Journal of Alzheimer's Disease - Volume 61, issue 4

Authors: Kaindlstorfer, Christine | Jellinger, Kurt A. | Eschlböck, Sabine | Stefanova, Nadia | Weiss, Günter | Wenning, Gregor K.

Article Type: Review Article

Abstract: Iron is essential for cellular development and maintenance of multiple physiological processes in the central nervous system. The disturbance of its homeostasis leads to abnormal iron deposition in the brain and causes neurotoxicity via generation of free radicals and oxidative stress. Iron toxicity has been established in the pathogenesis of Parkinson’s disease; however, its contribution to multiple system atrophy (MSA) remains elusive. MSA is characterized by cytoplasmic inclusions of misfolded α-synuclein (α-SYN) in oligodendrocytes referred to as glial cytoplasmic inclusions (GCIs). Remarkably, the oligodendrocytes possess high amounts of iron, which together with GCI pathology make a contribution toward MSA pathogenesis …likely. Consistent with this observation, the GCI density is associated with neurodegeneration in central autonomic networks as well as olivopontocerebellar and striatonigral pathways. Iron converts native α-SYN into a β-sheet conformation and promotes its aggregation either directly or via increasing levels of oxidative stress. Interestingly, α-SYN possesses ferrireductase activity and α-SYN expression underlies iron mediated translational control via RNA stem loop structures. Despite a correlation between progressive putaminal atrophy and iron accumulation as well as clinical decline, it remains unclear whether pathologic iron accumulation in MSA is a secondary event in the cascade of neuronal degeneration rather than a primary cause. This review summarizes the current knowledge of iron in MSA and gives evidence for perturbed iron homeostasis as a potential pathogenic factor in MSA-associated neurodegeneration. Show more

Keywords: Iron, multiple system atrophy, α-SYN, neurodegeneration, Parkinson’s disease

DOI: 10.3233/JAD-170601

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1253-1273, 2018

Authors: Gómez-Tortosa, Estrella | Ruggiero, María | Sainz, Ma José | Villarejo-Galende, Alberto | Prieto-Jurczynska, Cristina | Venegas Pérez, Begoña | Ordás, Carlos | Agüero, Pablo | Guerrero-López, Rosa | Pérez-Pérez, Julián

Article Type: Short Communication

Abstract: The SORL1 gene encodes a protein involved in the amyloidogenic process, and its variants have been associated with Alzheimer’s disease (AD) physiopathology. We screened for SORL1 variants in 124 familial (44 early- and 80 late-onset) dementia of Alzheimer type (DAT) cases. Nine potentially pathogenic changes (three not previously reported and six rare variants) were found in nine probands (7%). After screening the control population and siblings (presence in at least 1/200 controls and/or absence of segregation pattern), a causal relationship with the disease was considered unlikely in six variants and uncertain in one. The change Trp848Ter and a …splice-site variant remained likely correlated with the disease. SORL1 mutations are present in 7% of our familial DAT cohort, though in most cases cannot be considered the direct cause of the disease. Show more

Keywords: Alzheimer’s disease, familial, neurogenetics, SORL1 gene, SORLA protein

DOI: 10.3233/JAD-170590

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1275-1281, 2018

Authors: Che, Xiang-Qian | Zhao, Qian-Hua | Huang, Yue | Li, Xia | Ren, Ru-Jing | Chen, Sheng-Di | Guo, Qi-Hao | Wang, Gang

Article Type: Short Communication

Abstract: As an important multifunctional protein involved in regulation of mitochondrial metabolism, CHCHD2 was identified as a causative gene for Parkinson’s disease (PD), yet the relationship between CHCHD2 and neurodegenerative dementia is not well understood. We directly sequenced the entire coding region of CHCHD2 gene in 150 AD patients, 84 FTD patients, and 417 controls. Four rare putative pathogenic variants of CHCHD2 , including rs142444896 (c.5C>T, p.P2L), rs752705344 (c.15C>G, p.S5R), rs145190179 (c.94G>A, p.A32T), and rs182992574 (c.255T>A, p.S85R) were identified from a cohort composed of 150 AD and 84 FTD patients. These results suggest the CHCHD2 gene may …an important role in other neurodegenerative disorders from our dementia study in China. Show more

Keywords: Alzheimer’s disease, CHCHD2, dementia, frontotemporal dementia

DOI: 10.3233/JAD-170692

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1283-1288, 2018

Authors: Serpente, Maria | Fenoglio, Chiara | Cioffi, Sara Maria Giulia | Oldoni, Emanuela | Arcaro, Marina | Arighi, Andrea | Fumagalli, Giorgio Giulio | Ghezzi, Laura | Scarpini, Elio | Galimberti, Daniela

