Journal of Alzheimer's Disease - Volume 72, issue 4

Authors: Itzhaki, Ruth F.

Article Type: Article Commentary

DOI: 10.3233/JAD-191171

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 977-980, 2019

Authors: Cioffi, Federica | Adam, Rayan Hassan Ibrahim | Broersen, Kerensa

Article Type: Review Article

Abstract: Alzheimer’s disease is the most common neurodegenerative disorder that can cause dementia in elderly over 60 years of age. One of the disease hallmarks is oxidative stress which interconnects with other processes such as amyloid-β deposition, tau hyperphosphorylation, and tangle formation. This review discusses current thoughts on molecular mechanisms that may relate oxidative stress to Alzheimer’s disease and identifies genetic factors observed from in vitro , in vivo , and clinical studies that may be associated with Alzheimer’s disease-related oxidative stress.

Keywords: Alzheimer’s disease, amyloid-β, genetic factors, neurodegeneration, oxidative stress, reactive oxygen species, tau

DOI: 10.3233/JAD-190863

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 981-1017, 2019

Authors: Parodi-Rullán, Rebecca | Sone, Je Yeong | Fossati, Silvia

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most prevalent form of dementia. Cerebrovascular dysfunction is one of the earliest events in the pathogenesis of AD, as well as in vascular and mixed dementias. Cerebral amyloid angiopathy (CAA), the deposition of amyloid around cerebral vessels, is observed in up to 90% of AD patients and in approximately 50% of elderly individuals over 80 years of age. CAA is a strong contributor to vascular dysfunction in AD. CAA-laden brain vessels are characterized by dysfunctional hemodynamics and leaky blood-brain barrier (BBB), contributing to clearance failure and further accumulation of amyloid-β (Aβ) in the cerebrovasculature and …brain parenchyma. Mitochondrial dysfunction is increasingly recognized as an important early initiator of the pathogenesis of AD and CAA. The objective of this review is to discuss the effects of Aβ on cerebral microvascular cell function, focusing on its impact on endothelial mitochondria. After introducing CAA and its etiology and genetic risk factors, we describe the pathological relationship between cerebrovascular amyloidosis and brain microvascular endothelial cell dysfunction, critically analyzing its roles in disease progression, hypoperfusion, and BBB integrity. Then, we focus on discussing the effect of Aβ challenge on endothelial mitochondrial dysfunction pathways, and their contribution to the progression of neurovascular dysfunction in AD and dementia. Finally, we report potential pharmacological and non-pharmacological mitochondria-targeted therapeutic strategies which may help prevent or delay cerebrovascular failure. Show more

Keywords: Alzheimer’s disease, amyloid, apoptosis, blood-brain barrier, cerebral amyloid angiopathy, endothelial cells, mitochondria, neurodegeneration, reactive nitrogen species, reactive oxygen species

DOI: 10.3233/JAD-190357

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1019-1039, 2019

Authors: van den Noort, Maurits | Vermeire, Katrien | Staudte, Heike | Perriard, Benoît | Bosch, Peggy | Lim, Sabina

Article Type: Article Commentary

Abstract: In a recent article of the Journal of Alzheimer ’s Disease , Hack et al. (2019) argue that linguistic ability rather than multilingualism is a significant predictor of dementia. In their longitudinal study, they investigated 325 religious sisters who were older than 75 years of age. Self-reports were used in order to determine multilingualism. They found that speaking two or three languages did not delay the onset of dementia. However, they did find that individuals speaking four or more languages were less likely to suffer from dementia than those speaking only one language and concluded that having linguistic ability was …a more significant predictor of dementia than being multilingual. However, more research is needed in order to identify the characteristics of multilingualism most salient for the risk of dementia. In this commentary, we raise several important methodological and statistical issues that are likely to have affected the findings of Hack et al.’s study. As a result, although their study makes an important contribution to the research field, drawing a conclusion at this time that linguistic ability is more a predictor of dementia than multilingualism would be premature; moreover, their preliminary results cannot be generalized to the general population. Show more

