (MW8) light sensor to determine: 1) light versus dark, 2) electrical light versus daylight, and 3) device-based BLT versus light which was not BLT. …Methods: We tested the MW8 under 17 daily light scenarios. Light exposure data was collected for 5 minutes during each scenario. Concurrently, we measured light exposure using the LT40 Light Meter, a sensitive measure of light intensity. We then developed individual cut-points using receiver operator characteristics analyses to determine optimal MW8 cut-points for 1) light versus dark; 2) electrical light versus daylight; and 3) light from a BLT box versus light which was not BLT. Bland-Altman plots tested the precision of the MW8 compared to the LT40. Results: The MW8 accurately discriminated light versus dark (>32 lux), and electrical light versus daylight (<323 lux). However, the MW8 had poor accuracy for 1) discriminating BLT from light which was not BLT; and 2) low precision compared to the LT40. Conclusion: The MW8 appears to be able to discern light versus dark and electrical light versus daylight; however, there remains a need for accurate field methods capable of measuring light exposure. Show more

Keywords: Actigraphy, light, luxometer, measurement, sleep

DOI: 10.3233/ADR-200242

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 55-63, 2021

Authors: Dake, Manmohi D. | De Marco, Matteo | Blackburn, Daniel J. | Wilkinson, Iain D. | Remes, Anne | Liu, Yawu | Pikkarainen, Maria | Hallikainen, Merja | Soininen, Hilkka | Venneri, Annalena

Article Type: Research Article

Abstract: Background: How the relationship between obesity and MRI-defined neural properties varies across distinct stages of cognitive impairment due to Alzheimer’s disease is unclear. Objective: We used multimodal neuroimaging to clarify this relationship. Methods: Scans were acquired from 47 patients clinically diagnosed with mild Alzheimer’s disease dementia, 68 patients with mild cognitive impairment, and 57 cognitively healthy individuals. Voxel-wise associations were run between maps of gray matter volume, white matter integrity, and cerebral blood flow, and global/visceral obesity. Results: Negative associations were found in cognitively healthy individuals between obesity and white …matter integrity and cerebral blood flow of temporo-parietal regions. In mild cognitive impairment, negative associations emerged in frontal, temporal, and brainstem regions. In mild dementia, a positive association was found between obesity and gray matter volume around the right temporoparietal junction. Conclusion: Obesity might contribute toward neural tissue vulnerability in cognitively healthy individuals and mild cognitive impairment, while a healthy weight in mild Alzheimer’s disease dementia could help preserve brain structure in the presence of age and disease-related weight loss. Show more

Keywords: Alzheimer’s disease, body mass index, neuroimaging, overweight

DOI: 10.3233/ADR-200267

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 65-77, 2021

Authors: Olsen, Ingar

Article Type: Research Article

Abstract: Iron accumulates in the brain of subjects with Alzheimer’s disease (AD). Here it promotes the aggregation of amyloid-β plaques in which it is abundant. Iron induces amyloid-β neurotoxicity by damaging free radicals and causing oxidative stress in brain areas with neurodegeneration. It can also bind to tau in AD and enhance the toxicity of tau through co-localization with neurofibrillary tangles and induce accumulation of these tangles. Porphyromonas gingivalis is a key oral pathogen in the widespread biofilm-induced disease “chronic” periodontitis, and recently, has been suggested to have an important role in the pathogenesis of AD. P. gingivalis has …an obligate requirement for iron. The current paper suggests that P. gingivalis seeks the AD brain, where it has been identified, to satisfy this need. If this is correct, iron chelators binding iron could have beneficial effects in the treatment of AD. Indeed, studies from both animal AD models and humans with AD have indicated that iron chelators, e.g., lactoferrin, can have such effects. Lactoferrin can also inhibit P. gingivalis growth and proteinases and its ability to form biofilm. Show more

Keywords: Biofilm, brain, immunity, iron dysregulation, iron requirement, senescence

DOI: 10.3233/ADR-200272

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 79-86, 2021

Authors: Zenuni, Henri | Grillo, Piergiorgio | Sancesario, Giulia Maria | Bernardini, Sergio | Mercuri, Nicola Biagio | Schirinzi, Tommaso

Article Type: Short Communication

Abstract: Systemic comorbidity precipitates the risk for dementia. To comprehend the underlying mechanisms into a therapeutic perspective, we analyzed how comorbidity affects neurodegeneration-related cerebrospinal fluid (CSF) biomarkers of 55 cognitively intact subjects. The Charson Comorbidity Index (CCI) was correlated with CSF amyloid-β42 (Aβ42 ), amyloid-β40 , total-tau, 181-phosphorylated-tau (p-tau), the Aβ42 /p-tau ratio, neurogranin, and lactate. The age-related brain lesions at imaging were also considered. CCI had a raw association with Aβ42 /p-tau and p-tau, and a stronger, age-independent correlation with lactate. These preliminary findings suggested that, in normal subjects, systemic comorbidity might increase CNS oxidative stress and, together with …aging, contribute to develop an Alzheimer’s disease-like biochemical profile. Show more

Keywords: Cerebrospinal fluid biomarkers, comorbidity, neurodegeneration, neuroprotection, oxidative stress

DOI: 10.3233/ADR-200280

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 87-92, 2021

Authors: Giannouli, Vaitsa | Tsolaki, Magda

Article Type: Short Communication

Abstract: This study aims to explore a little investigated topic, i.e., whether the presence of the APOE eɛ 4 allele in patients with a diagnosis of mild Alzheimer’s disease (AD) can influence financial capacity. Twenty-eight elders with mild AD carrying the APOE ɛ 4 allele and 28 matched non-carrier patients were examined with an extensive battery of neuropsychological tests, and a specific test measuring financial capacity: Legal Capacity for Property Law Transactions Assessment Scale (LCPLTAS). The presence of the APOE ɛ 4 allele does not differentiate the group of mild AD patients regarding a number of cognitive domains …necessary for financial capacity scores as measured by LCPLTAS. Show more

Keywords: APOE ɛ4, financial capacity, mild Alzheimer’s disease

DOI: 10.3233/ADR-200254

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 93-97, 2021

Authors: Moazzami, Kasra | Wittbrodt, Matthew T. | Lima, Bruno B. | Kim, Jeong Hwan | Almuwaqqat, Zakaria | Shah, Amit J. | Hajjar, Ihab | Goldstein, Felicia C. | Levey, Allan I. | Nye, Jonathon A. | Bremner, J. Douglas | Vaccarino, Viola | Quyyumi, Arshed A.

Article Type: Research Article

Abstract: Background: Individuals with coronary artery disease (CAD) have worse executive function compared to the general population but the mechanisms are unknown. Objective: To investigate the role of acute mental stress (MS) on the executive function of patients with CAD. Methods: Participants with stable CAD underwent acute MS testing with simultaneous peripheral vascular function measurements and brain imaging using high resolution-positron emission tomography. Digital pulse wave amplitude was continuously measured using peripheral artery tonometry (PAT, Itamar Inc). Stress/rest PAT ratio (sPAT) of pulse wave amplitude during MS/baseline was calculated as a measure of microvascular constriction during MS. …Plasma levels of catecholamine and interleukin-6 were assessed at baseline and after MS. Executive function was assessed both at baseline and at 2 years follow-up using the Trail Making Test parts A and B. Results: We studied 389 individuals with brain data available for 148 participants. Of this population follow-up cognitive assessments were performed in 226 individuals (121 with brain imaging). After multivariable adjustment for baseline demographics, risk factors, and medication use, a lower sPAT, indicating greater vasoconstriction, a higher inferior frontal lobe activation with MS, and increases in norepinephrine and IL-6 levels with MS were all independently associated with greater time to complete Trail B test.-38.4pt Conclusion: In response to acute MS, greater peripheral vasoconstriction, higher inferior frontal lobe brain activation, and increases in the levels of norepinephrine and IL-6 are associated with worse executive function. Show more

Keywords: Brain activation, cognitive impairment, mental stress, vasoconstriction

DOI: 10.3233/ADR-200287

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 99-109, 2021

Authors: Fernandez, Shane | Burnham, Samantha C. | Milicic, Lidija | Savage, Greg | Maruff, Paul | Peretti, Madeline | Sohrabi, Hamid R. | Lim, Yen Ying | Weinborn, Michael | Ames, David | Masters, Colin L. | Martins, Ralph N. | Rainey-Smith, Stephanie | Rowe, Christopher C. | Salvado, Olivier | Groth, David | Verdile, Giuseppe | Villemagne, Victor L. | Porter, Tenielle | Laws, Simon M.