Article Type: Short Communication

Abstract: Herein, we performed a gene expression profiling in a cohort of 10 mild cognitive impairment (MCI), subdivided, according to the analysis of cerebrospinal fluid biomarkers, in prodromal Alzheimer’s disease (AD) and non-AD MCI, as compared with 27 AD patients and 24 controls, in order to detect early gene expression alterations. We observed a significant upregulation of insulin (INS ) and INS Receptor (INSR) expression levels in AD both prodromal and fully symptomatic, as compared with controls, but not in MCI subjects. Our results suggest an early dysregulation of INS and INSR in AD pathogenesis and pave the …way to a possible utility of these transcripts as peripheral biomarkers. Show more

Keywords: Gene expression, insulin, insulin receptor, peripheral biomarkers, prodromal Alzheimer’s disease

DOI: 10.3233/JAD-170861

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1289-1294, 2018

Authors: Clemens, Vera | Regen, Francesca | Le Bret, Nathalie | Heuser, Isabella | Hellmann-Regen, Julian

Article Type: Short Communication

Abstract: Apolipoprotein E (ApoE) represents a pivotal target in Alzheimer’s disease (AD) and is modulated through retinoic acid (RA), an endogenous neuroprotective and anti-inflammatory compound. A major source of ApoE are microglia, which are pathologically activated in AD. Activated microglia are known to block RA signaling. This suggests a vicious cycle between inflammation, RA signaling, and ApoE homeostasis in AD pathogenesis. To test this hypothesis, we investigated effects of RA and proinflammatory activation on ApoE synthesis in primary human macrophage-derived microglial-like cells. Our results indicate that proinflammatory activation attenuates ApoE synthesis, an effect blocked by RA.

Keywords: Alzheimer’s disease, Apolipoprotein E, macrophages, retinoic acid, vitamin A

DOI: 10.3233/JAD-170823

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1295-1300, 2018

Authors: Rizzuto, Debora | Feldman, Adina L. | Karlsson, Ida K. | Dahl Aslan, Anna K. | Gatz, Margaret | Pedersen, Nancy L.

Article Type: Research Article

Abstract: Background: Population-based health registers are potential assets in epidemiological research; however, the quality of case ascertainment is crucial. Objective: To compare the case ascertainment of dementia, from the National Patient Register (NPR) and the Cause of Death Register (CDR) with dementia diagnoses from six Swedish population based studies. Methods: Sensitivity, specificity, and positive predictive value (PPV) of dementia identification in NPR and CDR were estimated by individual record linkage with six Swedish population based studies (n  = 19,035). Time to detection in NPR was estimated using data on dementia incidence from longitudinal studies with more than two …decades of follow-up. Results: Barely half of the dementia cases were ever detected by NPR or CDR. Using data from longitudinal studies we estimated that a record with a dementia diagnosis appears in the NPR on average 5.5 years after first diagnosis. Although the ability of the registers to detect dementia cases was moderate, the ability to detect non-dementia cases was almost perfect (99%). When registers indicate that there is a dementia diagnosis, there are very few instances in which the clinicians determined the person was not demented. Indeed, PPVs were close to 90%. However, misclassification between dementia subtype diagnoses is quite common, especially in NPR. Conclusions: Although the overall sensitivity is low, the specificity and the positive predictive value are very high. This suggests that hospital and death registers can be used to identify dementia cases in the community, but at the cost of missing a large proportion of the cases. Show more

Keywords: Alzheimer’s disease, dementia, population-based registers, validation study, vascular dementia

DOI: 10.3233/JAD-170572

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1301-1310, 2018

Authors: Lu, Jing | Shu, Runzhe | Zhu, Yan

Article Type: Research Article

Abstract: SFPQ (Splicing factor proline- and glutamine-rich) is a DNA and RNA binding protein involved in transcription, pre-mRNA splicing, and DNA damage repair. SFPQ was found dysregulated in a few tauopathies such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD). In addition, knock-down of SFPQ induced FTD-like behavior in mouse. To confirm the role of SFPQ in AD and FTD, we analyzed the brain sections from the AD and FTD brain samples with SFPQ upregulation and dislocation. Specifically, we observed SFPQ dislocated to the cytoplasm and nuclear envelopes, and DNA structures and organizations were associated with these dislocation phenotypes in AD …and FTD brains. Consistently, we also found decreased DAPI intensities and smaller chromocenters associated with SFPQ dislocation in nerural-2a (N2a) cells. As the upregulation and hyperphosphorylation of tau protein is a hallmark of AD and FTD, our study sought to investigate potential interactions between tau and SFPQ by co-transfection and co-immunoprecipitation assays in N2a cells. SFPQ dislocation was found enhanced with tau co-transfection and tau co-transfection further resulted in extended DNA disorganization in N2a cells. Overall, our results indicate that dysregulation and dislocation of SFPQ and subsequent DNA disorganization might be a novel pathway in the progression of AD and FTD. Show more