Keywords: Dementia, idea density, linguistic ability, longitudinal, multilingualism, risk

DOI: 10.3233/JAD-190807

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1041-1044, 2019

Authors: Lejri, Imane | Grimm, Amandine | Hallé, François | Abarghaz, Mustapha | Klein, Christian | Maitre, Michel | Schmitt, Martine | Bourguignon, Jean-Jacques | Mensah-Nyagan, Ayikoe Guy | Bihel, Frederic | Eckert, Anne

Article Type: Research Article

Abstract:  Translocator protein 18 kDa (TSPO) is located in the mitochondrial outer membrane and plays an important role in steroidogenesis and cell survival. In the central nervous system (CNS), its expression is upregulated in neuropathologies such as Alzheimer’s disease (AD). Previously, we demonstrated that two new TSPO ligands based on an imidazoquinazolinone termed 2a and 2b, stimulated pregnenolone synthesis and ATP production in vitro . In the present study, we compared their effects to those of TSPO ligands described in the literature (XBD173, SSR-180,575, and Ro5-4864) by profiling the mitochondrial bioenergetic phenotype before and after treatment and investigating the protective effects …of these ligands after oxidative injury in a cellular model of AD overexpressing amyloid-β (Aβ). Of note, ATP levels increased with rising pregnenolone levels suggesting that the energetic performance of mitochondria is linked to an increased production of this neurosteroid via TSPO modulation. Our results further demonstrate that the TSPO ligands 2a and 2b exerted neuroprotective effects by improving mitochondrial respiration, reducing reactive oxygen species and thereby decreasing oxidative stress-induced cell death as well as lowering Aβ levels. The compounds 2a and 2b show similar or even better functional effects than those obtained with the reference TSPO ligands XBD173 and SSR-180.575. These findings indicate that the new TSPO ligands modulate mitochondrial bioenergetic phenotype and protect against oxidative injury probably through the de novo synthesis of neurosteroids, suggesting that these compounds could be potential new therapeutic tools for the treatment of neurodegenerative disease. Show more

Keywords: Alzheimer’s disease, bioenergetics phenotype, mitochondria, neuroprotection, oxidative stress, pregnenolone, TSPO ligands

DOI: 10.3233/JAD-190127

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1045-1058, 2019

Authors: Dowjat, Karol | Adayev, Tatyana | Wojda, Urszula | Brzozowska, Katarzyna | Barczak, Anna | Gabryelewicz, Tomasz | Hwang, Yu-Wen

Article Type: Research Article

Abstract: Background: DYRK1A is implicated in mental retardation and Alzheimer’s disease (AD) dementia of Down syndrome (DS) individuals. The protein is associated with cytoskeleton and altered expression has been shown to impair the cytoskeletal network via dosage effect. Objective: Our original observations of marked reduction of cytoskeletal proteins associated with DYRK1A in brains and lymphoblastoid cell lines from DS and AD prompted an investigation whether cytoskeleton abnormalities could potentially be used as biomarkers of AD. Methods: Our assay relied on quantification of co-immunoprecipitated cytoskeletal proteins with DYRK1A (co-IP assay) and analysis of the profile of G- and …F-actin fractions obtained by high-speed centrifugations (spin-down assay). Results: In co-IP assay, both DS and AD samples displayed reduced abundance of associated cytoskeletal proteins. In spin-down assay, G-actin fractions of controls displayed two closely spaced bands of actin in SDS-PAGE; while in AD and DS, only the upper band of the doublet was present. In both assays, alterations of actin cytoskeleton were present in DS, sporadic and familial AD cases, and in asymptomatic persons who later progressed to confirmed AD, but not in non-AD donors. In blind testing involving six AD and six controls, the above tests positively identified ten cases. Analysis of blood samples revealed the diversity of mild cognitive impairment (MCI) cases regarding the presence of the AD biomarker allowing distinction between likely prodromal AD and non-AD MCI cases. Conclusions: Both brain tissue and lymphocytes from DS and AD displayed similar semi-quantitative and qualitative alterations of actin cytoskeleton. Their specificity for AD-type dementia and the presence before clinical onset of the disease make them suitable biomarker candidates for early and definite diagnosis of AD. The presence of alterations in peripheral tissue points to systemic underlying mechanisms and suggests that early dysfunction of cytoskeleton may be a predisposing factor in the development of AD. Show more

