Journal of Alzheimer's Disease - Volume 85, issue 3

Authors: Tran, Shirley | Kuruppu, Sanjaya | Rajapakse, Niwanthi W.

Article Type: Review Article

Abstract: Hypertension is a major risk factor for the pathogenesis of vascular dementia and Alzheimer’s disease. Chronic activation of the renin-angiotensin system (RAS) contributes substantially to neuroinflammation. We propose that neuroinflammation arising from chronic RAS activation can initiate and potentiate the onset of hypertension and related dementia. Neuroinflammation induced by chronic activation of the RAS plays a key role in the pathogenesis of dementia. Increased levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and transforming growth factor (TGF)-β have been reported in brain tissue of vascular dementia patients and animal models of vascular dementia induced by either angiotensin II …infusion or transverse aortic coarctation. It is proposed that neuronal cell death and synaptic dysfunction induced by neuroinflammation lead to cognitive impairment in dementia. The neuroprotective RAS pathway, regulated by angiotensin-converting enzyme 2 (ACE2) which converts angiotensin II into angiotensin-(1–7), can attenuate hypertension and dementia. Furthermore, the use of anti-hypertensive medications in preventing dementia or cognitive decline in hypertensive patients and animal models of dementia have mostly been beneficial. Current evidence suggests a strong link between RAS induced neuroinflammation and the onset of hypertension and dementia, which warrants further investigation. Strategies to counteract an overactive RAS and enhance the neuroprotective arm of the RAS may help prevent or improve cognitive impairment associated with hypertension. Show more

Keywords: Alzheimer’s disease, cognitive impairment, dementia, hypertension, inflammation, neuroinflammation, renin-angiotensin system, vascular dementia

DOI: 10.3233/JAD-215231

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 943-955, 2022

Authors: Kouki, Mhd Ammar | Pritchard, Anna Barlach | Alder, Jane Elizabeth | Crean, StJohn

Article Type: Review Article

Abstract: The central nervous system (CNS) is protected by a highly selective barrier, the blood-brain barrier (BBB), that regulates the exchange and homeostasis of bloodborne molecules, excluding xenobiotics. This barrier forms the first line of defense by prohibiting pathogens from crossing to the CNS. Aging and chronic exposure of the BBB to pathogens renders it permeable, and this may give rise to pathology in the CNS such as Alzheimer’s disease (AD). Researchers have linked pathogens associated with periodontitis to neuroinflammation and AD-like pathology in vivo and in vitro . Although the presence of periodontitis-associated bacteria has been linked to AD …in several clinical studies as DNA and virulence factors were confirmed in brain samples of human AD subjects, the mechanism by which the bacteria traverse to the brain and potentially influences neuropathology is unknown. In this review, we present current knowledge about the association between periodontitis and AD, the mechanism whereby periodontal pathogens might provoke neuroinflammation and how periodontal pathogens could affect the BBB. We suggest future studies, with emphasis on the use of human in vitro models of cells associated with the BBB to unravel the pathway of entry for these bacteria to the CNS and to reveal the molecular and cellular pathways involved in initiating the AD-like pathology. In conclusion, evidence demonstrates that bacteria associated with periodontitis and their virulence factors are capable of inflecting damage to the BBB and have a role in giving rise to pathology similar to that found in AD. Show more

Keywords: Alzheimer’s disease, bacteria, blood-brain barrier, periodontitis, virulence factors

DOI: 10.3233/JAD-215103

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 957-973, 2022

Authors: Cutuli, Debora | Landolfo, Eugenia | Petrosini, Laura | Gelfo, Francesca

Article Type: Review Article

Abstract: Brain-derived neurotrophic factor (BDNF), a protein belonging to the neurotrophin family, is known to be heavily involved in synaptic plasticity processes that support brain development, post-lesion regeneration, and cognitive performances, such as learning and memory. Evidence indicates that BDNF expression can be epigenetically regulated by environmental stimuli and thus can mediate the experience-dependent brain plasticity. Environmental enrichment (EE), an experimental paradigm based on the exposure to complex stimulations, constitutes an efficient means to investigate the effects of high-level experience on behavior, cognitive processes, and neurobiological correlates, as the BDNF expression. In fact, BDNF exerts a key role in mediating and …promoting EE-induced plastic changes and functional improvements in healthy and pathological conditions. This review is specifically aimed at providing an updated framework of the available evidence on the EE effects on brain and serum BDNF levels, by taking into account both changes in protein expression and regulation of gene expression. A further purpose of the present review is analyzing the potential of BDNF regulation in coping with neurodegenerative processes characterizing Alzheimer’s disease (AD), given BDNF expression alterations are described in AD patients. Moreover, attention is also paid to EE effects on BDNF expression in other neurodegenerative disease. To investigate such a topic, evidence provided by experimental studies is considered. A deeper understanding of environmental ability in modulating BDNF expression in the brain may be fundamental in designing more tuned and effective applications of complex environmental stimulations as managing approaches to AD. Show more

