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

Authors: Tournier, Benjamin B. | Tsartsalis, Stergios | Ceyzériat, Kelly | Fraser, Ben H. | Grégoire, Marie-Claude | Kövari, Enikö | Millet, Philippe

Article Type: Research Article

Abstract: Background: In vivo PET/SPECT imaging of neuroinflammation is primarily based on the estimation of the 18 kDa-translocator-protein (TSPO). However, TSPO is expressed by different cell types which complicates the interpretation. Objective: The present study evaluates the cellular origin of TSPO alterations in Alzheimer’s disease (AD). Methods: The TSPO cell origin was evaluated by combining radioactive imaging approaches using the TSPO radiotracer [125 I]CLINDE and fluorescence-activated cell sorting, in a rat model of AD (TgF344-AD) and in AD subjects. Results: In the hippocampus of TgF344-AD rats, TSPO overexpression not only concerns glial cells but the …increase is visible at 12 and 24 months in astrocytes and only at 24 months in microglia. In the temporal cortex of AD subjects, TSPO upregulation involved only glial cells. However, the mechanism of this upregulation appears different with an increase in the number of TSPO binding sites per cell without cell proliferation in the rat, and a microglial cell population expansion with a constant number of binding sites per cell in human AD. Conclusion: These data indicate an earlier astrocyte intervention than microglia and that TSPO in AD probably is an exclusive marker of glial activity without interference from other TSPO-expressing cells. This observation indicates that the interpretation of TSPO imaging depends on the stage of the pathology, and highlights the particular role of astrocytes. Show more

Keywords: Alzheimer’s disease, amyloid, FACS-RTT, neuroinflammation, TgF344-AD, TSPO

DOI: 10.3233/JAD-200136

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1043-1056, 2020

Authors: Lim, Yen Ying | Maruff, Paul | Kaneko, Naoki | Doecke, James | Fowler, Christopher | Villemagne, Victor L. | Kato, Takashi | Rowe, Christopher C. | Arahata, Yutaka | Iwamoto, Shinichi | Ito, Kengo | Tanaka, Koichi | Yanagisawa, Katsuhiko | Masters, Colin L. | Nakamura, Akinori

Article Type: Research Article

Abstract: Background: Using immunoprecipitation-mass spectrometry, we recently developed and validated a plasma composite biomarker for the assessment of amyloid-β (Aβ) levels. However, as yet, its relationship with clinical outcomes remains unclear. Objective: We aimed to examine the relationship between this plasma Aβ composite biomarker and cognitive function in cognitively normal older adults in two independent cohorts. Methods: Participants enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study and the National Centre for Geriatrics and Gerontology (NCGG) study had undergone Aβ neuroimaging using positron emission tomography (PET), cognitive assessments and provided blood samples. We derived a high-performance …plasma Aβ composite biomarker by immunoprecipitation with mass-spectrometry. Results: Both continuous and categorical measures of the plasma Aβ composite biomarker were significantly related to decline in episodic memory and executive function. The magnitude of effects of the plasma Aβ composite on episodic memory and executive function were comparable to that observed for the effects of PET Aβ levels on these same outcome measures. Conclusion: Several plasma Aβ biomarkers have been developed, but none have yet been applied to investigate their relationship with cognitive outcomes. Our results have important implications for the use of this biomarker in the detection of at-risk individuals. Show more

Keywords: Amyloid-β , cognition, memory, plasma, plasma biomarker, preclinical Alzheimer’s disease

DOI: 10.3233/JAD-200475

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1057-1065, 2020

Authors: Parker, Ashleigh F. | Smart, Colette M. | Scarapicchia, Vanessa | Gawryluk, Jodie R. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Individuals with subjective cognitive decline (SCD) are thought to be the earliest along the cognitive continuum between healthy aging and Alzheimer’s disease (AD). Objective: The current study used a multi-modal neuroimaging approach to examine differences in brain structure and function between individuals with SCD and healthy controls (HC). Methods: 3T high-resolution anatomical images and resting-state functional MRI scans were retrieved for 23 individuals with SCD and 23 HC from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Results: The SCD and HC groups were not significantly different in age or education level. Voxel-based morphometry …results did not show significant differences in grey matter volume between the groups. Functional MRI results revealed significantly greater functional connectivity in the default mode network in regions including the bilateral precuneus cortex, bilateral thalamus, and right hippocampal regions in individuals with SCD relative to controls. Conversely, those with SCD showed decreased functional connectivity in the bilateral frontal pole, caudate, angular gyrus, and lingual gyrus, compared to HC. Conclusion: Findings revealed differences in brain function but not structure between individuals with SCD and HC. Overall, this study represents a crucial step in characterizing individuals with SCD, a group recognized to be at increased risk for AD. It is imperative to identify biomarkers of AD prior to significant decline on clinical assessment, so that disease-delaying interventions may be delivered at the earliest possible time point. Show more