Keywords: Actin cytoskeleton, AD biomarkers, Alzheimer’s disease, diagnostic tests in blood cells, Down syndrome, DYRK1A

DOI: 10.3233/JAD-190475

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1059-1075, 2019

Authors: Garcia-Segura, Monica Emili | Fischer, Corinne E. | Schweizer, Tom A. | Munoz, David G.

Article Type: Research Article

Abstract: Background: Aberrant motor behavior (AMB) is a neuropsychiatric symptom (NPS) prevalent in Alzheimer’s disease (AD), known to cause great distress to both patients and caregivers. Apolipoprotein E4 (APOE4 ) is the most important genetic predictor of AD, and it has been associated with high NPS prevalence. Objective: To investigate the neuropathological substrates and risk factors associated with AMB in AD patients. Methods: Cases with Braak stage I-II and CERAD 0-1 were classified as Low AD (LAD), while Braak stage III-IV and CERAD 2 were grouped as Intermediate AD (IAD). Cases with Braak stage V-VI and CERAD …3 were classified as High AD (HAD) in accordance with NIA-Reagan criteria. All cases were stratified by APOE genotype, yielding No ɛ 4 & ɛ 4 and ɛ 4/ɛ 4 groups depending on ɛ 4 copy number within APOE . Presence of AMB was assessed using NPI-Q. Results and Conclusion: AMB increased in parallel with CERAD and Braak & Braak scores. Hypercholesterolemia, but no other cardiovascular risk factors, was associated with AMB in HAD. AMB prevalence in HAD was significantly increased in the presence of two APOE ɛ 4 alleles as compared to No ɛ 4 & ɛ 4. The relationship between homozygous APOE4 and AMB was strongly associated with the presence of both Lewy bodies and cerebral amyloid angiopathy pathologies in both sexes. Show more

Keywords: Aberrant motor behavior, Alzheimer’s disease, APOE gene, cerebral amyloid angiopathy, Lewy bodies, neuropathology, neuropsychiatric symptoms

DOI: 10.3233/JAD-190643

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1077-1087, 2019

Authors: Ferrari, Camilla | Polito, Cristina | Berti, Valentina | Lombardi, Gemma | Lucidi, Giulia | Bessi, Valentina | Bagnoli, Silvia | Piaceri, Irene | Nacmias, Benedetta | Sorbi, Sandro

Article Type: Research Article

Abstract: Background: Primary progressive aphasia (PPA) has been described as a neurodegenerative language disorder mainly affecting the left hemisphere. Few cases of right hemisphere damage in right-handed PPA subjects have been reported. This condition, named crossed aphasia in dextral (CAD), is relatively rare and probably related to an alteration during neurodevelopment of language networks. Objective: To explore the prevalence of CAD in an Italian cohort of 68 PPA patients, in order to evaluate whether right hemisphere language lateralization could be a risk factor for PPA. Methods: Clinical-demographic and cerebral [18 F]-fluorodeoxyglucose positron emission tomography ([18 F]FDG-PET) scan …were analyzed, resulting in 23 logopenic variant (lvPPA) patients, 26 non-fluent variant (nfvPPA) patients, and 19 semantic variant (svPPA) patients. SPM single subject routine was performed for diagnostic purposes in order to identify the hypometabolic pattern of each patient. Based on brain metabolic profile, PPA patients were divided in right and left lvPPA, nfvPPA, and svPPA. [18 F]FDG-PET group analyses were performed with SPM two-sample t -test routine. Results: 26% of lvPPA cases were identified as CAD based on right hypometabolic pattern. CAD patients did not differ from left lvPPA regarding demographic features and general cognitive performance; however, they performed better in specific working memory tasks and showed brain hypometabolism limited to the superior, middle, and supramarginal temporal gyri. Conclusion: Atypical lateralization of language function could determine a vulnerability of the phonological language loop and in that way could be a risk factor for lvPPA. Show more

