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

Authors: Levy, Sigal | Guttmann-Beck, Nili | Shweiki, Dorit

Article Type: Research Article

Abstract: Background: The multiple appearance phenotypes in Alzheimer’s disease (AD) are manifested in epidemiologic sexual dimorphism, variation in age of onset, progress, and severity of the disease. Objective: In this study, we focused on sexual dimorphism, aiming to untie some of the complex interconnections in AD between sex, disease status, and gene expression profiles. Two strategic decisions guided our study: 1) to value transcriptomic multi-layered profiles over alterations in single genes expression; and 2) to embrace a sexual dimorphism centered approach, as we suspect that transcriptomic profiles may dramatically differ not only between healthy and sick individuals but between …men and women as well. Methods: Microarray dataset GSE15222, fulfilling our strict criteria, was retrieved from the GEO repository. We performed cluster analysis for each sex separately, comparing the proportion of healthy and AD individuals in each cluster. Results: We were able to identify a biased, female, AD-typified cluster. Furthermore, we showed that this female AD-typified cluster is highly similar to one of the male clusters. While the female cluster constitutes mostly sick individuals, the male cluster constitutes healthy and sick individuals in almost identical proportion. Conclusion: Our results clearly indicate that similar transcriptomic profiles in the two sexes are “physiologically translated” in to a very different, dramatic outcome. Thus, our results suggest the need for a sex-based and transcriptomic profile-based study, for a better understanding of the onset and progression of AD. Show more

Keywords: Alzheimer’s disease, early onset Alzheimer’s disease, functional genomics, gene expression profiling, P-center cluster analysis, sexual dimorphism

DOI: 10.3233/ADR-210014

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 541-547, 2021

Authors: Huang, Jie | Beach, Paul | Bozoki, Andrea | Zhu, David C.

Article Type: Research Article

Abstract: Background: Postmortem studies of brains with Alzheimer’s disease (AD) not only find amyloid-beta (Aβ) and neurofibrillary tangles (NFT) in the visual cortex, but also reveal temporally sequential changes in AD pathology from higher-order association areas to lower-order areas and then primary visual area (V1) with disease progression. Objective: This study investigated the effect of AD severity on visual functional network. Methods: Eight severe AD (SAD) patients, 11 mild/moderate AD (MAD), and 26 healthy senior (HS) controls undertook a resting-state fMRI (rs-fMRI) and a task fMRI of viewing face photos. A resting-state visual functional connectivity (FC) network …and a face-evoked visual-processing network were identified for each group. Results: For the HS, the identified group-mean face-evoked visual-processing network in the ventral pathway started from V1 and ended within the fusiform gyrus. In contrast, the resting-state visual FC network was mainly confined within the visual cortex. AD disrupted these two functional networks in a similar severity dependent manner: the more severe the cognitive impairment, the greater reduction in network connectivity. For the face-evoked visual-processing network, MAD disrupted and reduced activation mainly in the higher-order visual association areas, with SAD further disrupting and reducing activation in the lower-order areas. Conclusion: These findings provide a functional corollary to the canonical view of the temporally sequential advancement of AD pathology through visual cortical areas. The association of the disruption of functional networks, especially the face-evoked visual-processing network, with AD severity suggests a potential predictor or biomarker of AD progression. Show more

Keywords: Alzheimer’s disease, face-evoked visual-processing network, FAUPA, functional areas of unitary pooled activity, resting-state visual functional connectivity network

DOI: 10.3233/ADR-210017

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 549-562, 2021

Authors: Mendez, Mario F.