Article Type: Research Article

Abstract: Abstract. Background: Genetic variation in Spondin-1, specifically rs11023139, has been associated with reduced rates of cognitive decline in individuals with Alzheimer’s disease. Objective: The aim of this study was to assess whether the association was present in cognitively normal older adults. Methods: Longitudinal cognitive decline was investigated using linear mixed modelling in a cohort of 590 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Study. Results: No independent effect of Spondin-1 rs11023139 on cognitive decline was observed. However, significant associations were observed for the interaction between Apolipoprotein E …(APOE) ɛ 4 and rs11023139 in individuals with high amyloid-β burden. APOE ɛ 4/rs11023139-A carriers declined significantly faster than APOE ɛ 4/rs11023139-G_G carriers in measures of global cognition (p  = 0.011) and verbal episodic memory (p  = 0.020). Conclusion: These results suggest that carriage of the Spondin-1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in APOE ɛ 4 cognitively normal older adults with a high neocortical amyloid-β burden. Show more

Keywords: Alzheimer’s disease, amyloid-β, APOE, cognitive decline, SPON1, Spondin-1

DOI: 10.3233/ADR-200246

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 111-120, 2021

Authors: Sheladia, Shyam | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: The emergence of age-related chronic diseases within the United States has led to the direct increase of Alzheimer’s disease (AD) as well as other neurological diseases which ultimately contribute to the development of dementia within the general population. To be specific, age-related chronic diseases such as cardiovascular disease, high cholesterol, diabetes, and kidney disease contribute greatly to the advancement and rapid progression of dementia. Furthermore, unmodifiable risk factors such as advancing age and genetics as well as modifiable risk factors such as socioeconomic status, educational attainment, exercise, and diet further contribute to the development of dementia. Current statistics and research …show that minority populations such as Hispanic Americans in the United States face the greatest burden of dementia due to the increase in the prevalence of overall population age, predisposing genetics, age-related chronic diseases, low socioeconomic status, as well as poor lifestyle choices and habits. Additionally, Hispanic Americans living within Texas and the rural areas of West Texas face the added challenge of finding appropriate healthcare services. This article will focus upon the research associated with AD as well as the prevalence of AD within the Hispanic American population of Texas and rural West Texas. Furthermore, this article will also discuss the prevalence of age-related chronic diseases, unmodifiable risk factors, and modifiable risk factors which lead to the progression and development of AD within the Hispanic American population of the United States, Texas, and rural West Texas. Show more

Keywords: Alzheimer’s disease, chronic diseases, dementia, Hispanic Americans, risk factors, Texas

DOI: 10.3233/ADR-200277

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 121-133, 2021

Authors: Swerdlow, Russell H. | de Leon, Mony J. | Marcus, David L.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) features perturbed brain glucose utilization, which could contribute to brain bioenergetic failure. This led some to consider using ketone bodies to enhance AD brain bioenergetics and treat AD. Objective: We evaluated the rate at which brain homogenates from persons with Alzheimer’s disease (AD) metabolize D-β-hydroxybutyrate (BHB). Methods: We homogenized pieces of temporal cortex from frozen autopsy brains obtained from recently deceased AD subjects (n  = 4), and age-matched subjects that did not have clinical AD (n  = 3). Measuring the rate of CO2 production that followed the introduction of radiolabeled BHB to the homogenates …yielded a BHB utilization rate. Results: Compared to the control homogenates, the BHB-supported CO2 production rate was 66%lower in the AD homogenates (p  < 0.05). Conclusions: AD brains can utilize BHB, albeit less robustly than control brains. In conjunction with a previous study that demonstrated reduced glucose utilization in AD brain homogenates, our BHB data provide further evidence of AD brain mitochondrial dysfunction or altered mitochondrial biology. Show more

Keywords: Alzheimer’s disease, betahydroxybutyrate, ketone body, metabolism, mitochondria

DOI: 10.3233/ADR-210002

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 135-141, 2021

Authors: Pike, Kerryn E. | Moller, Carl I. | Bryant, Christina | Farrow, Maree | Dao, Duy P. | Ellis, Kathryn A.

Article Type: Research Article

Abstract: Memory interventions for older adults with cognitive concerns result in improved memory performance and maintenance of cognitive health. These programs are typically delivered face-to-face, which is resource intensive and creates access barriers, particularly for those with reduced mobility, limited transportation, and living in rural or remote areas. The COVID-19 pandemic has created an additional access barrier, given the increased risk this disease poses to older adults. Internet-based interventions seek to overcome these barriers. This paper describes the protocol of a pilot study that aims to evaluate the feasibility, acceptability, and efficacy of one such internet-based intervention: the Online Personalised Training …in Memory Strategies for Everyday (OPTIMiSE) program. OPTIMiSE focuses on improving knowledge regarding memory and providing training in effective memory strategies for everyday life. The pilot study described in this protocol will be a single-arm pre-post study of 8 weeks duration, with a single maintenance session 3 months post-intervention. Participants will be Australian adults aged ≥60 years reporting cognitive changes compared with 10 years ago. Primary outcome measures will address feasibility, acceptability, and efficacy. Secondary outcome measures assessing sense of community and self-efficacy will be administered at the 8-week and 3-month timepoints. Data collection will conclude mid-2021, and results will be presented in a subsequent publication. Translation of memory interventions to internet-based delivery has the potential to remove many access barriers for older adults; however, the acceptability and feasibility of this modality needs investigation. OPTIMiSE is the initial step in what could be an important program enabling access to an evidence-based memory intervention for older adults worldwide. Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12620000979954 Show more

Keywords: Aged, aging, cognition, learning, internet-based intervention, memory, self efficacy, social support

DOI: 10.3233/ADR-200251

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 143-152, 2021

Authors: Ruiter, Marvin | Lützkendorf, Christine | Liang, Jian | Wierenga, Corette J.

Article Type: Short Communication

Abstract: The amyloid-β protein precursor is highly expressed in a subset of inhibitory neuron in the hippocampus, and inhibitory neurons have been suggested to play an important role in early Alzheimer’s disease plaque load. Here we investigated bouton dynamics in axons of hippocampal interneurons in two independent amyloidosis models. Short-term (24 h) amyloid-β (Aβ)-oligomer application to organotypic hippocampal slices slightly increased inhibitory bouton dynamics, but bouton density and dynamics were unchanged in hippocampus slices of young-adult AppNL  - F  - G -mice, in which Aβ levels are chronically elevated. These results indicate that loss or defective adaptation of inhibitory synapses are not …a major contribution to Aβ-induced hyperexcitability. Show more

Keywords: Amyloidosis models, hyperexcitability, inhibitory synapses, presynaptic boutons, structural plasticity, two-photon imaging

DOI: 10.3233/ADR-200291

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 153-160, 2021

Authors: Limoncu, Hatice | Boz, Hatice Eraslan | Zygouris, Stelios | Tsolaki, Magda | Giakoumis, Dimitrios | Votis, Konstantinos | Tzovaras, Dimitrios | Öztürk, Vesile | Yener, Görsev Gülmen

Article Type: Research Article

Abstract: Background: There is a need for new practical tools to assess the cognitive impairment of small vessel disease (SVD) patients in the clinic. Objective: This study aimed to examine cognitive functioning by administering the Virtual Supermarket (VST) in patients with SVD with cognitive impairment (SVD-CI, N = 32), cognitively normal SVD (SVD-CN, N = 37), and age-and education-matched healthy controls (HC, N = 30). Methods: The tablet-based VST application and comprehensive traditional pencil-and-paper neuropsychological tests assessing memory, attention, executive function, visuospatial function, and language were administered to all participants. Results: A moderate correlation was found between the “Duration” and “Correct …Quantities” variables of VST and visuospatial function and general cognitive status composite Z scores across SVD-CI patients. “Duration” and “Correct Money” variables were moderately related to memory, executive functions, and visuospatial function composite Z scores across SVD-CN patients. A combination of all VST variables discriminated SVD-CI and HC with a correct classification rate of 81%, a sensitivity of 78%, and a specificity of 84%. Conclusion: This study is the first to evaluate cognitive functions employing the VST in SVD with and without cognitive impairment. It provides encouraging preliminary findings of the utility of the VST as a screening tool in the assessment of cognitive impairment and the differentiation of SVD patients from HC. In the future, validation studies of the VST with larger samples are needed. Show more

Keywords: Cognitive testing, small vessel disease, vascular cognitive impairment, virtual reality, virtual shopping task

DOI: 10.3233/ADR-200257

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 161-169, 2021

Authors: Mendez, Mario F.

