Journal of Alzheimer's Disease - Volume 77, issue 3

Authors: Yatawara, Chathuri | Ng, Kok Pin | Cristine Guevarra, Anne | Wong, Benjamin | Yong, TingTing | Kandiah, Nagaendran

Article Type: Research Article

Abstract: Background: Small vessel disease (SVD) and Alzheimer’s disease (AD) frequently coexist; however, it remains unclear how they collectively affect cognition. Objective: We investigated associations between SVD and AD biomarkers, namely amyloid, tau, and neurodegeneration (ATN) in young onset dementia (YOD) and explored how SVD and ATN interact to affect cognition. Methods: 80 YOD individuals were recruited from a memory clinic. SVD burden (SVD+) was operationalized as a score >1 on the Staals scale and ATN was measured using cerebrospinal fluid (CSF). Results: SVD+ was associated with lower CSF Aβ1–42 (B = –0.20, 95% CI: –0.32 …to –0.08) and greater neurodegeneration, indexed as hippocampal atrophy (B = –0.24, 95% CI: –0.40 to –0.04). SVD+ was not associated with tau. Cognitive impairment was associated with CSF Aβ1–42 (B = –0.35, 95% CI: –0.55 to –0.18) but not SVD. Rather, SVD was indirectly associated with cognition via reduced CSF Aβ1–42 , specifically with global cognition (B = –0.03, 95% CI: –0.09 to –0.01) and memory (B = 0.08, 95% CI: –.01 to .21). SVD was indirectly associated with cognition via increased neurodegeneration in grey matter (Global cognition: B = –0.06, 95% CI: –0.17 to –0.03; Memory: B = 0.05, 95% CI: 0.01 to 0.18) and the hippocampus (Global cognition: B = –0.05, 95% CI: –0.11 to –0.01; Memory: B = 0.06, 95% CI: 0.01 to 0.17). Conclusion: In YOD, SVD burden was associated with AD pathology, namely CSF Aβ1–42 . SVD indirectly contributed to cognitive impairment via reducing CSF Aβ1–42 and increasing neurodegeneration. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrovascular disease, cognitive impairment

DOI: 10.3233/JAD-200311

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1305-1314, 2020

Authors: Chu, Tak-Ho | Cummins, Karen | Stys, Peter K.

Article Type: Research Article

Abstract: Background: Axonal injury has been implicated in the development of amyloid-β in experimental brain injuries and clinical cases. The anatomy of the spinal cord provides a tractable model for examining the effects of trauma on amyloid deposition. Objective: Our goal was to examine the effects of axonal injury on plaque formation and clearance using wild type and 5xFAD transgenic Alzheimer’s disease mice. Methods: We contused the spinal cord at the T12 spinal level at 10 weeks, an age at which no amyloid plaques spontaneously accumulate in 5xFAD mice. We then explored plaque clearance by impacting spinal …cords in 27-week-old 5xFAD mice where amyloid deposition is already well established. We also examined the cellular expression of one of the most prominent amyloid-β degradation enzymes, neprilysin, at the lesion site. Results: No plaques were found in wild type animals at any time points examined. Injury in 5xFAD prevented plaque deposition rostral and caudal to the lesion when the cords were examined at 2 and 4 months after the impact, whereas age-matched naïve 5xFAD mice showed extensive amyloid plaque deposition. A massive reduction in the number of plaques around the lesion was found as early as 7 days after the impact, preceded by neprilysin upregulation in astrocytes at 3 days after injury. At 7 days after injury, the majority of amyloid was found inside microglia/macrophages. Conclusion: These observations suggest that the efficient amyloid clearance after injury in the cord may be driven by the orchestrated efforts of astroglial and immune cells. Show more

Keywords: Amyloid plaque, astrocyte, microglia, spinal cord injury, neprilysin

DOI: 10.3233/JAD-200387

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1315-1330, 2020

Authors: Amen, Daniel G. | Wu, Joseph | George, Noble | Newberg, Andrew

Article Type: Research Article

Abstract: Background: While obesity has been shown to be a risk factor for Alzheimer’s disease, the potential mechanisms underlying this risk may be clarified with better understanding of underlying physiology in obese persons. Objective: To identify patterns of cerebral perfusion abnormality in adults as a function of body mass index (BMI) defined weight categories, including overweight or obese status. Methods: A large psychiatric cohort of 35,442 brain scans across 17,721 adults (mean age 40.8±16.2 years, range 18–94 years) were imaged with SPECT during baseline and concentration scans, the latter done after each participant completed the Connors Continuous …Performance Test II. ANOVA was done to identify patterns of perfusion abnormality in this cohort across BMI designations of underweight (BMI < 18.5), normal weight (BMI = 18.5 to 24.9), overweight (BMI 24.9 to 29.9), obesity (BMI≥30), and morbid obesity (BMI≥40). This analysis was done for 128 brain regions quantifying SPECT perfusion using the automated anatomical labeling (AAL) atlas. Results: Across adulthood, higher BMI correlated with decreased perfusion on both resting and concentration brain SPECT scans. These are seen in virtually all brain regions, including those influenced by AD pathology such as the hippocampus. Conclusion: Greater BMI is associated with cerebral perfusion decreases in both resting and concentration SPECT scans across adulthood. Show more