Article Type: Correction

DOI: 10.3233/ADR-219003

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 563-563, 2021

Authors: Barclay, Sarah F. | Potocki, Kendra | Burles, Ford | Bech-Hansen, N. Torben | Iaria, Giuseppe

Article Type: Short Communication

Abstract: The three common alleles of the APOE gene, ɛ2/ɛ3/ɛ4, have been linked to human spatial orientation. We investigated the genetic role of APOE in developmental topographical disorientation (DTD), a lifelong condition that results in topographical disorientation. We genotyped the APOE ɛ2/ɛ3/ɛ4 alleles in a cohort of 20 unrelated DTD probands, and found allele frequencies not statistically different from the those seen in the population as a whole. Therefore, we found no evidence that DTD occurs preferentially on a genetic background containing any particular APOE allele, making it unlikely that these APOE alleles are contributing to …the development of DTD. Show more

Keywords: Cognition disorders, genotype, memory, navigation, spatial learning

DOI: 10.3233/ADR-210304

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 565-570, 2021

Authors: Paley, Elena L.

Article Type: Research Article

Abstract: Background: COVID-19 can be related to any diseases caused by microbial infection(s) because 1) co-infection with COVID-19-related virus and other microorganism(s) and 2) because metabolites produced by microorganisms such as bacteria, fungi, and protozoan can be involved in necrotizing pneumonia and other necrotizing medical conditions observed in COVID-19. Objective: By way of illustration, the microbial metabolite of aromatic amino acid tryptophan, a biogenic amine tryptamine inducing neurodegeneration in cell and animal models, also induces necrosis. Methods: This report includes analysis of COVID-19 positivity by zip codes in Florida and relation of the positivity to population density, …possible effect of ecological and social factors on spread of COVID-19, autopsy analysis of COVID-19 cases from around the world, serum metabolomics analysis, and evaluation of autoantigenome related to COVID-19. Results: In the present estimations, COVID-19 positivity percent per zip code population varied in Florida from 4.65% to 44.3% (February 2021 data). COVID-19 analysis is partially included in my book Microbial Metabolism and Disease (2021). The autoantigenome related to COVID-19 is characterized by alterations in protein biosynthesis proteins including aminoacyl-tRNA synthetases. Protein biosynthesis alteration is a feature of Alzheimer’s disease. Serum metabolomics of COVID-19 positive patients show alteration in shikimate pathway metabolism, which is associated with the presence of Alzheimer’s disease-associated human gut bacteria. Conclusion: Such alterations in microbial metabolism and protein biosynthesis can lead to toxicity and neurodegeneration as described earlier in my book Protein Biosynthesis Interference in Disease (2020). Show more

Keywords: Aminoacyl-tRNA synthetases, biogenic amines, co-infections, COVID-19, microbial metabolism, necrotizing factor, protein biosynthesis, shikimate pathway, tryptamine, tryptophan metabolism

DOI: 10.3233/ADR-210010

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 571-600, 2021

Authors: Li, Danni | Zhang, Lin | Nelson, Nathaniel W. | Mielke, Michelle M. | Yu, Fang

Article Type: Research Article

Abstract: Background: Utilities of blood-based biomarkers in Alzheimer’s disease (AD) clinical trials remain unknown. Objective: To evaluate the ability of plasma neurofilament light chain (NfL) to predict future declines in cognition and activities of daily living (ADL) outcomes in 26 older adults with mild-to-moderate AD dementia from the FIT-AD Trial. Methods: Plasma NfL was measured at baseline and 3 and 6 months. Cognition and ADL were assessed using the AD Assessment Scale-Cognition (ADAS-Cog) and AD Uniform Dataset Instruments and Disability Assessment for Dementia (DAD), respectively, at baseline, 3, 6, 9, and 12 months. Linear mixed effects models …were used to examine the associations between baseline or change in plasma NfL and changes in outcomes. Results: Higher baseline plasma NfL was associated with greater rate of decline in ADAS-Cog from baseline to 6 months (standardized estimate of 0.00462, p  = 0.02853) and in ADL from baseline to 12 months (standardized estimate of –0.00284, p  = 0.03338). Greater increase in plasma NfL in short term from baseline to 3 months was associated with greater rate of decline in memory and ADL from 3 to 6 months (standardized estimate of –0.04638 [0.003], p  = 0.01635; standardized estimate of –0.03818, p  = 0.0435) and greater rate of decline in ADL from 3 to 12 month (standardized estimate of –0.01492, p  = 0.01082). Conclusion: This study demonstrated that plasma NfL might have the potential to predict cognitive and function decline up to 12 months. However, future studies with bigger sample sizes need to confirm the findings. Show more