Article Type: Review Article

Abstract: Although Alzheimer’s disease (AD) is primarily a neurocognitive disorder, it also results in prominent neuropsychiatric symptoms (NPS). Much literature has investigated the NPS of apathy and depression in association with AD, but relatively less is known regarding anxiety, the third most common NPS in this disorder. The prevalence of anxiety symptoms in AD is about 40%, and it can be a prelude of AD. Anxiety can be especially present among patients with mild cognitive impairment, mild dementia, or early-onset forms of the disease, and can promote progression or conversion to Alzheimer’s clinical syndrome. A number of studies have established that …anxiety is associated with positive amyloid scans, mesial temporal changes with atrophy and hypometabolism in the entorhinal region, and neurofibrillary tangles present on pathological examination of this region. In addition to psychosocial factors, proposed neurobiological mechanisms for increased anxiety in AD include decreased sensorimotor gating, relatively increased activation of amygdalae or the Salience Network, and the presence of comorbid pathology, particularly Lewy bodies. Having management strategies for anxiety in patients with AD is important as anxiety can worsen cognitive deficits. Interventions involve psychological support, behavioral management, and the judicious use of the psychiatric armamentarium of medications. Show more

Keywords: Alzheimer’s disease, anxiety

DOI: 10.3233/ADR-210294

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 171-177, 2021

Authors: Moradi, Kamyar | Faghani, Shahriar | Abdolalizadeh, AmirHussein | Khomeijani-Farahani, Mohammadreza | Ashraf-Ganjouei, Amir | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a transitional condition between normal cognition and dementia. Although a significant proportion of the population with MCI experience reversion to normal cognition, it is still poorly understood. Objective: This study was designed to extend the present evidence regarding the difference between stable and reverting MCI by including whole brain atrophy measures as possible parameters involved. Methods: 405 patients diagnosed with MCI at baseline were selected. After one-year follow-up period, 337 patients (83.2%) were categorized as stable MCI and 68 patients (16.8%) reverted to cognitively normal status (reversion group). Several baseline …biomarkers including cerebrospinal fluid (CSF) biomarkers of AD, including Aβ42 , t-tau, and p-tau and MRI-based atrophy measurements were compared. Results: Participants with stable MCI demonstrated greater brain atrophy as well as lower Aβ and higher tau proteins in the CSF. The atrophy rate was found to be associated with CSF biomarkers merely in the stable group, after adjustment for confounding variables. Conclusion: These findings provide novel evidence regarding the biological perspective of the reversion phenomenon in individuals with MCI. Show more

Keywords: Brain atrophy, cerebrospinal fluid, mild cognitive impairment, reversion

DOI: 10.3233/ADR-200229

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 179-186, 2021

Authors: Innes, Kim E. | Montgomery, Caitlin | Selfe, Terry Kit | Wen, Sijin | Khalsa, Dharma Singh | Flick, Madison

Article Type: Research Article

Abstract: Background: Recent studies suggest meditation and music listening (ML) may improve cognitive and psychosocial outcomes in adults with subjective cognitive decline (SCD). However, lack of a usual care group has limited conclusions. Objective: To assess the: 1) feasibility of incorporating an enhanced usual care (EUC) comparator in a trial of Kirtan Kriya meditation (KK) and ML for adults experiencing SCD; and 2) preliminary effects of active treatment (KK/ML) versus an EUC program. Methods: Forty participants with SCD were randomized 1:1:2 to a 12-week KK, ML, or EUC program. KK and ML participants were asked to practice …12 minutes/day; EUC participants were given a comprehensive educational packet regarding healthy aging and strategies for improving/maintaining brain health and asked to record any activities or strategies used. Feasibility was assessed using measures of retention, adherence, treatment expectancies, and participant satisfaction, as well as information from exit questionnaires and daily practice/activity logs. Cognitive functioning, stress, mood, sleep-quality, and health-related quality of life (QOL) were measured pre- and post-intervention using well-validated instruments. Results: Thirty-two participants (80%) completed the 3-month study, with retention highest in the EUC group (p  < 0.05). Active treatment participants averaged 6.0±0.4 practice sessions/week, and EUC participants, 7.5±0.6 brain health activities/week. Treatment expectancies were similar across groups. EUC participants indicated high satisfaction with the program and study. Despite limited study power, the active treatment group showed significantly greater gains in subjective memory functioning (ps≤0.025) and nonsignificant improvements in cognitive performance (TMT-B), perceived stress, QOL, and mood (ps≤0.08) compared to the EUC group. Conclusion: Findings of this pilot feasibility trial suggest incorporation of an EUC program is feasible, and that participation in a simple 12-week relaxation program may be helpful for adults with SCD versus engagement in an EUC program. Show more

Keywords: Acceptability, Alzheimer’s disease, cognition, memory complaints, mind-body therapy, mood, quality of life, stress, subjective cognitive impairment

DOI: 10.3233/ADR-200249

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 187-206, 2021

Authors: Sabbagh, Marwan | Miller, Justin | Jones, Stephen | Ritter, Aaron | Shi, Jiong | DeCourt, Boris | Wint, Dylan

Article Type: Research Article

Abstract: Background: Informant-based measures are effective screening tools for cognitive impairment. The Alzheimer’s Questionnaire (AQ) is a subjective, informant-based measure that detects amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) with high sensitivity and specificity and has been shown to predict amyloid burden. Objective: To determine whether informant-based report of cognitive decline correlates with hippocampal volume changes in MCI and AD. Methods: Retrospective chart review of 139 clinically referred patients with clinical diagnoses of aMCI or mild dementia due to AD was conducted. Diagnostic status (clinical diagnosis made by a neurologist), NeuroQuant measured MRI brain with …percentile rank hippocampal volume, Montreal Cognitive Assessment (MoCA) total, AQ-Total score, and demographic variables were extracted from medical records. Spearman correlation was used to assess the relationship between hippocampal volume and AQ-Total. The AQ was used to assign diagnostic status. Thus, the relationship between the AQ and diagnostic status was excluded. Results: The sample include 88 female and 51 male participants. The mean age was 74.37±9.45, mean MOCA was 22.65±4.18, mean education was 14.80±3.35, and mean AQ score was 10.54±5.22. Hippocampal volume and the AQ correlation was r  = –0.33 [95%CI –0.47 to –0.17], p  < 0.0001. Conclusion: In a mixed-clinical sample of patients presenting to an outpatient memory disorders center, higher endorseme-nts of functional impairments by caregivers were significantly associated with smaller hippocampal volumes. When used in conjunction with other available measures, these findings further support the role of the AQ in clinical decision-making and demonstrate an additional relationship between clinical measures and volumetric MRI. Show more

Keywords: Alzheimer’s disease, Alzheimer’s Questionnaire, hippocampal volume, informant-based measures, screening tools

DOI: 10.3233/ADR-200260

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 207-211, 2021

Authors: Khan, Hafiz | Rafiq, Aamrin | Palle, Komaraiah | Faysel, Mohammad | Gabbidon, Kemesha | Chowdhury, Mohammed | Reddy, P. Hemachandra

Article Type: Research Article

Abstract: Background: The prevalence of cognitive dysfunction increases in elderly due to cardiovascular disease related risk factors in rural communities like West Texas. Objective: The purpose of this study was to find risk factors of cardiovascular disease (CVD) related to cognitive dysfunction and their impact on elderly adults in rural West Texans. Methods: Statistical methods such as Pearson’s chi-squared and a multinomial logistic regression were utilized to analyze data. We used SPSS software to detect and understand the nature of the risk factors. Results: A summary of statistics was obtained by using Pearson’s chi-squared test …for categorical variables. CVD, diabetes mellitus, and depression were significantly associated with cognitive dysfunction for both males and females (p  = 0.0001), whereas anxiety was found to be significantly associated with cognitive dysfunction for females (p  = 0.0001). Age group and race/ethnicity were significantly associated with cognitive dysfunction for both males and females (p  = 0.0001). By performing a multinomial logistic regression method and controlling for confounders, the significant risk factors (p  <  0.05)— age (65– 84 years), diabetes, and memory loss for age-associated cognitive impairment; diabetes for cognitive impairment no dementia; age (65– 84, ≥85 years), CVD, diabetes, depression, memory loss, non-Hispanic Whites, and Black/African-Americans for mild cognitive impairment; and age, memory loss, non-Hispanic Whites, Black/African-Americans, and male gender were found for dementia. Conclusion: CVD related risk factors in developing cognitive dysfunction exist and integrating such risk variables may guide relevant policy interventions to reduce Alzheimer’s incidence or dementia in rural communities in West Texans. Show more

