Journal of Alzheimer's Disease - Volume 68, issue 1

Authors: Li, Lexiao | Ismael, Saifudeen | Nasoohi, Sanaz | Sakata, Kazuko | Liao, Francesca-Fang | McDonald, Michael P. | Ishrat, Tauheed

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common form of age-associated dementia characterized by amyloid-β plaques and neurofibrillary tangles. Recent studies have demonstrated that thioredoxin-interacting protein (TXNIP), an endogenous regulator of redox/glucose induced stress and inflammation, is now known to be upregulated in stroke, traumatic brain injury, diabetes and AD. We hypothesized that TXNIP overexpression sustains neurodegeneration through activation of the nucleotide binding and oligomerization domain-like receptor protein 3 in human AD brains. We analyzed TXNIP and the components of the NLRP3 inflammasome in the cortex of postmortem human brain samples by western blotting, real-time PCR, and immunohistochemical techniques in comparison …with age-matched non-demented controls. Our results demonstrate that TXNIP protein as well as its mRNA levels in the cortex was significantly upregulated in AD compared to control brains. Moreover, using double immunofluorescence staining, TXNIP and interlukin-1β (IL-1β) were co-localized near Aβ plaques and p-tau. These results suggest an association between TXNIP overexpression levels and AD pathogenesis. Further, a significant increased expression of cleaved caspase-1 and IL-1β, the products of inflammasome activation, was detected in the cortex of AD brains. Together, these findings suggest that TXNIP, an upstream promising new therapeutic target, is a molecular link between inflammation and AD. The significant contribution of TXNIP to AD pathology suggests that strategies focusing on specific targeting of the TXNIP-NLRP3 inflammasome may lead to novel therapies for the management of AD and other age-related dementias. Show more

Keywords: Alzheimer’s disease, amyloid plaques, hyperphosphorylated tau, NLRP3 inflammasome interlukin-1, thioredoxin-interacting protein

DOI: 10.3233/JAD-180814

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 255-265, 2019

Authors: Manniche, Christina | Hejl, Anne-Mette | Hasselbalch, Steen Gregers | Simonsen, Anja Hviid

Article Type: Research Article

Abstract: Background: The diagnostic workup of idiopathic normal pressure hydrocephalus (iNPH) can be challenging due to an overlap in symptoms and neuroimaging features with other disorders. Despite a growing interest, a cerebrospinal fluid (CSF) biomarker profile in iNPH has not yet been identified. Objective: To determine the CSF biomarkers with the greatest evidence for differentiating iNPH from the most common differential diagnoses, Alzheimer’s disease (AD) and subcortical ischemic vascular disease (SIVD). Methods: A systematic literature search was conducted in PubMed to identify relevant articles up to July 2018 using the following MESH-terms: “Cerebrospinal fluid”, “diagnos*”, “hydrocephalus, normal …pressure”. Relevant data were extracted to assess the risk of bias in the included studies. Results: Twenty-five studies including 664 patients with iNPH, 502 with AD, 57 with SIVD, 81 with other disorders, and 338 healthy controls (HC) were included. They investigated the diagnostic value of 92 CSF biomarkers. Most evidence existed for amyloid-β 42 (Aβ 42 ), phosphorylated tau (p-tau), and total tau (t-tau) in iNPH versus AD and HC: Aβ 42 did not differ between iNPH and AD, but was lower than in HC subjects. T-tau and p-tau were lower in iNPH versus AD on a level comparable to HC subjects. There was moderate or limited evidence for 62 and 88 biomarkers, respectively. Several plausible biases characterize the literature including small sample sizes and inconsistent diagnostic criteria. Conclusion: T-tau and p-tau may differentiate iNPH from AD and Aβ 42 from HC. A combination of these biomarkers may improve the diagnostic accuracy in iNPH. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, normal pressure hydrocephalus, vascular dementia

DOI: 10.3233/JAD-180816

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 267-279, 2019

Authors: Depciuch, Joanna | Zawlik, Izabela | Skrzypa, Marzena | Pająk, Justyna | Potocka, Natalia | Łach, Kornelia | Bartosik-Psujek, Halina | Koziorowska, Anna | Kaznowska, Ewa | Cebulski, Józef