Keywords: Cerebral perfusion, obesity, SPECT

DOI: 10.3233/JAD-200655

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1331-1337, 2020

Authors: Guglielmotto, Michela | Manassero, Giusi | Vasciaveo, Valeria | Venezia, Marika | Tabaton, Massimo | Tamagno, Elena

Article Type: Research Article

Abstract: Background: The risk of developing Alzheimer’s disease as well as its progression and severity are known to be different in men and women, and cognitive decline is greater in women than in men at the same stage of disease and could be correlated at least in part on estradiol levels. Objective: In our work we found that biological sex influences the effect of amyloid-β42 (Aβ42 ) monomers on pathological tau conformational change. Methods: In this study we used transgenic mice expressing the wild-type human tau (hTau) which were subjected to intraventricular (ICV) injections of Aβ …peptides in nanomolar concentration. Results: We found that Aβ42 produces pathological conformational changes and hyperphosphorylation of tau protein in male or ovariectomized female mice but not in control females. The treatment of ovariectomized females with estradiol replacement protects against the pathological conformation of tau and seems to be mediated by antioxidant activity as well as the ability to modulate the expression of miRNA 218 linked to tau phosphorylation. Conclusion: Our study indicates that factors as age, reproductive stage, hormone levels, and the interplay with other risk factors should be considered in women, in order to identify the best appropriate therapeutic approach in prevention of cognitive impairment. Show more

Keywords: Alzheimer’s disease, antioxidants, estradiol, miRNA, tau protein

DOI: 10.3233/JAD-200707

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1339-1351, 2020

Authors: Shi, Liu | Winchester, Laura M. | Liu, Benjamine Y. | Killick, Richard | Ribe, Elena M. | Westwood, Sarah | Baird, Alison L. | Buckley, Noel J. | Hong, Shengjun | Dobricic, Valerija | Kilpert, Fabian | Franke, Andre | Kiddle, Steven | Sattlecker, Martina | Dobson, Richard | Cuadrado, Antonio | Hye, Abdul | Ashton, Nicholas J. | Morgan, Angharad R. | Bos, Isabelle | Vos, Stephanie J.B. | ten Kate, Mara | Scheltens, Philip | Vandenberghe, Rik | Gabel, Silvy | Meersmans, Karen | Engelborghs, Sebastiaan | De Roeck, Ellen E. | Sleegers, Kristel | Frisoni, Giovanni B. | Blin, Olivier | Richardson, Jill C. | Bordet, Régis | Molinuevo, José L. | Rami, Lorena | Wallin, Anders | Kettunen, Petronella | Tsolaki, Magda | Verhey, Frans | Lleó, Alberto | Alcolea, Daniel | Popp, Julius | Peyratout, Gwendoline | Martinez-Lage, Pablo | Tainta, Mikel | Johannsen, Peter | Teunissen, Charlotte E. | Freund-Levi, Yvonne | Frölich, Lutz | Legido-Quigley, Cristina | Barkhof, Frederik | Blennow, Kaj | Rasmussen, Katrine Laura | Nordestgaard, Børge Grønne | Frikke-Schmidt, Ruth | Nielsen, Sune Fallgaard | Soininen, Hilkka | Vellas, Bruno | Kloszewska, Iwona | Mecocci, Patrizia | Zetterberg, Henrik | Morgan, B. Paul | Streffer, Johannes | Visser, Pieter Jelle | Bertram, Lars | Nevado-Holgado, Alejo J. | Lovestone, Simon

Article Type: Research Article

Abstract: Background: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer’s disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. Objective: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. Methods: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) …to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). Results: We identified a 100-protein signature induced by DKK1 in vitro . Subsets of proteins, along with age and apolipoprotein E ɛ 4 genotype distinguished amyloid pathology (A + T–N–, A+T+N–, A+T–N+, and A+T+N+) from no AD pathology (A–T–N–) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. Conclusions: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo . Show more

Keywords: ATN framework, Dickkopf-1, replication, SomaScan, Wnt signaling

DOI: 10.3233/JAD-200208

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1353-1368, 2020