Keywords: Alzheimer’s disease, cardiovascular disease, cognitive dysfunction FRONTIER database

DOI: 10.3233/ADR-200278

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 213-226, 2021

Authors: Gorantla, Nalini V. | Das, Rashmi | Mulani, Fayaj A. | Thulasiram, Hirekodathakallu V. | Chinnathambi, Subashchandrabose

Article Type: Correction

DOI: 10.3233/ADR-219001

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 227-227, 2021

Authors: Lopatko Lindman, Karin | Weidung, Bodil | Olsson, Jan | Josefsson, Maria | Johansson, Anders | Eriksson, Sture | Hallmans, Göran | Elgh, Fredrik | Lövheim, Hugo

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ), the key constituent of Alzheimer’s disease (AD) plaques, has antimicrobial properties. Objective: To investigate the association between plasma Aβ and antibodies against the AD-related pathogens herpes simplex virus (HSV), cytomegalovirus (CMV), and C. pneumoniae . Methods: Plasma from 339 AD cases, obtained on average 9.4 years (±4.00) before diagnosis, and their matched controls were analyzed for Aβ40 and Aβ42 concentrations with Luminex xMAP technology and INNOBIA plasma Aβ-form assays. Enzyme-linked immunosorbent assays were utilized for analyses of anti-HSV immunoglobulin (Ig) G, anti-HSV1 IgG, anti-HSV2 IgG, anti-CMV IgG, and anti-C. pneumoniae …IgG. Follow-up samples were available for 150 of the cases. Results: Presence and levels of anti-HSV1 IgG, anti-HSV2 IgG, anti-CMV IgG, and anti-C. pneumoniae IgG did not correlate with concentrations of Aβ42 or Aβ40 in cases or controls. Conclusion: Levels of plasma Aβ were not associated with antibodies against different AD-related pathogens. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, Chlamydophila pneumoniae, cytomegalovirus, dementia, Herpes simplex, nested case-control study

DOI: 10.3233/ADR-210008

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 229-235, 2021

Authors: Olsen, Ingar

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) has been associated with periodontitis, which starts as gingivitis. Similar to periodontitis, gingivitis bacteria, bacterial products, and inflammatory mediators can travel to the brain via the blood stream and promote brain inflammation. Periodontal pathogens such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, both associated with AD, have been found in dental plaque of children already at the age of 3. It is suggested that these bacteria during long-term exposure may drive microglia (brain resident macrophage cells) into a pro-inflammatory M1 phase where they contribute to AD rather than protect against it. This notion comes from studies …in mice showing that microglia actually can “remember” previous inflammatory challenge and become “trained” or “tolerant” to toxins like lipopolysaccharide. If gingivitis has an impact on AD, which should be verified, AD prophylaxis should start already at this pre-periodontitis stage with removal of supragingival plaque. Show more

Keywords: Bacteria, bacteremia, inflammation, microglia, periodontitis, systemic

DOI: 10.3233/ADR-210006

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 237-241, 2021

Authors: Tombini, Mario | Assenza, Giovanni | Ricci, Lorenzo | Lanzone, Jacopo | Boscarino, Marilisa | Vico, Carlo | Magliozzi, Alessandro | Di Lazzaro, Vincenzo

Article Type: Review Article

Abstract: Increasing evidence coming from both experimental and humans’ studies strongly suggest the existence of a link between epilepsy, in particular temporal lobe epilepsy (TLE), and Alzheimer’s disease (AD). Patients with mild cognitive impairment and AD are more prone to have seizures, and seizures seem to facilitate amyloid-β and tau deposits, thus promoting neurodegenerative processes. Consistent with this view, long-lasting drug-resistant TLE and AD have been shown to share several pathological and neuroimaging features. Even if studies addressing prevalence of interictal and subclinical epileptiform activity in these patients are not yet conclusive, their findings raise the possibility that epileptiform activity might …negatively impact memory and hasten cognitive decline, either directly or by association with unrecognized silent seizures. In addition, data about detrimental effect of network hyperexcitability in temporal regions in the premorbid and early stages ofADopen up newtherapeutic opportunities for antiseizure medications and/or antiepileptic strategies that might complement or enhance existing therapies, and potentially modify disease progression. Here we provide a review of evidence linking epileptiform activity, network hyperexcitability, and AD, and their role promoting and accelerating neurodegenerative process. Finally, the effects of antiseizure medications on cognition and their optimal administration in patients with AD are summarized. Show more

Keywords: Alzheimer’s disease, antiseizure medications, cognition, epilepsy, epileptiform activity, network hyperexcitability

DOI: 10.3233/ADR-200286

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 243-261, 2021

Authors: Pahrudin Arrozi, Aslina | Yanagisawa, Daijiro | Kato, Tomoko | Akatsu, Hiroyasu | Hashizume, Yoshio | Kaneda, Daita | Tooyama, Ikuo

Article Type: Research Article

Abstract: Background: Emerging evidence indicates that the misfolded tau protein can propagate aggregates between cells in a prion-like manner. This prion activity has been typically studied in brain extracts of patients with Alzheimer’s disease (AD), but not in the olfactory region that can be a potential biomarker in AD. Objective: To investigate the prion seeding activity of tau in nasal mucosa tissues using a cell culture model of tau propagation. Methods: Brain and nasal mucosa homogenates were added to HEK293T cells expressing three repeat or four-repeat domains of tau with the L266V, V337M (3RD* VM) and P301L …and V377M mutations (4RD* LM) fused to the enhanced green fluorescence protein (EGFP) respectively. We also measured the level of phosphorylated tau (p-tau), total tau (t-tau), and p-tau/t-tau ratio and performed correlation analysis between tau prion activity and the level of tau. Results: We found that brain and nasal tissue homogenates from patients with AD significantly induced tau aggregation in HEK293T cells either expressing tau 3RD* VM-EGFP or 4RD* LM-EGFP compared with control brain and nasal tissue homogenates. The levels of p-tau and p-tau/t-tau ratio were significantly increased in the brain of patients with AD; however, no significant difference was found in nasal tissue compared with their respective control tissue homogenates. Conclusion: These results suggest that the nasal tissues contain tau seeds, similar to the brain, albeit without changes in the levels of p-tau and t-tau. Therefore, a cellular bioassay using nasal tissues would have great potential as an AD biomarker because of the usefulness of nasal tissue biopsy. Show more

Keywords: Alzheimer’s disease, nasal extracts, tau aggregation, tau propagation

DOI: 10.3233/ADR-210298

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 263-274, 2021

Authors: Bezuch, Natalia | Bradburn, Steven | Robinson, Andrew C. | Pendleton, Neil | Payton, Antony | Murgatroyd, Chris

Article Type: Research Article

Abstract: Background: The APOE ɛ4 allele is the strongest known genetic risk factor for sporadic Alzheimer’s disease (AD). The neighboring TOMM40 gene has also been implicated in AD due to its close proximity to APOE . Objective: Here we tested whether methylation of the TOMM40-APOE locus may influence ApoE protein levels and AD pathology. Methods: DNA methylation levels across the TOMM40-APOE locus and ApoE levels were measured in superior frontal gyrus tissues of 62 human brains genotyped for APOE and scored for AD neuropathology. Results: Methylation levels within the TOMM40 …CpG island in the promoter or APOE CpG island in Exon 4 did not differ between APOE ɛ4 carriers versus non-carriers. However, APOE ɛ4 carriers had significantly higher methylation the APOE promoter compared with non-carriers. Although DNA methylation at TOMM40 , APOE promoter region, or APOE did not differ between AD pathological groups, there was a negative association between TOMM40 methylation and CERAD scores. ApoE protein concentrations did not significantly different between APOE ɛ4 carriers and non-carriers, or between AD pathological groups. Finally, there was no correlation between ApoE protein concentrations and DNA methylation levels. Conclusion: APOE gene methylation may not be affected by genotype, relate to AD pathology or ApoE protein levels in the superior frontal gyrus, though, DNA methylation at the ApoE promoter differed between genotype. DNA methylation at TOMM40 associated with amyloid-β plaques and longitudinal fluid intelligence. In sum, these results suggest a complicated regulation of the TOMM40-APOE locus in the brain in controlling ApoE protein levels and AD neuropathology. Show more