Keywords: Alzheimer’s disease, animal models, brain-derived neurotrophic factor, environmental enrichment, neurodegeneration, neuroplasticity, rodents

DOI: 10.3233/JAD-215193

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 975-992, 2022

Authors: Besser, Lilah M. | Galvin, James E.

Article Type: Short Communication

Abstract: We used data on 718 dementia caregivers and multivariable linear regression to test associations between residential locale and psychosocial outcomes (grief, wellbeing, burden, quality of life [QOL], self-efficacy/mastery, and social networks). Rural residence (versus urban or suburban) was not associated with the psychosocial outcomes. However, for rural caregivers, greater self-efficacy/mastery was associated with lower grief (versus urban/suburban) and burden (versus suburban), and greater social network quality was associated with lower burden (versus suburban) and higher QOL (versus urban). Interventions targeting self-efficacy/mastery and social networks may be particularly effective at improving rural caregivers’ mental health and QOL.

Keywords: Caregivers, dementia, mental health, quality of life, residence characteristics

DOI: 10.3233/JAD-215162

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 993-999, 2022

Authors: Yoo, Tai June

Article Type: Short Communication

Abstract: The immune system plays a critical role in neurodegenerative processes involved in Alzheimer’s disease (AD). In this study, a gene-based immunotherapeutic method examined the effects of anti-inflammatory cellular immune response elements (CIREs) in the amyloid-β protein precursor (AβPP) mouse model. Bi-monthly intramuscular administration, beginning at either 4 or 6 months, and examined at 7.5 through 16 months, with plasmids encoding Interleukin (IL)-10, IL-4, TGF-β polynucleotides, or a combination thereof, into AβPP mice improved spatial memory performance. This work demonstrates an efficient gene therapy strategy to downregulate neuroinflammation, and possibly prevent or delay cognitive decline in AD.

Keywords: Alzheimer’s disease, amyloid-β protein precursor, genetic therapy, immunotherapy, interleukin-10, interleukin-4, neuroinflammation, spatial memory, transgenic mice, transforming growth factor beta

DOI: 10.3233/JAD-215270

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1001-1008, 2022

Authors: Sacchi, Luca | Carandini, Tiziana | Fumagalli, Giorgio Giulio | Pietroboni, Anna Margherita | Contarino, Valeria Elisa | Siggillino, Silvia | Arcaro, Marina | Fenoglio, Chiara | Zito, Felicia | Marotta, Giorgio | Castellani, Massimo | Triulzi, Fabio | Galimberti, Daniela | Scarpini, Elio | Arighi, Andrea

Article Type: Research Article

Abstract: Background: Association between cerebrospinal fluid (CSF)-amyloid-β (Aβ)42 and amyloid-PET measures is inconstant across the Alzheimer’s disease (AD) spectrum. However, they are considered interchangeable, along with Aβ42/40 ratio, for defining ‘Alzheimer’s Disease pathologic change’ (A+). Objective: Herein, we further characterized the association between amyloid-PET and CSF biomarkers and tested their agreement in a cohort of AD spectrum patients. Methods: We included 23 patients who underwent amyloid-PET, MRI, and CSF analysis showing reduced levels of Aβ42 within a 365-days interval. Thresholds used for dichotomization were: Aβ42  < 640 pg/mL (Aβ42 +); pTau > 61 pg/mL (pTau+); and …Aβ42/40  < 0.069 (ADratio +). Amyloid-PET scans were visually assessed and processed by four pipelines (SPMCL , SPMAAL , FSGM , FSWC ). Results: Different pipelines gave highly inter-correlated standardized uptake value ratios (SUVRs) (rho = 0.93–0.99). The most significant findings were: pTau positive correlation with SPMCL SUVR (rho = 0.56, p  = 0.0063) and Aβ42/40 negative correlation with SPMCL and SPMAAL SUVRs (rho = –0.56, p  = 0.0058; rho = –0.52, p  = 0.0117 respectively). No correlations between CSF-Aβ42 and global SUVRs were observed. In subregion analysis, both pTau and Aβ42/40 values significantly correlated with cingulate SUVRs from any pipeline (R2  = 0.55–0.59, p  < 0.0083), with the strongest associations observed for the posterior/isthmus cingulate areas. However, only associations observed for Aβ42/40 ratio were still significant in linear regression models. Moreover, combining pTau with Aβ42 or using Aβ42/40 , instead of Aβ42 alone, increased concordance with amyloid-PET status from 74% to 91% based on visual reads and from 78% to 96% based on Centiloids. Conclusion: We confirmed that, in the AD spectrum, amyloid-PET measures show a stronger association and a better agreement with CSF-Aβ42/40 and secondarily pTau rather than Aβ42 levels. Show more