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a disease of advanced civilization and a common form of dementia in people over 65 years of age. We used Fourier transform infrared (FTIR) spectroscopy combined with principal component analysis (PCA) to determine changes in the quantity and quality of the cerebrospinal fluid from AD patients at three different stages of the disease (ADI, ADII, and ADIII), as well as from patients with mild cognitive impairment (MCI). Moreover, based on the FTIR spectra, we calculated the ratio of α -helix and β-sheet secondary protein structures as well as the lipid-protein balance as potential AD markers. The …FTIR spectra of cerebrospinal fluid obtained from MCI, ADI, ADII, and ADIII patients showed that peaks corresponding to protein and deoxyribonucleic acid (DNA), and phospholipid and lipid vibrations were shifted in comparison with those of control subjects. Furthermore, the levels of these chemical compounds were lower in the patients than in the control subjects. The β-sheet secondary protein structure levels were increased in the MCI and AD patients compared with the control subjects. In addition, significant changes in the lipid-protein balance were observed. Interestingly, as the disease progressed, the lipid-protein balance became further disrupted, that is, the lipid amount decreased with disease progression. PCA analysis of lipid-protein FTIR regions revealed that the spectra could be used to distinguish between controls and patients with MCI, ADI, ADII, and ADIII. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, Fourier transform infrared spectroscopy, lipid-protein balance, PCA-LDA

DOI: 10.3233/JAD-181008

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 281-293, 2019

Authors: Cedres, Nira | Machado, Alejandra | Molina, Yaiza | Diaz-Galvan, Patricia | Hernández-Cabrera, Juan Andres | Barroso, Jose | Westman, Eric | Ferreira, Daniel

Article Type: Research Article

Abstract: Subjective cognitive complaints in cognitively normal individuals are a relevant predictor of Alzheimer’s disease (AD), cerebrovascular disease, and age-related tauopathy. Complaints starting after the age of 60 increase the likelihood of preclinical AD. However, this criterion is arbitrary and current data show that neurodegenerative disorders likely start before that age. Further, data on the role of subjective complaints below the age of 60 in individuals qualifying for subjective cognitive decline (SCD) are lacking. We investigated the association of subjective cognitive complaints with an extensive number of neuroimaging, demographic, clinical, and cognitive measures in individuals fulfilling criteria for SCD below and …above the age of 60. Nine complaints were scored in 416 individuals. Complaints were related to a higher load of white matter signal abnormalities, and this association was stronger the more subclinical changes in personality, interest, and drive were reported. In individuals <60 years, complaints were associated with lower global cognitive performance. In individuals ≥60 years, complaints were related to greater global brain atrophy and smaller total intracranial volume, and this association was stronger the more subclinical difficulties in activities of daily living were reported. Also, complaints were associated with increased depressive symptomatology irrespective of age. We conclude that complaints below the age of 60 may be associated with subtle signs of brain pathology. In the community, screening for risk of future cognitive decline should include subjective cognitive complaints, depressive symptomatology, and subclinical reduced cognition (<60 years)/activities of daily living (≥60 years), supported by basic neuroimaging examinations. Show more

Keywords: Brain atrophy, depressive symptomatology, middle-age, multivariateanalysis, subjective cognitive decline, white matter signal abnormalities

DOI: 10.3233/JAD-180720

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 295-309, 2019

Authors: Groeneveld, Onno N. | Moneti, Costanza | Heinen, Rutger | de Bresser, Jeroen | Kuijf, Hugo J. | Exalto, Lieza G. | Boomsma, Jooske M.F. | Kappelle, L.Jaap | Barkhof, Frederik | Prins, Niels D. | Scheltens, Philip | van der Flier, Wiesje M. | Biessels, Geert Jan | and on behalf of the TRACE-VCI study group