Keywords: Alzheimer’s disease, APOE, DNA methylation, frontal gyrus, neuropathology, TOMM40

DOI: 10.3233/ADR-201000

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 275-282, 2021

Authors: Mold, Matthew John | O’Farrell, Adam | Morris, Benjamin | Exley, Christopher

Article Type: Research Article

Abstract: Background: Familial Alzheimer’s disease (fAD) is driven by genetic predispositions affecting the expression and metabolism of the amyloid-β protein precursor. Aluminum is a non-essential yet biologically-reactive metal implicated in the etiology of AD. Recent research has identified aluminum intricately and unequivocally associated with amyloid-β in senile plaques and, more tentatively, co-deposited with neuropil-like threads in the brains of a Colombian cohort of donors with fAD. Objective: Herein, we have assessed the co-localization of aluminum to immunolabelled phosphorylated tau to probe the potential preferential binding of aluminum to senile plaques or neurofibrillary tangles in the same Colombian kindred. …Methods: Herein, we have performed phosphorylated tau-specific immunolabelling followed by aluminum-specific fluorescence microscopy of the identical brain tissue sections via a sequential labelling method. Results: Aluminum was co-localized with immunoreactive phosphorylated tau in the brains of donors with fAD. While aluminum was predominantly co-located to neurofibrillary tangles in the temporal cortex, aluminum was more frequently co-deposited with cortical senile plaques. Conclusion: These data suggest that the co-deposition of aluminum with amyloid-β precedes that with neurofibrillary tangles. Extracellularly deposited amyloid-β may also be more immediately available to bind aluminum versus intracellular aggregates of tau. Therapeutic approaches to reduce tau have demonstrated the amelioration of its synergistic interactions with amyloid-β, ultimately reducing tau pathology and reducing neuronal loss. These data support the intricate associations of aluminum in the neuropathology of fAD, of which its subsequent reduction may further therapeutic benefits observed in ongoing clinical trials in vivo . Show more

Keywords: Aluminum in human brain tissue, amyloid-β , familial Alzheimer’s disease, neurofibrillary tangles, senile plaques, tau

DOI: 10.3233/ADR-210011

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 283-294, 2021

Authors: Rangasamy, Suresh B. | Dasarathi, Sridevi | Nutakki, Aparna | Mukherjee, Shreya | Nellivalasa, Rohith | Pahan, Kalipada

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is one of the most important neurodegenerative disorders in human in which recovery of functions could be achieved by improving the survival and function of residual dopaminergic neurons in the substantia nigra pars compacta. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the dopamine (DA) biosynthesis pathway. Objective: Earlier our laboratory has shown that sodium benzoate (NaB), a metabolite of cinnamon and an FDA-approved drug against urea cycle disorders and glycine encephalopathy, increases neuroprotective molecules and protects dopaminergic neurons in a mouse model of PD. Here, we examined whether NaB could stimulate the production …of DA in dopaminergic neurons. Methods: We employed PCR, real-time PCR, western blot, immunostaining, and HPLC to study the signature function of dopaminergic neurons. Locomotor functions were monitored in mice by open-field. Results: NaB increased the mRNA and protein expression of TH to produce DA in mouse MN9D dopaminergic neuronal cells. Accordingly, oral feeding of NaB increased the expression of TH in the nigra, upregulated striatal DA, and improved locomotor activities in striatum of normal C57/BL6 and aged A53T-α -syn transgenic mice. Rapid induction of cAMP response element binding (CREB) activation by NaB in dopaminergic neuronal cells and the abrogation of NaB-induced expression of TH by siRNA knockdown of CREB suggest that NaB stimulates the transcription of TH in dopaminergic neurons via CREB. Conclusion: These results indicate a new function of NaB in which it may be beneficial in PD via stimulation of DA production from residual dopaminergic neurons. Show more

Keywords: A53T, CREB, dopamine, sodium benzoate, striatum, substantia nigra pars compacta, tyrosine hydroxylase

DOI: 10.3233/ADR-210001

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 295-310, 2021

Authors: Pezzoli, Stefania | De Marco, Matteo | Zorzi, Giovanni | Cagnin, Annachiara | Venneri, Annalena

Article Type: Research Article

Abstract: Background: The presence of recurrent, complex visual hallucinations (VH) is among the core clinical features of dementia with Lewy bodies (DLB). It has been proposed that VH arise from a disrupted organization of functional brain networks. However, studies are still limited, especially investigating the resting-state functional brain features underpinning VH in patients with dementia. Objective: The aim of the present pilot study was to investigate whether there were any alterations in functional connectivity associated with VH in DLB. Methods: Seed-based analyses and independent component analysis (ICA) of resting-state fMRI scans were carried out to explore differences …in functional connectivity between DLB patients with and without VH. Results: Seed-based analyses reported decreased connectivity of the lateral geniculate nucleus, the superior parietal lobule and the putamen with the medial frontal gyrus in DLB patients with VH. Visual areas showed a pattern of both decreased and increased functional connectivity. ICA revealed between-group differences in the default mode network (DMN). Conclusion: Functional connectivity analyses suggest dysfunctional top-down and bottom-up processes and DMN-related alterations in DLB patients with VH. This impairment might foster the generation of false visual images that are misinterpreted, ultimately resulting in VH. Show more

Keywords: Dementia with Lewy bodies, functional connectivity, resting-state fMRI, resting-state networks, visual hallucinations

DOI: 10.3233/ADR-200288

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 311-320, 2021

Authors: Lo, Albert C. | Evans, Cynthia Duggan | Mancini, Michele | Wang, Hong | Shcherbinin, Sergey | Lu, Ming | Natanegara, Fanni | Willis, Brian A.

Article Type: Research Article

Abstract: Background: LY3202626 is a small molecule inhibitor of β-site amyloid precursor protein cleaving enzyme (BACE)1 shown to reduce amyloid-β (Aβ)1–40 and Aβ1–42 concentrations in plasma and cerebrospinal fluid developed for the treatment of Alzheimer’s disease (AD). Objective: To assess the change from baseline in flortaucipir positron emission tomography (PET) after treatment with LY3202626 compared with placebo in patients with mild AD dementia. Methods: Patients received daily 3 mg or 12 mg doses of LY3202626 or placebo for 52 weeks. The primary outcome was assessment of cerebral neurofibrillary tangle load by flortaucipir PET. The study was terminated …early following an interim analysis due to a low probability of identifying a statistically significant slowing of cognitive and/or functional decline. Results: A total of 316 patients were randomized and 47 completed the study. There was no statistically significant difference between placebo and either dose of LY3202626 from baseline to 52 weeks, or in annualized change for flortaucipir PET. There was no clinically meaningful difference between placebo and LY3202626 doses on efficacy measures of cognition and function. No deaths or serious adverse events considered related to LY3202626 were reported. A statistically significant increase in treatment-emergent adverse events in the psychiatric disorders system organ class was reported for both LY3202626 doses compared to placebo. Conclusion: LY3202626 tested at doses generating 70–90% BACE inhibition was generally well tolerated in this study. LY3202626 treatment did not result in a clinically significant change in cerebral tau burden as measured by flortaucipir nor in change of functional or cognitive decline compared to placebo. Show more

Keywords: Alzheimer’s disease, amyloid, neurofibrillary tangles, positron-emission tomography, tau

DOI: 10.3233/ADR-210296

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 321-336, 2021

Authors: Chung, Hojune E. | Chen, Jessica | Ghosalkar, Dhairyasheel | Christensen, Jared L. | Chu, Alice J. | Mantsounga, Chris S. | Neverson, Jade | Soares, Cullen | Shah, Nishant R. | Wu, Wen-Chih | Choudhary, Gaurav | Morrison, Alan R.