Keywords: Alzheimer’s disease, Aβ42/40 ratio, amyloid, amyloid-PET, biomarkers, centiloids, cerebrospinal fluid, Florbetaben, standardized uptake value ratio, tau

DOI: 10.3233/JAD-210593

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1009-1020, 2022

Authors: Schubert, Carla R. | Paulsen, Adam J. | Pinto, A. Alex | Merten, Natascha | Cruickshanks, Karen J.

Article Type: Research Article

Abstract: Background: Stored blood samples from longitudinal cohort studies may be useful for studying biomarkers of preclinical Alzheimer’s disease. Objective: This study aimed to determine the reliability of amyloid-β40 and amyloid-β42 (Aβ40 , Aβ42 ), total tau (TTau), and neurofilament light (NfL) concentrations measured in blood samples stored long-term at -80°C. Methods: Aβ40 , Aβ42 , TTau, and NfL were measured in serum and plasma samples from two longitudinal cohort studies. Serum samples had been stored at -80°C for 5 (n  = 24), 14 (n  = 24), and 20 years (N  = 78) and plasma …samples had been stored for 16 years (N  = 78). Biomarker concentrations were measured in duplicate using a single molecule array assay (Simoa; Quanterix, Billerica, MA). Replicate samples for each sample type and storage length were included. Results: The concentrations of Aβ40 , Aβ42 , TTau, and NfL were within expected ranges. Some serum TTau concentrations were below the limit of detection. The average intra-assay coefficients of variation (CV) for duplicate measures were 2–7% for all assays except for serum TTau, which were higher (CVs 13% and 17%). Mean differences in original replicate pair Aβ40 , Aβ42 , and NfL concentrations were slightly greater in samples stored for longer versus shorter time periods. Conclusion: Aβ40 , Aβ42 , TTau, and NfL can be measured in serum and plasma samples that have been stored up to 20 years at -80°C. Long-term storage may be associated with small increases in the variability of concentrations in samples stored 14 or more years. Show more

Keywords: Alzheimer’s disease, amyloid-β, blood biomarkers, epidemiology, neurofilament light, plasma, serum, single molecule array, total tau

DOI: 10.3233/JAD-215096

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1021-1029, 2022

Authors: Zhou, Andrew L. | Sharda, Nidhi | Sarma, Vidur V. | Ahlschwede, Kristen M. | Curran, Geoffry L. | Tang, Xiaojia | Poduslo, Joseph F. | Kalari, Krishna R. | Lowe, Val J. | Kandimalla, Karunya K.

Article Type: Research Article

Abstract: Background: Age is the most common risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder characterized by the hallmarks of toxic amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Moreover, sub-physiological brain insulin levels have emerged as a pathological manifestation of AD. Objective: Identify age-related changes in the plasma disposition and blood-brain barrier (BBB) trafficking of Aβ peptides and insulin in mice. Methods: Upon systemic injection of 125 I-Aβ40 , 125 I-Aβ42 , or 125 I-insulin, the plasma pharmacokinetics and brain influx were assessed in wild-type (WT) or AD transgenic (APP/PS1) mice at various ages. Additionally, publicly …available single-cell RNA-Seq data [GSE129788] was employed to investigate pathways regulating BBB transport in WT mice at different ages. Results: The brain influx of 125 I-Aβ40 , estimated as the permeability-surface area product, decreased with age, accompanied by an increase in plasma AUC. In contrast, the brain influx of 125 I-Aβ42 increased with age, accompanied by a decrease in plasma AUC. The age-dependent changes observed in WT mice were accelerated in APP/PS1 mice. As seen with 125 I-Aβ40 , the brain influx of 125 I-insulin decreased with age in WT mice, accompanied by an increase in plasma AUC. This finding was further supported by dynamic single-photon emission computed tomography (SPECT/CT) imaging studies. RAGE and PI3K/AKT signaling pathways at the BBB, which are implicated in Aβ and insulin transcytosis, respectively, were upregulated with age in WT mice, indicating BBB insulin resistance. Conclusion: Aging differentially affects the plasma pharmacokinetics and brain influx of Aβ isoforms and insulin in a manner that could potentially augment AD risk. Show more