Article Type: Research Article

Abstract: Background: Type 2 diabetes mellitus (T2DM) increases the risk of vascular cognitive impairment (VCI). It is unknown which type of vascular lesions and co-morbid etiologies, in particular Alzheimer’s disease pathology, are associated with T2DM in patients with VCI, and how this relates to cognition and prognosis. Objective: To compare brain MRI and cerebrospinal fluid (CSF) markers, cognition, and prognosis in patients with possible VCI with and without T2DM. Methods: We included 851 memory clinic patients with vascular brain injury on MRI (i.e., possible VCI) from a prospective cohort study (T2DM: n  = 147, 68.4±7.9 years, 63% men; …no T2DM: n  = 704, 67.6±8.5 years, 52% men). At baseline, we assessed between-group differences in brain MRI abnormalities, CSF markers of Alzheimer’s disease, and cognitive profile. After two years follow-up, we compared occurrence of cognitive decline, stroke, and death. Results: The distribution of clinical diagnoses did not differ between patients with and without T2DM. T2DM patients had more pronounced brain atrophy (total and white matter volume), and more lacunar infarcts, whereas microbleeds were less common (all p  < 0.05). CSF amyloid-β levels were similar between the groups. T2DM patients performed worse on working memory (effect size: – 0.17, p  = 0.03) than those without, whereas performance on other domains was similar. During follow-up, risk of further cognitive decline was not increased in T2DM.∥Conclusion: In patients with possible VCI, presence of T2DM is related to more pronounced brain atrophy and a higher burden of lacunar infarcts, but T2DM does not have a major impact on cognitive profile or prognosis.∥ Show more

Keywords: Cerebrospinal fluid, magnetic resonance imaging, prognosis, type 2 diabetes mellitus, vascular brain injury

DOI: 10.3233/JAD-180914

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 311-322, 2019

Authors: Fujikura, Mai | Iwahara, Naotoshi | Hisahara, Shin | Kawamata, Jun | Matsumura, Akihiro | Yokokawa, Kazuki | Saito, Taro | Manabe, Tatsuo | Matsushita, Takashi | Suzuki, Syuuichirou | Shimohama, Shun

Article Type: Research Article

Abstract: We previously demonstrated that microglia play an essential role in clearance of amyloid-β (Aβ) in Alzheimer’s disease (AD)-like pathology. Our prior work also showed that several receptors expressed on microglia participated in Aβ phagocytosis. However, clathrin-mediated endocytosis (CME), which is associated with production and release of Aβ in neurons, has received much less attention in the context of microglial Aβ uptake. To elucidate the detailed mechanisms of microglial Aβ uptake pathways, we focused on CD14 and Toll-like receptor 4 (TLR4), which have been shown to mediate fibrillar Aβ1 - 42 (fAβ42 ) phagocytosis in microglia. CD14 has also been known to …control lipopolysaccharide-induced internalization of TLR4 in a clathrin-dependent manner. However, it remains unclear whether CD14 and TLR4 engage in CME in microglial fAβ42 uptake, including whether CD14 interacts with TLR4 in the process. In the present study, we found that CD14-positive microglia increased in an age-dependent manner in the cortex of AD model mice. Immunostaining showed that CD14 interacted with TLR4 to internalize fAβ42 in the mouse microglial cell line MG6. Knock-down of CD14 and TLR4 in MG6 cells significantly reduced intracellular fAβ42 , showing their involvement in fAβ42 uptake. We also found that clathrin participated in fAβ42 uptake by MG6 cells. Furthermore, CD14 and TLR4 mediated fAβ42 uptake via clathrin-dependent mechanisms. These results indicate that CD14 and TLR4 participate not only in phagocytosis but also in clathrin-dependent fAβ42 internalization in microglia. These findings provide novel molecular understanding of microglial fAβ42 uptake, which could be of therapeutic relevance for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , CD14, clathrin, microglia, Toll-like receptor 4