Article Type: Research Article

Abstract: Background: While an association between atherosclerosis and dementia has been identified, few studies have assessed the longitudinal relationship between aortic valve calcification (AVC) and cognitive impairment (CI). Objective: We sought to determine whether AVC derived from lung cancer screening CT (LCSCT) was associated with CI in a moderate-to-high atherosclerotic risk cohort. Methods: This was a single site, retrospective analysis of 1401 U.S. veterans (65 years [IQI: 61, 68] years; 97%male) who underwent quantification of AVC from LCSCT indicated for smoking history. The primary outcome was new diagnosis of CI identified by objective testing (Mini-Mental Status Exam …or Montreal Cognitive Assessment) or by ICD coding. Time-to-event analysis was carried out using AVC as a continuous variable. Results: Over 5 years, 110 patients (8%) were diagnosed with CI. AVC was associated with new diagnosis of CI using 3 Models for adjustment: 1) age (HR: 1.104; CI: 1.023–1.191; p  = 0.011); 2) Model 1 plus hypertension, hyperlipidemia, diabetes, CKD stage 3 or higher (glomerular filtration rate < 60 mL/min) and CAD (HR: 1.097; CI: 1.014–1.186; p  = 0.020); and 3) Model 2 plus CVA (HR: 1.094; CI: 1.011–1.182; p  = 0.024). Sensitivity analysis demonstrated that the association between AVC and new diagnosis of CI remained significant upon exclusion of severe AVC (HR: 1.100 [1.013–1.194 ]; p  = 0.023). Subgroup analysis demonstrated that this association remained significant when including education in the multivariate analysis (HR: 1.127 [1.030–1.233 ]; p  = 0.009). Conclusion: This is the first study demonstrating that among mostly male individuals who underwent LCSCT, quantified aortic valve calcification is associated with new diagnosis of CI. Show more

Keywords: Atherosclerosis, calcific aortic valve disease, computed tomography, dementia

DOI: 10.3233/ADR-200253

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 337-343, 2021

Authors: Ávila-Villanueva, Marina | Gómez-Ramírez, Jaime | Ávila, Jesús | Fernández-Blázquez, Miguel A.

Article Type: Review Article

Abstract: In recent years there has been increasing interest in examining the role of empathic abilities in Alzheimer’s disease (AD). Empathy, the ability to understand and share another person’s feelings, implies the existence of emotional and cognitive processes and is a pivotal aspect for success in social interactions. In turn, self-empathy is oriented to one’s thoughts and feelings. Decline of empathy and self-empathy can occur during the AD continuum and can be linked to different neuroanatomical pathways in which the cingulate cortex may play a crucial role. Here, we will summarize the involvement of empathic abilities through the AD continuum and …further discuss the potential neurocognitive mechanisms that contribute to decline of empathy and self-empathy in AD. Show more

Keywords: Aging, Alzheimer’s disease, anosognosia, cingulate cortex, empathy

DOI: 10.3233/ADR-200282

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 345-352, 2021

Authors: Emblad, Shayla Y.M. | Mukaetova-Ladinska, Elizabeta B.

Article Type: Research Article

Abstract: Background: Non-pharmacological therapies have been shown to be effective in managing challenging behavior in people with dementia. However, the efficacy of art therapy has yet to be determined. Objective: In the present systematic review, we evaluate the efficacy of art therapy as a non-pharmacological intervention for dementia and examine whether art therapy improves wellbeing and quality of life while decreasing biological and psychological symptoms of dementia (BPSD). Methods: Research undertaken between 2015 and 2020 was examined and a total of seventeen studies met the specified search criteria, with 853 participants (657 people with dementia, 180 formal …and informal carers, and 16 volunteers) involved. Results: We identified four outcome domains: wellbeing, quality of life, BPSD, and cognitive function. One or more significant outcomes as having an impact on the efficacy of the intervention were reported in 88% (15/17) of the studies, whereas 17% (3/17) demonstrated significant outcomes across quality of life, wellbeing, and BPSD. Conclusion: People with dementia benefit from art therapy. These interventions when incorporating elements of being ‘in the moment’ increase opportunities for communication between people with dementia and their caregiver(s) and facilitate person-centered therapeutic activities. Show more

Keywords: Art therapy, behavioral and psychological symptoms of dementia, cognition, dementia, non-pharmacological therapy, systematic review

DOI: 10.3233/ADR-201002

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 353-364, 2021

Authors: Gallucci, Maurizio | Mazzarolo, Anna Paola | Focella, Lucia | Berlin, Elisa | Fiore, Vittorio | Di Paola, Francesco | Bendini, Matteo | Zanusso, Gianluigi | Fenoglio, Chiara | Galimberti, Daniela | Bonanni, Laura

Article Type: Research Article

Abstract: Background: A 57-year-old right-handed man was admitted to the Treviso Memory Clinic due to the presence of memory forgetfulness, repetition of the same questions, episodes of confusion, initial difficulties in performing complex tasks and easy distraction over the past two years, as well as recurrent and never-happened-before car accidents. Objective: We report a peculiar case of an early onset Alzheimer’s disease (AD) with an unusual symptomatology, apparently not fitting in any of the categorized atypical forms of AD nor being representative of a typical amnestic AD. Methods: The patient underwent a neuropsychological, structural, and metabolic cerebral …evaluation by MRI and 18 F-FDG PET, together with the search for cerebral amyloid (amyloid PET), a genetic testing for dementia related genes and the dosage of CSF protein biomarkers of neurodegenerative conditions. Results: We observed a convergence of predominant frontal (dysexecutive, verbal disinhibition) and posterior (visuospatial) features of cognitive impairment. Structural MRI sequences showed subarachnoid spaces of the vault enlarged in the fronto-parietal region with anterior and posterior cortical atrophy. The hippocampus appeared preserved. The 18 F-FDG PET scans showed hypometabolism in the prefrontal, lateral temporal, posterior parietal, and occipital regions bilaterally. The 18 F-Flutemetamol scan showed a diffused uptake of the amyloid tracer at the cerebral cortex. CSF biomarkers were compatible with Alzheimer’s disease (AD). Conclusion: This case report presented with clinical phenotypic aspects atypical of AD, both frontal and posterior, never described as concomitant in the most accredited criteria for atypical AD, and appeared therefore more atypical than each of the atypical AD phenotypes already reported. Show more

Keywords: Alzheimer’s disease, frontal variant, magnetic resonance, neurodegenerative diseases, PET scan, posterior cortical atrophy, TREDEM

DOI: 10.3233/ADR-210009

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 365-374, 2021

Authors: Fereshetian, Shaunt | Agranat, Joshua S. | Siegel, Nicole | Ness, Steven | Stein, Thor D. | Subramanian, Manju L.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is one of the most common causes of dementia worldwide. Although no formal curative therapy exists for the treatment of AD, considerable research has been performed to identify biomarkers for early detection of this disease, and thus improved subsequent management. Given that the eye can be examined and imaged non-invasively with relative ease, it has emerged as an exciting area of research for evidence of biomarkers and to aid in the early diagnosis of AD. This review explores the current understanding of both protein and retinal imaging biomarkers in the eye. Herein, primary findings in the literature …regarding AD biomarkers associated with the lens, retina, and other ocular structures are reviewed. Show more

Keywords: Alzheimer’s disease, amyloid, cataract, crystalline, eye, lens, retina, vitreous

DOI: 10.3233/ADR-210283

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 375-387, 2021

Authors: Deutsch, Curtis K. | Patnaik, Pooja P. | Greco, Frank A.

Article Type: Short Communication

Abstract: We sought to determine whether skin conductance level could warn of outbursts of combative behavior in dementia patients by using a wristband device. Two outbursts were captured and are reported here. Although no physiologic parameter measured by the wristband gave advance warning, there is a common pattern of parasympathetic withdrawal (increased heart rate) followed approximately 30 seconds later by sympathetic activation (increased skin conductance). In the literature, a similar pattern occurs in psychogenic non-epileptic seizures. We hypothesize that similar autonomic responses reflect similarities in pathophysiology and that physical activity may partially account for the time course of skin conductance.