Keywords: Alzheimer’s disease, magnetic resonance imaging, neuroimaging, subjective cognitive decline

DOI: 10.3233/JAD-200299

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1067-1076, 2020

Authors: Qu, Na | Wang, Xiao-Ming | Zhang, Teng | Zhang, Shu-Fang | Li, Yi | Cao, Fu-Yuan | Wang, Qun | Ning, Lin-Na | Tian, Qing

Article Type: Research Article

Abstract: Background: Women are reported more likely to develop depression and dementia. However, the involved mechanism is poorly understood. Objective: Here, we clarified the role of estrogen receptor α (ERα ) in depression and cognitive deficit in young female rats. Methods: After being exposed to 7-weeks’ chronic unpredicted mild stress (CUMS), the depression resilient rats (Res rats) and depressed rats (Dep rats) were selected according to their records in sucrose preference test, forced swimming test, and open field test. Their cognition abilities were tested by Morris water maze. Proteomic assay, immunoprecipitation, western blotting, immunohistochemical, and Nissl …staining were also used to understand the involved mechanism. Results: Compared with control rats and Res rats, Dep rats showed cognitive deficits and hippocampal impairments revealed by proteomic data, neuron losses, increased cleaved caspase-3, β-catenin phosphorylation, and glycogen synthase kinase3β (GSK3β) activation. As ERα , but not ERβ, was found declined in hippocampi of Dep rats, 4,4k,4a-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT, an ERα agonist, 1 mg/kg/day), was used to treat Dep rats (Dep + PPT). Twenty days later, the depressive behaviors, cognition deficits, and hippocampal neuron loss were rescued in Dep + PPT rats. Furthermore, Res and Dep + PPT rats had higher levels of β-catenin combined with ERα and lower levels of β-catenin combined with GSK3β than Dep rats in hippocampi. Conclusion: These results demonstrated hippocampal ERα is an important pro-resilient factor in CUMS-induced depressive behaviors and cognitive deficits. It was also given that the neuroprotection afforded by hippocampal ERα /Wnt interactions have significant implications for cognition and emotion in young females. Show more

Keywords: β-catenin, depression, estrogen receptor α , glycogen synthase kinase3β , resilience

DOI: 10.3233/JAD-200486

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1077-1093, 2020

Authors: Sutovsky, Stanislav | Petrovic, Robert | Fischerova, Maria | Haverlikova, Viera | Ukropcova, Barbara | Ukropec, Jozef | Turcani, Peter

Article Type: Research Article

Abstract: Background: Genetic risk factors play an important role in the pathogenesis of Alzheimer’s disease (AD). However, the gene-gene interaction (epistasis) between specific allelic variants is only partially understood. Objective: In our study, we examined the presence of the ɛ 4 allele of apolipoprotein E (APOE ) and the presence of C677T and A1298C (rs1801133 and rs1801131) polymorphisms in the methylenetetrahydrofolate reductase (MTHFR ) gene in patients with AD and controls. We also evaluated the epistatic interaction between MTHFR and the APOE variants. Methods: A total of 564 patients with AD and 534 cognitively unimpaired …age-matched controls were involved in the study. Results: The presence of the ɛ 4 allele of APOE increases the risk of developing AD in a dose-dependent manner (OR 32.7: homozygotes, 15.6: homozygotes + heterozygotes, 14.3: heterozygotes). The combination of genotypes also increases the risk of developing AD in a dose-dependent manner: OR 18.3 (APOE 4/X and 4/4 + CT rs1801133), OR 19.4 (APOE 4/X and 4/4 + CT rs1801133 + AC rs1801131), OR 22.4 (APOE 4/X and 4/4 + TT rs1801133), and OR 21.2 (APOE 4/X and 4/4 + CC rs1801131). Homozygotes for variant alleles of MTHFR as well as patients with AD had significantly higher levels of homocysteine than homozygotes for standard alleles or controls. Conclusion: Homozygotes for APOE4 and carriers of APOE4 with TT genotype of rs1801133 were found to be at the highest risk of developing AD. These findings suggest that the epistatic interaction of specific gene variants can have a significant effect on the development of AD. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, epistasis, MTHFR

DOI: 10.3233/JAD-200321

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1095-1105, 2020

Authors: van den Kieboom, Robin | Snaphaan, Liselore | Mark, Ruth | Bongers, Inge