DOI: 10.3233/JAD-180904

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 323-337, 2019

Authors: Han, Zhijie | Xue, Weiwei | Tao, Lin | Zhu, Feng

Article Type: Research Article

Abstract: The pathogenesis of Alzheimer’s disease (AD) is identified to be significantly regulated by long non-coding RNA (lncRNA) based on in vivo and clinical experiments. Single nucleotide polymorphisms (SNPs) can strongly impact expression and function of lncRNA in AD, and previous genome-wide associations studies (GWAS) have discovered substantial amount of risk SNPs associated with AD. However, current studies omit the important information about SNPs when identifying potential AD-related lncRNAs. In addition to single discovery approach and small-scale samples in these studies, the number of lncRNAs discovered as keys in AD is limited. Here, multiple computational methods were integrated to discover …novel and key lncRNA of the pathology of AD. First, large-scale GWAS data involved in three ethnicities were collected from two authoritative sources, and meta-analyses were conducted to find SNPs significantly associated with AD (tag SNPs). Second, these tag SNPs together with their linkage disequilibrium information were used to discover potential lncRNAs related to AD. Third, after validation by microarray probe re-annotation of 1,282 samples and RNA-seq data analysis of 117 samples, respectively, a total of five key lncRNAs of AD were identified. Finally, possible function of these lncRNAs was predicted by genome mapping, expression quantitative trait loci, differential co-expression, and gene set enrichment analysis. Based on function prediction, four of the five key lncRNAs were identified to affect the risk of AD by regulating corresponding pathogenic genes and pathways, which are involved in regulation of amyloid-β peptide and the immune system. In summary, these findings can facilitate the discovery of potential disease-related lncRNAs and enhance understanding of the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, differential co-expression, genome-wide association study, long non-coding RNA, microarray probe re-annotation

DOI: 10.3233/JAD-181051

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 339-355, 2019

Authors: Conner, Sarah C. | Benayoun, Laurent | Himali, Jayandra J. | Adams, Stephanie L. | Yang, Qiong | DeCarli, Charles | Blusztajn, Jan K. | Beiser, Alexa | Seshadri, Sudha | Delalle, Ivana

Article Type: Research Article

Abstract: Genome-wide association studies identified a single nucleotide polymorphism (SNP) in the MSRB3 gene encoding Methionine Sulfoxide Reductase-B3 (MsrB3) to be associated with the risk for low hippocampal volume and late onset Alzheimer’s disease (AD). Subsequently, we identified AD-associated abnormal patterns of neuronal and vascular MsrB3 expression in postmortem hippocampi. The present study investigated the relationship between the MSRB3 SNP rs61921502 , G (minor/risk allele) and MRI measures of brain injury including total brain volume, hippocampal volume, and white matter hyperintensities using linear regression models; the presence of brain infarcts using logistic regression models; and the incidence of stroke, …dementia, and AD using Cox proportional hazards models in 2,038 Framingham Heart Study Offspring participants with MRI administered close to examination cycle 7 (1998–2001). Participants with neurological conditions that impede evaluation of vascular pathology by MRI, i.e., brain tumors, multiple sclerosis, and major head trauma, were excluded from the study. When adjusted for age and age squared at MRI exam, sex, and presence of Apolipoprotein ɛ 4 allele (APOE4 ), individuals with MSRB3 rs61921502 minor allele had increased odds for brain infarcts on MRI compared to those with no minor allele. However, in stratified analyses, MSRB3 rs61921502 minor allele was significantly associated with increased odds for MRI brain infarcts only in the absence of APOE4 . Show more

Keywords: Framingham Heart Study, hippocampus, MSRB3 , vascular pathology

DOI: 10.3233/JAD-180977

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 357-365, 2019

Authors: Guo, Jing | Xu, Cheng | Ni, Shaozhou | Zhang, Shujuan | Li, Qihang | Zeng, Peng | Pi, Guilin | Liu, Enjie | Sun, Dong-Sheng | Liu, Yanchao | Wang, Zhouyi | Chen, Haote | Yang, Ying | Wang, Jian-Zhi