Keywords: Activities of daily living, ADAS-Cog, Alzheimer’s disease, blood-based biomarkers, cognition, longitudinal, neurofilament light

DOI: 10.3233/ADR-210302

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 601-611, 2021

Authors: Muñiz, Ruben | López-Álvarez, Jorge | Perea, Luis | Rivera, Sofía | González, Liliana | Olazarán, Javier

Article Type: Research Article

Abstract: Background: Over- and potentially inappropriate prescribing of psychotropic medications is a major public health concern among people with dementia. Objective: Describe the CH emical R estraints avO idance ME thodology (CHROME) criteria and evaluate its effects on psychotropic prescribing and quality of life (QoL). Methods: Observational, prospective, two-wave study conducted in two nursing homes. A multicomponent program to eliminate chemical restraints and attain quality prescription of psychotropic medications was implemented. CHROME’s diagnostic criteria comprise constellations of behavioral and psychological symptoms of dementia under six primary syndromic diagnoses. Since pharmacologic treatment is aimed at only one syndrome, …polypharmacy is avoided. Psychotropic prescription, QoL, neuropsychiatric symptoms (NPS), and other clinical measurements were collected before and one year after the intervention. Results are presented for all residents (n  = 171) and for completer subjects (n  = 115). Results: Mean age (SD) of the residents was 87.8 (5.7), 78.9% were women, and 68.5% suffered advanced dementia. Psychotropic prescriptions decreased from 1.9 (1.1) to 0.9 (1.0) (p  < 0.0005). Substantive reduction in prescribing frequency was observed for antidepressants (76.9% pre-intervention, 33.8% post-intervention) and for atypical neuroleptics (38.8% pre-intervention, 15.1% post-intervention). There was improvement in patient’s response to surroundings (p  < 0.0005) and total NPS (p  < 0.01), but small worsening occurred in social interaction (p  < 0.02, completer subjects). Safety measurements remained stable. Conclusion: CHROME criteria appear to optimize psychotropic prescriptions, avoid chemical restraints, and allow external verification of quality prescriptions. Extensive use seems feasible, related to substantial reduction of prescriptions, and of benefit for people with dementia as de-prescriptions are not associated to increased NPS or QoL loss. Show more

Keywords: Chemical restraint, dementia, neuropsychiatric symptoms, nursing home, psychotropic medications, quality of life

DOI: 10.3233/ADR-210015

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 613-624, 2021

Authors: Richards, Emma | Tales, Andrea | Bayer, Antony | Norris, Jade E. | Hanley, Claire J. | Thornton, Ian M.

Article Type: Research Article

Abstract: Background: The study of reaction time (RT) and its intraindividual variability (IIV) in aging, cognitive impairment, and dementia typically fails to investigate the processing stages that contribute to an overall response. Applying “mental chronometry” techniques makes it possible to separately assess the role of processing components during environmental interaction. Objective: To determine whether RT and IIV-decomposition techniques can shed light on the nature of underlying deficits in subcortical ischemic vascular cognitive impairment (VCI). Using a novel iPad task, we examined whether VCI deficits occur during both initiation and movement phases of a response, and whether they are equally …reflected in both RT and IIV. Methods: Touch cancellation RT and its IIV were measured in a group of younger adults (n  = 22), cognitively healthy older adults (n  = 21), and patients with VCI (n  = 21) using an iPad task. Results: Whereas cognitively healthy aging affected the speed (RT) of response initiation and movement but not its variability (IIV), VCI resulted in both slowed RT and increased IIV for both response phases. Furthermore, there were group differences with respect to response phase. Conclusion: These results indicate that IIV can be more sensitive than absolute RT in separating VCI from normal aging. Furthermore, compared to cognitively healthy aging, VCI was characterized by significant deficits in planning/initiating action as well as performing movements. Such deficits have important implications for real life actions such as driving safety, employment, and falls risk. Show more