Keywords: Autonomic nervous system, dementia, galvanic skin response, heart rate, non-epileptic seizures

DOI: 10.3233/ADR-210007

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 389-394, 2021

Authors: Barthelson, Karissa | Pederson, Stephen Martin | Newman, Morgan | Jiang, Haowei | Lardelli, Michael

Article Type: Research Article

Abstract: Background: Mutations in PRESENILIN 2 (PSEN2 ) cause early onset familial Alzheimer’s disease (EOfAD) but their mode of action remains elusive. One consistent observation for all PRESENILIN gene mutations causing EOfAD is that a transcript is produced with a reading frame terminated by the normal stop codon—the “reading frame preservation rule”. Mutations that do not obey this rule do not cause the disease. The reasons for this are debated. Objective: To predict cellular functions affected by heterozygosity for a frameshift, or a reading frame-preserving mutation in zebrafish psen2 using bioinformatic techniques. Methods: A …frameshift mutation (psen2N 140fs ) and a reading frame-preserving (in-frame) mutation (psen2T 141 _ L 142delinsMISLISV ) were previously isolated during genome editing directed at the N140 codon of zebrafish psen2 (equivalent to N141 of human PSEN2 ). We mated a pair of fish heterozygous for each mutation to generate a family of siblings including wild type and heterozygous mutant genotypes. Transcriptomes from young adult (6 months) brains of these genotypes were analyzed. Results: The in-frame mutation uniquely caused subtle, but statistically significant, changes to expression of genes involved in oxidative phosphorylation, long-term potentiation and the cell cycle. The frameshift mutation uniquely affected genes involved in Notch and MAPK signaling, extracellular matrix receptor interactions and focal adhesion. Both mutations affected ribosomal protein gene expression but in opposite directions. Conclusion: A frameshift and an in-frame mutation at the same position in zebrafish psen2 cause discrete effects. Changes in oxidative phosphorylation, long-term potentiation and the cell cycle may promote EOfAD pathogenesis in humans. Show more

Keywords: Alzheimer’s disease, mitochondria, PSEN2, RNA-seq, zebrafish

DOI: 10.3233/ADR-200279

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 395-404, 2021

Authors: Priya, Khadgawat | Siddesha, J.M. | Dharini, Shashank | Shashanka, K. Prasad

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the primary cause of dementia affecting millions each year across the world, though still remains incurable. This might be attributed to the lack of knowledge about the associated proteins, their cellular and molecular mechanisms, and the genesis of the disease. The discovery of drugs that earlier revolved around targeting the amyloid-β cascade has now been reformed with the upgraded knowledge of the cross-seeding ability of tau protein which opens new gateways for therapeutic targets. This article provides a comprehensive review of various direct and indirect connecting pathways between the two main proteins involved in development and …progression of AD, enabling us to further expand our repertoire of information regarding the etiology of AD. The current review indicates the need for extensive research in this niche, thus considerable advances can be made in understanding AD which eventually helps to improve the current therapeutics against AD. Show more

Keywords: AGE, Alzheimer’s disease, CDK5, GSK3, oxidative stress, RAGE

DOI: 10.3233/ADR-210018

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 405-411, 2021

Authors: Lindblom, Nina | Lindquist, Lars | Westman, Jacob | Åström, Mikael | Bullock, Roger | Hendrix, Suzanne | Wahlund, Lars-Olof

Article Type: Research Article

Abstract: Background: Accumulating data suggest infectious agents are involved in Alzheimer’s disease (AD). The two primary aims of this trial were to assess safety and efficacy of an antiviral drug combination on AD progression. Objective: The trial evaluated whether Apovir, a combination of two antiviral agents, pleconaril (active on enteroviruses) and ribavirin (active on several viruses), could slow AD progression. Methods: Sixty-nine patients 60–85 years were treated with Apovir or placebo for 9 months and followed until 12 months after end of treatment. Cognitive tests, safety, biomarkers, drug plasma, and cerebrospinal fluid concentrations were assessed. …Results: The tolerability of Apovir was compromised as demonstrated by the large drop-out rate and increased frequency and severity of adverse events. The primary endpoint, demonstrating a difference in change from baseline to 9 months between groups in ADAS-cog total score, was not met (p  = 0.1809). However, there were observations indicating potential effects on both ADAS-cog and CDR-SB but these effects need to be verified. Also, there was a decrease in cerebrospinal fluid amyloid-β in Apovir at 9 months (p  = 0.0330) but no change in placebo. Conclusion: This was the first randomized, placebo controlled clinical trial exploring antiviral treatment on AD progression. The trial is considered inconclusive due to the large drop-out rate. New trials are needed to verify if the indications of effect observed can be confirmed and which component(s) in Apovir contributed to such effects. Pleconaril alone may be studied to improve the tolerability and to verify if enterovirus is involved in the disease process. Show more

Keywords: Alzheimer’s disease, amyloid-β , antiviral agents, clinical trial, infection, pleconaril, ribavirin

DOI: 10.3233/ADR-210301

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 413-431, 2021

Authors: Rodriguez, Katie | Fugard, Madison | Amini, Shawna | Smith, Glenn | Marasco, Deann | Shatzer, Julie | Guerrero, Michelle | Garvan, Cynthia | Davis, Jonathan | Price, Catherine

Article Type: Research Article

Abstract: Background: Web-based educational interventions are emerging as a potential solution to improve caregiver dementia knowledge and overall well-being. Objective: To assess the feasibility of delivering a web-based intervention for dementia caregivers by examining: 1) engagement with the online platform, 2) skill implementation, and 3) changes on outcome metrics over the 30-day study period. Methods: Enrolled participants were onboarded by a trained research coordinator and provided 24/7 access to the platform over 30 days. At study onset and completion, caregivers completed assessments of care recipient dementia severity and neuropsychiatric symptoms along with instruments which measured dementia knowledge, …caregiver burden, and carer experience. Results: Of 84 referrals, 60 caregivers met study inclusion criteria and 55 completed pre and post study measures. Caregivers completed an average of 8 hours of learning over the 30-day web-based intervention, with 84.4%of participants reporting using at least one skill they learned from the online platform. Eighty-nine percent of participants reported high satisfaction with the web-based educational intervention. There were small effect sizes for decreases in NPIQ neuropsychiatric symptom severity and caregiver distress scores from pre- to post-intervention. Small effect sizes were observed for changes in caregiver burden from pre- to post-intervention among caregivers who perceived their care recipient as having high global deterioration. Conclusion: Findings show online educational programs are feasible for informal family caregivers of dementia and have perceived value. Future studies should address caregiver response to online education in less severe versus more severe care recipients, and explore the value of caregiver online platforms in diverse caregiver samples. Show more

Keywords: Alzheimer’s disease, caregiver burden, dementia knowledge, feasibility studies, internet-based intervention, personal satisfaction

DOI: 10.3233/ADR-200292

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 433-442, 2021

Authors: Fowler, Christopher | Rainey-Smith, Stephanie R. | Bird, Sabine | Bomke, Julia | Bourgeat, Pierrick | Brown, Belinda M. | Burnham, Samantha C. | Bush, Ashley I. | Chadunow, Carolyn | Collins, Steven | Doecke, James | Doré, Vincent | Ellis, Kathryn A. | Evered, Lis | Fazlollahi, Amir | Fripp, Jurgen | Gardener, Samantha L. | Gibson, Simon | Grenfell, Robert | Harrison, Elise | Head, Richard | Jin, Liang | Kamer, Adrian | Lamb, Fiona | Lautenschlager, Nicola T. | Laws, Simon M. | Li, Qiao-Xin | Lim, Lucy | Lim, Yen Ying | Louey, Andrea | Macaulay, S. Lance | Mackintosh, Lucy | Martins, Ralph N. | Maruff, Paul | Masters, Colin L. | McBride, Simon | Milicic, Lidija | Peretti, Madeline | Pertile, Kelly | Porter, Tenielle | Radler, Morgan | Rembach, Alan | Robertson, Joanne | Rodrigues, Mark | Rowe, Christopher C. | Rumble, Rebecca | Salvado, Olivier | Savage, Greg | Silbert, Brendan | Soh, Magdalene | Sohrabi, Hamid R. | Taddei, Kevin | Taddei, Tania | Thai, Christine | Trounson, Brett | Tyrrell, Regan | Vacher, Michael | Varghese, Shiji | Villemagne, Victor L. | Weinborn, Michael | Woodward, Michael | Xia, Ying | Ames, David | the AIBL investigators

Article Type: Research Article

Abstract: Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer’s disease dementia (AD)) as an ‘Inception cohort’ who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an ‘Enrichment cohort’ (as of 10 April 2019). Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. Methods: Participants underwent reassessment every 18 months including comprehensive …cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims. Show more

Keywords: Aβ-amyloid imaging, Alzheimer’s disease, biomarkers, cognition, cohort study, lifestyle, mild cognitive impairment, observational longitudinal, preclinical Alzheimer’s disease, prodromal Alzheimer’s disease

DOI: 10.3233/ADR-210005

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 443-468, 2021

Authors: Gan, Li | Wan, Xiaonan | Ma, Delin | Yang, Fu-Chen | Zhu, Jingpeng | Rogers, Robert S. | Wheatley, Joshua L. | Koch, Lauren G. | Britton, Steven L. | Thyfault, John P. | Geiger, Paige C. | Stanford, John A.