Keywords: Aging, amyloid-β, blood-brain barrier, insulin, pharmacokinetics

DOI: 10.3233/JAD-215128

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1031-1044, 2022

Authors: Rotondo, Emanuela | Galimberti, Daniela | Mercurio, Matteo | Giardinieri, Giulia | Forti, Sara | Vimercati, Roberto | Borracci, Vittoria | Fumagalli, Giorgio G. | Pietroboni, Anna M. | Carandini, Tiziana | Nobili, Alessandro | Scarpini, Elio | Arighi, Andrea

Article Type: Research Article

Abstract: Background: COVID-19 pandemic worsened vulnerability of patients with dementia (PWD). This new reality associated with government restriction and isolation worsened stress burden and psychological frailties in PWD caregivers. Objective: To give tele-psychological support to caregivers and evaluate the effect of this intervention by quantifying stress burden and quality of life during the first COVID-19 lockdown. Methods: 50 caregivers were divided into two groups: “Caregiver-focused group” (Cg) and “Patient-focused group” (Pg). Both groups received telephone contact every 2 weeks over a 28-week period, but the content of the call was different: in Cg, caregivers answered questions about …the state of the PWD but also explored their own emotional state, stress burden, and quality of life. In Pg instead, telephone contacts were focused only on the PWD, and no evaluation regarding the caregiver mood or state of stress was made. Psychometric scales were administered to evaluate COVID-19 impact, stress burden, and quality of life. Results: Considering the time of intervention, from baseline (W0) to W28, Zarit Burden Interview and Quality of Life-caregiver questionnaires remained unchanged in Cg as compared with baseline (p  > 0.05), whereas they worsened significantly in Pg (p  < 0.01), showing increased stress over time and decreased quality of life in this group. Moreover, Impact on Event Scale values improved over the weeks in Cg (p  = 0.015), while they remained unchanged in Pg (p  = 0.483). Conclusion: Caregivers who received telephone support about their mood and stress burden did not worsen their psychological state during the time of intervention, as did instead those who did not get such support. Show more

Keywords: Caregiver, COVID-19 pandemic, people with dementia, quality of life, stress burden, tele-psychological support

DOI: 10.3233/JAD-215185

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1045-1052, 2022

Authors: Sun, Xiaoru | Zhang, Hui | Yao, Dongdong | Xu, Yaru | Jing, Qi | Cao, Silu | Tian, Li | Li, Cheng

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a fatal neurodegenerative disease, the etiology of which is unclear. Previous studies have suggested that some viruses are neurotropic and associated with AD. Objective: By using bioinformatics analysis, we investigated the potential association between viral infection and AD. Methods: A total of 5,066 differentially expressed genes (DEGs) in the temporal cortex between AD and control samples were identified. These DEGs were then examined via weighted gene co-expression network analysis (WGCNA) and clustered into modules of genes with similar expression patterns. Of identified modules, module turquoise had the highest …correlation with AD. The module turquoise was further characterized using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis. Results: Our results showed that the KEGG pathways of the module turquoise were mainly associated with viral infection signaling, specifically Herpes simplex virus, Human papillomavirus, and Epstein-Barr virus infections. A total of 126 genes were enriched in viral infection signaling pathways. In addition, based on values of module membership and gene significance, a total of 508 genes within the module were selected for further analysis. By intersecting these 508 genes with those 126 genes enriched in viral infection pathways, we identified 4 hub genes that were associated with both viral infection and AD: TLR2, COL1A2, NOTCH3, and ZNF132. Conclusion: Through bioinformatics analysis, we demonstrated a potential link between viral infection and AD. These findings may provide a platform to further our understanding of AD pathogenesis. Show more

Keywords: Alzheimer’s disease, anti-viral, bioinformatics analysis, hub genes, viral infection

DOI: 10.3233/JAD-215232

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1053-1061, 2022