Article Type: Research Article

Abstract: Background: Caring for patients with dementia at home is often a long-term process, in which the independence of the patient declines, and more responsibility and supervision time is required from the informal caregiver. Objective: In order to minimize and reduce caregiver burden, it is important to explore its trajectory and the accompanying risk factors as dementia progresses; the objective of this systematic review. Methods: PRISMA guidelines were followed in this systematic review. Three databases, PubMed, PsycINFO, and EMbase, were systematically searched in November 2019 using specific keywords. Results: 1,506 hits emerged during the systematic …search but only eleven articles actually met the inclusion criteria for this review. The trajectory of caregiver burden is highly variable and depends on multiple factors. Important risk factors included: patients’ behavioral and neuropsychiatric symptoms, and their decline in functioning in (I)ADL; the caregiver’s age, gender, and physical and mental health; and, within the dyads (patient/caregiver), cohabitation and kinship. Conclusion: There is no one-size-fits-all for predicting how caregiver burden will change over time, but specific factors (like being a spouse and increased behavioral impairment and decline in functional status in the patient) may heighten the risk. Other factors, not yet comprehensively included in the published studies, might also prove to be important risk factors. Future research in the field of reducing caregiver burden is recommended to integrate the patient, caregiver, and context characteristics in the trajectory of caregiver burden, and to assess more clearly the phase of the dementia progression and use of external resources. Show more

Keywords: Caregiver burden, dementia, informal caregiver, longitudinal study, progression, systematic review

DOI: 10.3233/JAD-200647

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1107-1115, 2020

Authors: Bergland, Anne Katrine | Proitsi, Petroula | Kirsebom, Bjørn-Eivind | Soennesyn, Hogne | Hye, Abdul | Larsen, Alf Inge | Xu, Jin | Legido-Quigley, Cristina | Rajendran, Lawrence | Fladby, Tormod | Aarsland, Dag

Article Type: Research Article

Abstract: Background: Lipids have important structural roles in cell membranes and changes to these membrane lipids may influence β- and γ -secretase activities and thus contribute to Alzheimer’s disease (AD) pathology. Objective: To explore baseline plasma lipid profiling in participants with mild cognitive impairment (MCI) with and without AD pathology. Methods: We identified 261 plasma lipids using reversed-phase liquid chromatography/mass spectrometry in cerebrospinal fluid amyloid positive (Aβ+) or negative (Aβ–) participants with MCI as compared to controls. Additionally, we analyzed the potential associations of plasma lipid profiles with performance on neuropsychological tests at baseline and after two …years. Results: Sphingomyelin (SM) concentrations, particularly, SM(d43:2), were lower in MCI Aβ+ individuals compared to controls. Further, SM(d43:2) was also nominally reduced in MCI Aβ+ individuals compared to MCI Aβ–. No plasma lipids were associated with performance on primary neuropsychological tests at baseline or between the two time points after correction for multiple testing. Conclusion: Reduced plasma concentrations of SM were associated with AD. Show more

Keywords: Alzheimer’s disease, lipid, mild cognitive impairment, sphingomyelin

DOI: 10.3233/JAD-200441

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1117-1127, 2020

Authors: Benussi, Alberto | Ashton, Nicholas J. | Karikari, Thomas K. | Gazzina, Stefano | Premi, Enrico | Benussi, Luisa | Ghidoni, Roberta | Rodriguez, Juan Lantero | Emeršič, Andreja | Binetti, Giuliano | Fostinelli, Silvia | Giunta, Marcello | Gasparotti, Roberto | Zetterberg, Henrik | Blennow, Kaj | Borroni, Barbara

Article Type: Research Article

Abstract: Background: It is still unknown if serum glial fibrillary acidic protein (GFAP) is a useful marker in frontotemporal lobar degeneration (FTLD). Objective: To assess the diagnostic and prognostic value of serum GFAP in a large cohort of patients with FTLD. Methods: In this retrospective study, performed on 406 participants, we measured serum GFAP concentration with an ultrasensitive Single molecule array (Simoa) method in patients with FTLD, Alzheimer’s disease (AD), and in cognitively unimpaired elderly controls. We assessed the role of GFAP as marker of disease severity by analyzing the correlation with clinical variables, neurophysiological data, and …cross-sectional brain imaging. Moreover, we evaluated the role of serum GFAP as a prognostic marker of disease survival. Results: We observed significantly higher levels of serum GFAP in patients with FTLD syndromes, except progressive supranuclear palsy, compared with healthy controls, but not compared with AD patients. In FTLD, serum GFAP levels correlated with measures of cognitive dysfunction and disease severity, and were associated with indirect measures of GABAergic deficit. Serum GFAP concentration was not a significant predictor of survival. Conclusion: Serum GFAP is increased in FTLD, correlates with cognition and GABAergic deficits, and thus shows promise as a biomarker of disease severity in FTLD. Show more