Article Type: Research Article

Abstract: Background: Aerobic capacity is associated with metabolic, cardiovascular, and neurological health. Low-capacity runner (LCR) rats display low aerobic capacity, metabolic dysfuction, and spatial memory deficits. A heat treatment (HT) can improve metabolic dysfunction in LCR peripheral organs after high fat diet (HFD). Little is known about metabolic changes in the brains of these rats following HT. Objective: Our objective was to examine the extent to which high or low aerobic capacity impacts Akt (a protein marker of metabolism) and heat shock protein 72 (HSP72, a marker of heat shock response) after HFD and HT in hippocampus. …Methods: We measured phosphorylated Akt (pAkt) in the striatum and hippocampus, and HSP72 in the hippocampus, of HFD-fed and chow-fed LCR and high-capacity runner (HCR) rats with and without HT. Results: pAkt was lower in the hippocampus of chow-fed LCR than HCR rats. HFD resulted in greater pAkt in LCR but not HCR rats, but HT resulted in lower pAkt in the LCR HFD group. HSP72 was greater in both HCR and LCR rat hippocampus after HT. The HFD blunted this effect in LCR compared to HCR hippocampus. Conclusion: The abnormal phosphorylation of Akt and diminished HSP response in the hippocampus of young adult LCR rats might indicate early vulnerability to metabolic challenges in this key brain region associated with learning and memory. Show more

Keywords: Acute high fat diet, Akt, heat treatment, intrinsic aerobic running capacity

DOI: 10.3233/ADR-200289

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 469-475, 2021

Article Type: Correction

DOI: 10.3233/ADR-219002

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 477-477, 2021

Authors: Sun, Xicui | Duan, Songwei | Cao, Anna | Villagomez, Bryan | Lin, Runxuan | Chen, Hongxia | Pi, Liya | Ren, Bin | Chen, Rong | Chen, Minjie | Ying, Zhekang | Fang, Shenyun | Cao, Qi

Article Type: Research Article

Abstract: Background: Current understanding of amyloid-β protein (Aβ) aggregation and toxicity provides an extensive list of drugs for treating Alzheimer’s disease (AD); however, one of the most promising strategies for its treatment has been tri-peptides. Objective: The aim of this study is to examine those tri-peptides, such as Arg-Arg-Try (RRY), which have the potential of Aβ1–42 aggregating inhibition and Aβ clearance. Methods: In the present study, in silico , in vitro , and in vivo studies were integrated for screening tri-peptides binding to Aβ, then evaluating its inhibition of aggregation of Aβ, and finally its …rescuing cognitive deficit. Results: In the in silico simulations, molecular docking and molecular dynamics determined that seven top-ranking tri-peptides could bind to Aβ1–42 and form stable complexes. Circular dichroism, ThT assay, and transmission electron microscope indicated the seven tri-peptides might inhibit the aggregation of Aβ1–42 in vitro . In the in vivo studies, Morris water maze, ELISA, and Diolistic staining were used, and data showed that RRY was capable of rescuing the Aβ1–42 -induced cognitive deficit, reducing the Aβ1–42 load and increasing the dendritic spines in the transgenic mouse model. Conclusion: Such converging outcomes from three consecutive studies lead us to conclude that RRY is a preferred inhibitor of Aβ1–42 aggregation and treatment for Aβ-induced cognitive deficit. Show more

Keywords: Alzheimer’s disease, amyloid-β , APP/PS1 transgenic mice, high throughput screening, small peptide

DOI: 10.3233/ADR-210012

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 479-495, 2021

Authors: Lazarou, Ioulietta | Stavropoulos, Thanos G. | Mpaltadoros, Lampros | Nikolopoulos, Spiros | Koumanakos, George | Tsolaki, Magda | Kompatsiaris, Ioannis (Yiannis)

Article Type: Research Article

Abstract: Background: Mobile Health (mHealth) apps can delay the cognitive decline of people with dementia (PwD), by providing both objective assessment and cognitive enhancement. Objective: This patient involvement survey aims to explore human factors, needs and requirements of PwD, their caregivers, and Healthcare Professionals (HCPs) with respect to supportive and interactive mHealth apps, such as brain games, medication reminders, and geolocation trackers through a constructive questionnaire. Methods: Following the principles of user-centered design to involve end-users in design we constructed a questionnaire, containing both open-ended and closed-ended questions as well as multiple choice and Likert scale, in …order to investigate the specific requirements and preferences for mHealth apps. We recruited 48 participants including people with cognitive impairment (n  = 15), caregivers (n  = 16), and HCPs (n  = 17) and administered the questionnaire. Results: All participants are likely to use mHealth apps, with the primary desired features being the improvement of memory and cognition, assistance on medication treatment, and perceived ease to use. HCPs, caregivers, and PwD consider brain games as an important technology-based, non-pharmaceutical intervention. Both caregivers and patients are willing to use a medication reminder app frequently. Finally, caregivers are worried about the patient wandering. Therefore, global positioning system tracking would be particularly important to them. On the other hand, patients are concerned about their privacy, but are still willing to use a geolocation app for cases of emergency. Conclusion: This research contributes to mHealth app design and potential adoption. All three groups agree that mHealth services could facilitate care and ameliorate behavioral and cognitive disturbances of patients. Show more

Keywords: Alzheimer’s disease, apps, eHealth, information technologies, mHealth, mild cognitive impairment, remote monitoring, serious games, telemedicine

DOI: 10.3233/ADR-201001

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 497-513, 2021

Authors: Fernandes, Mariana | Placidi, Fabio | Mercuri, Nicola Biagio | Liguori, Claudio

Article Type: Review Article

Abstract: Obstructive sleep apnea (OSA) is a highly frequent sleep disorder in the middle-aged and older population, and it has been associated with an increased risk of developing cognitive decline and dementia, including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). In more recent years, a growing number of studies have focused on: 1) the presence of OSA in patients with MCI or AD, 2) the link between OSA and markers of AD pathology, and 3) the role of OSA in accelerating cognitive deterioration in patients with MCI or AD. Moreover, some studies have also assessed the effects of continuous positive …airway pressure (CPAP) treatment on the cognitive trajectory in MCI and AD patients with comorbid OSA. This narrative review summarizes the findings of studies that analyzed OSA as a risk factor for developing MCI and/or AD in the middle-aged and older populations with a special focus on cognition. In addition, it describes the results regarding the effects of CPAP treatment in hampering the progressive cognitive decline in AD and delaying the conversion to AD in MCI patients. Considering the importance of identifying and treating OSA in patients with MCI or AD in order to prevent or reduce the progression of cognitive decline, further larger and adequately powered studies are needed both to support these findings and to set programs for the early recognition of OSA in patients with cognitive impairment. Show more

Keywords: Alzheimer’s disease, cognitive impairment, continuous positive airway pressure, neuropsychological function, sleep-disordered breathing

DOI: 10.3233/ADR-210004

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 515-533, 2021

Authors: Zhong, Wenjun | Liu, Xinyue | Voss, Tiffini | Khalilieh, Sauzanne | Khandker, Rezaul Karim | Bortnichak, Edward | Liaw, Kai-Li

Article Type: Research Article

Abstract: Background: Behavioral disturbance (BD) is common in dementia patients, with no FDA approved medications for this condition. Little data exists on the real-world medication use in this population. Objective: To describe real-world medications use in this population. Methods: A cross-sectional study was conducted using the MarketScan database for outpatient medications and the Cerner database for inpatient medications. The study period was Oct 2015–Jun 2018. Patients with dementia and BD were identified through ICD-10-CM. We examined outpatient medications prescribed during 6-month before or after BD event date, and inpatient medications during inpatient visits, especially on central nervous …systems (CNS) drugs including antidementia drugs, antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Results: A total of 56,544 outpatients and 34,245 patient hospitalizations were assessed separately. Among outpatients, patients filled more medications after a BD event. The use of the five CNS drug classes generally increased after a BD event, and the largest increase was seen in antipsychotics (23%to 33%). Among inpatients, the median number of medications used in each hospitalization was 14. The use of antipsychotics was particularly high (64%), followed by anxiolytics (51%). A list of 60 unique medications were suggested to be the commonly used drugs in dementia patients with BD. Conclusion: In dementia patients with BD, anti-dementia medications, antidepressants, anticonvulsants, hypnotics and antipsychotics were the most used drug classes. Antidepressants and antipsychotics use were more frequent after a BD event, which suggests a need for safe drugs targeting BD in dementia patients. Show more

Keywords: Behavioral disturbance, Cerner Health Facts, dementia, IBM Marketscan, prescriptions

DOI: 10.3233/ADR-210023

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 535-540, 2021