Keywords: Aging, attention, cerebral small vessel disease, dementia, intra-individual variability, mental chronometry, reaction time, stimulus response/movement initiation & control, vascular cognitive impairment

DOI: 10.3233/ADR-210029

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 625-636, 2021

Authors: Daly, Timothy | Houot, Marion | Barberousse, Anouk | Petit, Amélie | Epelbaum, Stéphane

Article Type: Research Article

Abstract: Background: Therapeutic research into Alzheimer’s disease (AD) has been dominated by the amyloid cascade hypothesis (ACH) since the 1990s. However, targeting amyloid in AD patients has not yet resulted in highly significant disease-modifying effects. Furthermore, other promising theories of AD etiology exist. Objective: We sought to directly investigate whether the ACH still dominates the opinions of researchers working on AD and explore the implications of this question for future directions of research. Methods: During 2019, we undertook an international survey promoted with the help of the Alzheimer’s Association with questions on theories and treatments of AD. …Further efforts to promote a similar study in 2021 did not recruit a significant number of participants. Results: 173 researchers took part in the 2019 survey, 22% of which held “pro-ACH” opinions, tended to have more publications, were more likely to be male, and over 60. Thus, pro-ACH may now be a minority opinion in the field but is nevertheless the hypothesis on which the most clinical trials are based, suggestive of a representation bias. Popular vote of all 173 participants suggested that lifestyle treatments and anti-tau drugs were a source of more therapeutic optimism than anti-amyloid treatments. Conclusion: We propose a more democratic research structure which increases the likelihood that promising theories are published and funded fairly, promotes a broader scientific view of AD, and reduces the larger community’s dependence on a fragile economic model. Show more

Keywords: Alzheimer’s disease, amyloid-β , dementia prevention, diversity in science, gender, lifestyle factors, lifestyle interventions, pharmaceutical industry, tau protein, women in science

DOI: 10.3233/ADR-210030

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 637-645, 2021

Authors: Chakrabarti, Sudipta | Prorok, Tim | Roy, Avik | Patel, Dhruv | Dasarathi, Sridevi | Pahan, Kalipada

Article Type: Research Article

Abstract: Background: Neuroinflammation is a recognized aspect of Alzheimer’s disease (AD) and other neurological illnesses. Interleukin 1 receptor antagonist (IL-1Ra) is an anti-inflammatory molecule, which inhibits inflammatory molecules in different cells including brain cells. However, mechanisms for upregulating IL-1Ra in brain cells are poorly understood. Objective: Since aspirin is a widely available pain reliever that shows promise beyond its known pain-relieving capacity, we examined whether aspirin could upregulate the IL-1Ra in the brain. Methods: We employed PCR, real-time PCR, western blot, immunostaining, chromatin immunoprecipitation (ChIP), and lentiviral transduction in glial cells. 5xFAD mice, an animal model of …AD, were treated with aspirin orally via gavage. Results: Aspirin increased the expression of IL-1Ra mRNA and protein in primary mouse astrocytes and mouse BV-2 microglial cells. While investigating the mechanism, we found that the IL-1Ra gene promoter harbors peroxisome proliferator response element (PPRE) and that aspirin upregulated IL-1Ra in astrocytes isolated from peroxisome proliferator-activated receptor-beta knockout (PPARβ–/– ), but not PPARα–/– , mice. Moreover, we observed that aspirin bound to tyrosine 314 residue of PPARα to stimulate IL-1Ra and that aspirin treatment also increased the recruitment of PPARα to the IL-1Ra promoter. Accordingly, aspirin increased IL-1Ra in vivo in the brain of wild type and PPARβ–/– , but not in PPARα–/– mice. Similarly, aspirin treatment also increased astroglial and microglial IL-1Ra in the cortex of 5xFAD, but not 5xFAD/PPARα–/– mice. Conclusion: Aspirin may reduce the severity of different neurological conditions by upregulating IL-1Ra and reducing the inflammation. Show more

Keywords: 5xFAD model, aspirin, astrocytes, IL-1Ra, microglia, PPARα

DOI: 10.3233/ADR-210026

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 647-661, 2021