Keywords: Biomarker, frontotemporal dementia, glial fibrillary acidic protein, magnetic resonance imaging, serum, survival, transcranial magnetic stimulation

DOI: 10.3233/JAD-200608

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1129-1141, 2020

Authors: Enache, Daniela | Pereira, Joana B. | Jelic, Vesna | Winblad, Bengt | Nilsson, Per | Aarsland, Dag | Bereczki, Erika

Article Type: Research Article

Abstract: Background: Cognitive deficits arising in the course of Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and Parkinson’s disease with dementia (PDD) are directly linked to synaptic loss. Postmortem studies suggest that zinc transporter protein 3 (ZnT3), AMPA glutamate receptor 3 (GluA3), and Dynamin1 are associated with cognitive decline in AD and Lewy body dementia patients. Objective: We aimed to evaluate the diagnostic value of ZnT3, GluA3, and Dynamin 1 in the cerebrospinal fluid (CSF) of patients with dementia due to AD, DLB, and PDD compared to cognitively normal subjective cognitive decline (SCD) patients in a retrospective study. …In addition, we assessed the relationship between synaptic markers and age, sex, cognitive impairment, and depressive symptoms as well as CSF amyloid, phosphorylated tau (p-tau), and total tau (T-tau). Methods: Commercially available ELISA immunoassay was used to measure the levels of proteins in a total of 97 CSF samples from AD (N = 24), PDD (N = 18), DLB (N = 27), and SCD (N = 28) patients. Cognitive impairment was assessed using the Mini-Mental State Examination (MMSE). Results: We found a significant increase in the concentrations of ZnT3, GluA3, and Dynamin1 in AD (p  = 0.002) and of ZnT3 and Dynamin 1 in DLB (p  = 0.001, p  = 0.002) when compared to SCD patients. Changes in ZnT3 concentrations correlated with MMSE scores in AD (p  = 0.011), and with depressive symptoms in SCD (p  = 0.041). Conclusion: We found alteration of CSF levels of synaptic proteins in AD, PDD, and DLB. Our results reveal distinct changes in CSF concentrations of ZnT3 that could reflect cognitive impairment in AD with implications for future prognostic and diagnostic marker development. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cognitive impairment, depression, Lewy body dementia, synaptic proteins, ZnT3

DOI: 10.3233/JAD-200498

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1143-1155, 2020

Authors: Yang, Zhirong | Edwards, Duncan | Burgess, Stephen | Brayne, Carol | Mant, Jonathan

Article Type: Research Article

Abstract: Background: Prior atherosclerotic cardiovascular disease (ASCVD), including coronary heart disease (CHD) and peripheral artery disease (PAD), are common among patients with stroke, a known risk factor for dementia. However, whether these conditions further increase the risk of post-stroke dementia remains uncertain. Objective: To examine whether prior ASCVD is associated with increased risk of dementia among stroke patients. Methods: A retrospective cohort study was conducted using the Clinical Practice Research Datalink with linkage to hospital data. Patients with first-ever stroke between 2006 and 2017 were followed up to 10 years. We used multi-variable Cox regression models to …examine the associations of prior ASCVD with dementia and the impact of prior ASCVD onset and duration. Results: Among 63,959 patients, 7,265 cases (11.4%) developed post-stroke dementia during a median of 3.6-year follow-up. The hazard ratio (HR) of dementia adjusted for demographics and lifestyle was 1.18 (95% CI: 1.12–1.25) for ASCVD, 1.16 (1.10–1.23) for CHD, and 1.25 (1.13–1.37) for PAD. The HRs additionally adjusted for multimorbidity and medications were 1.07 (1.00–1.13), 1.04 (0.98–1.11), and 1.11 (1.00–1.22), respectively. Based on the fully adjusted estimates, there was no linear relationship between the age of ASCVD onset and post-stroke dementia (all p-trend >0.05). The adjusted risk of dementia was not increased with the duration of pre-stroke ASCVD (all p-trend >0.05). Conclusion: Stroke patients with prior ASCVD are more likely to develop subsequent dementia. After full adjustment for confounding, however, the risk of post-stroke dementia is attenuated, with only a slight increase with prior ASCVD. Show more

Keywords: Atherosclerotic cardiovascular disease, cohort study, coronary artery disease, dementia, peripheral arterial disease, stroke

DOI: 10.3233/JAD-200536

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1157-1167, 2020