Keywords: Crossed-aphasia in dextral, dementia, language, lateralization, logopenic variant, primary progressive aphasia, risk factor

DOI: 10.3233/JAD-190677

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1089-1096, 2019

Authors: Al Rihani, Sweilem B. | Lan, Renny S. | Kaddoumi, Amal

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by a compromised blood-brain barrier (BBB) and disrupted intracellular calcium homeostasis in the brain. Therefore, rectifying the BBB integrity and restoring calcium homeostasis could provide an effective strategy to treat AD. Recently, we developed a high throughput-screening assay to screen for compounds that enhance a cell-based BBB model integrity, which identified multiple hits among which is granisetron, a Food and Drug Administration approved drug. Here, we evaluated the therapeutic potential of granisetron against AD. Granisetron was tested in C57Bl/6J young and aged wild-type mice, and in a transgenic mouse model of AD namely TgSwDI for …its effect on BBB intactness and amyloid-β (Aβ)-related pathology. Our study findings showed that granisetron enhanced BBB integrity in both aged and TgSwDI mice. This effect was associated with an overall reduction in Aβ load and neuroinflammation in TgSwDI mice brains. In addition, and supported by proteomics analysis, granisetron significantly reduced Aβ induced calcium influx in vitro , and rectified calcium dyshomeostasis in TgSwDI mice brains by restoring calmodulin-dependent protein kinase II/cAMP-response element binding protein pathway, which was associated with cognitive improvement. These results support granisetron repurposing as a potential drug to hold, slow, and/or treat AD. Show more

Keywords: Alzheimer’s disease, calcium homeostasis, CamKII/CREB pathway, granisetron, repurposing

DOI: 10.3233/JAD-190849

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1097-1117, 2019

Authors: Christl, Julia | Verhülsdonk, Sandra | Pessanha, Francesca | Menge, Til | Seitz, Rüdiger J. | Kujovic, Milenko | Höft, Barbara | Supprian, Tillmann | Lange-Asschenfeldt, Christian

Article Type: Research Article

Abstract: Background: Increased expression of the astroglial Ca2+ -binding protein S100B has been observed in various neurodegenerative diseases and also seems to play a role in the unfolding of pathophysiological events at early stages of Alzheimer’s disease (AD). Objective: To examine the association of cerebrospinal fluid (CSF) levels of S100B with 1) established CSF core biomarkers total tau (tau), hyperphosphorylated tau (p -tau), and amyloid β1–42 (Aβ1–42 ) as well as neuron-specific enolase (NSE) CSF levels and 2) cognition in early AD and mild cognitive impairment (MCI) due to AD (MCI-AD). Methods: Retrospective study assessing 49 …pooled charts of Memory Clinic and inpatients diagnosed with AD (N = 26) and MCI-AD (N = 23) according to the National Institute of Aging and Alzheimer’s Disease Association (NIA-AA) criteria. Neuropsychological testing was performed with the Consortium to Establish a Registry for AD (CERAD)-Plus battery. Results: CSF levels of S100B correlated with NSE, but not the other CSF parameters. Stepwise multiple linear regression, adjusted for age, sex, and educational level, revealed that only increased CSF S100B was independently associated with lower CERAD-Plus total and Mini-Mental Status Examination scores together with poorer performance in wordlist learning (delayed recall and overall performance). We found no independent associations with other CSF biomarkers or cognitive domains. Conclusion: Our data suggest that CSF S100B may have a diagnostic value particularly at early stages of AD reflecting the significance of neuroinflammatory/astroglial processes. Thus, CSF S100B may complement the established array of available AD biomarkers to improve early stage diagnosis. Show more

Keywords: Alzheimer’s disease, CERAD-Plus, cerebrospinal fluid biomarkers, mild cognitive impairment, S100B protein

DOI: 10.3233/JAD-190550

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1119-1127, 2019