Article Type: Research Article

Abstract: Hyperhomocysteinemia is an independent risk factor of Alzheimer’s disease (AD), which is not diagnosed for many years before onset due to lack of peripherally detectable early biomarkers. Visual dysfunction is prevalent in AD patients and correlates with the severity of cognitive defects. Importantly, alterations in eyes can be non-invasively detected. To search for early biomarkers in eyes from high risk factors of AD, we injected homocysteine (Hcy) into the rats via vena caudalis for 3, 7, and 14 days, respectively, and characterized the chronological order of the AD-like pathologies appearing in retina and the hippocampus during the progression of …hyperhomocysteinemia, and their correlations with cognitive impairment. We found that administration of Hcy for 14 days, but not 3 or 7 days, induced hyperhomocysteinemia, although a gradually increased blood Hcy level was detected. In retina and/or the hippocampus, significant loss of retinal ganglion cells and stenosis of retinal arteries with the AD-like tau and amyloid-β (Aβ) pathologies and memory deficit were shown only in the 14-day Hcy group. Interestingly, accumulation of Ser262 hyperphosphorylated tau (pS262-tau) but not Aβ with decreased methylation of protein phosphatase-2A catalytic subunit (M-PP2Ac) and increased de-methylated PP2Ac (DM-PP2Ac) was detected in retina of the 3-day Hcy group, in which the retinal pathologies were preceded by those of the hippocampus. These findings suggest that elevated pS262-tau and DM-PP2Ac and reduced M-PP2Ac in retina may serve as surveillance biomarkers for diagnosis of the hyperhomocysteinemia-induced AD in the early stage. Show more

Keywords: Alzheimer’s disease, hyperhomocysteinemia, methylated/de-methylated protein phosphatase-2A, phosphorylated tau, retina

DOI: 10.3233/JAD-180978

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 367-381, 2019

Authors: Brugnolo, Andrea | De Carli, Fabrizio | Pagani, Marco | Morbelli, Slivia | Jonsson, Cathrine | Chincarini, Andrea | Frisoni, Giovanni B. | Galluzzi, Samantha | Perneczky, Robert | Drzezga, Alexander | van Berckel, Bart N.M. | Ossenkoppele, Rik | Didic, Mira | Guedj, Eric | Arnaldi, Dario | Massa, Federico | Grazzini, Matteo | Pardini, Matteo | Mecocci, Patrizia | Dottorini, Massimo E. | Bauckneht, Matteo | Sambuceti, Gianmario | Nobili, Flavio

Article Type: Research Article

Abstract: Background: Several automatic tools have been implemented for semi-quantitative assessment of brain [18 ]F-FDG-PET. Objective: We aimed to head-to-head compare the diagnostic performance among three statistical parametric mapping (SPM)-based approaches, another voxel-based tool (i.e., PALZ), and a volumetric region of interest (VROI-SVM)-based approach, in distinguishing patients with prodromal Alzheimer’s disease (pAD) from controls. Methods: Sixty-two pAD patients (MMSE score = 27.0±1.6) and one hundred-nine healthy subjects (CTR) (MMSE score = 29.2±1.2) were enrolled in five centers of the European Alzheimer’s Disease Consortium. The three SPM-based methods, based on different rationales, included 1) a cluster identified through the correlation analysis between …[18 ]F-FDG-PET and a verbal memory test (VROI-1), 2) a VROI derived from the comparison between pAD and CTR (VROI-2), and 3) visual analysis of individual maps obtained by the comparison between each subject and CTR (SPM-Maps). The VROI-SVM approach was based on 6 VROI plus 6 VROI asymmetry values derived from the pAD versus CTR comparison thanks to support vector machine (SVM). Results: The areas under the ROC curves between pAD and CTR were 0.84 for VROI-1, 0.83 for VROI-2, 0.79 for SPM maps, 0.87 for PALZ, and 0.95 for VROI-SVM. Pairwise comparisons of Youden index did not show statistically significant differences in diagnostic performance between VROI-1, VROI-2, SPM-Maps, and PALZ score whereas VROI-SVM performed significantly (p  < 0.005) better than any of the other methods. Conclusion: The study confirms the good accuracy of [18 ]F-FDG-PET in discriminating healthy subjects from pAD and highlights that a non-linear, automatic VROI classifier based on SVM performs better than the voxel-based methods. Show more

Keywords: European Alzheimer Disease Consortium, FDG-PET, head-to-head comparison, prodromal Alzheimer’s disease, statistical parametric mapping, volumetric region of interest

DOI: 10.3233/JAD-181022

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 383-394, 2019