Keywords: Alzheimer’s disease, DNA organization, dislocation, splicing factor proline- and glutamine-rich, tau

DOI: 10.3233/JAD-170659

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1311-1321, 2018

Authors: Yang, Che-Chuan | Chiu, Ming-Jang | Chen, Ta-Fu | Chang, Hui-Ling | Liu, Bing-Hsien | Yang, Shieh-Yueh

Article Type: Research Article

Abstract: The feasibility of assaying plasma phosphorylated tau protein (threonine 181), denoted p-tau181, using immunomagnetic reduction (IMR) is explored. The reagent for assaying p-tau181 with IMR was synthesized, and its analytic performances were characterized. Seventy-three subjects were recruited. Each participant was examined with neuropsychological tests, magnetic resonance imaging, and IMR assay for plasma p-tau181. Using commercially available IMR kits, the plasma total tau protein (T-tau) of each subject was assayed. The dynamic range for assaying p-tau181 using IMR was 1.96×10-2 pg/ml to 104 pg/ml. There was no significant interference from total tau protein in the assay of p-tau181. The …measured concentrations of plasma p-tau181 were 2.46±1.09 pg/ml for healthy controls, 4.41±1.85 pg/ml for MCI due to AD, and 6.14±1.59 pg/ml for very mild AD. Meanwhile, the measured concentrations of plasma T-tau were 18.85±10.16 pg/ml for healthy controls, 32.98±10.18 pg/ml for MCI due to AD, and 37.54±12.29 pg/ml for very mild AD. A significant difference in plasma p-tau181 was observed between healthy controls and MCI due to AD (p  < 0.001) and between MCI due to AD and very mild AD (p  < 0.001). However, for the plasma T-tau concentration, a significant difference existed only between healthy controls and MCI due to AD (p  < 0.001). This implies that the plasma p-tau181 level is correlated more to AD severity than plasma T-tau is. Additionally, p-tau181 was observed as approximately 14% of T-tau in human plasma. Show more

Keywords: Alzheimer’s disease, human plasma, immunomagnetic reduction, phosphorylated tau protein, total tau protein

DOI: 10.3233/JAD-170810

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1323-1332, 2018

Authors: Ding, Ding | Xiong, Yunyun | Zhao, Qianhua | Guo, Qihao | Chu, Shuguang | Chu, Winnie W.C. | Luo, Jianfeng | Liang, Xiaoniu | Zheng, Li | Hong, Zhen | Wong, Lawrence K.S. | Mok, Vincent C.T.

Article Type: Research Article

Abstract: Background: Unlike western countries, data on white matter hyperintensity (WMH) in community dwelling elderly in Asian population is very limited. Objective: To examine the relation between baseline WMH burden and the risk of incident cognitive decline in a community-based cohort with Chinese-dwelling elderly. Methods: We prospectively evaluated the incident cognitive decline for 226 participants in the Shanghai Aging Study. Baseline WMH severity was visually rated by the age-related white matter changes (ARWMC) scale based on MRI. Cox proportional hazards regression model was used to estimate the relative risk (RR) of total ARWMC scale, global ARWMC score, …presence of lacune and microbleed, for incident cognitive decline by adjusting potential confounders. Results: Forty subjects were identified with incident cognitive decline (new onset 34 mild cognitive impairment and 6 dementia) during a median duration of 6 years follow–up. The incidence of cognitive decline was 3.0 (95% confidence interval [CI] 2.2–4.1) per 100 person-years. Increasing total ARWMC scale [RR1.21 (95% CI 1.06–1.39), p  = 0.004)], confluent WMH [RR3.16 (95% CI 1.50–6.64), p  = 0.002), and presence of lacunes [RR 2.73 (95% CI 1.21–6.15)] at baseline were independent predictors of incident cognitive decline. Conclusion: Our study demonstrated that confluent WMH may increase the risk of incident cognitive decline by 3 folds in community dwelling subjects. Small vessel disease may cause heavy burden of cognitive impairment in the elderly in China. Show more

Keywords: Cognitive decline, dementia, mild cognitive impairment, small vessel disease, white matter hyperintensity

DOI: 10.3233/JAD-170876

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1333-1341, 2018

Authors: Kumfu, Sirinart | Charununtakorn, Savitree T. | Jaiwongkam, Thidarat | Chattipakorn, Nipon | Chattipakorn, Siriporn C.

Article Type: Research Article

Abstract:  Cardiac ischemia-reperfusion (I/R) injury has been shown to impair brain function. Humanin analogue (HNG) given prior to cardiac ischemia has been shown to attenuate both heart and brain mitochondrial dysfunction caused by cardiac I/R injury. In a clinical setting, patients received medical treatment for acute myocardial infarction either during or after the onset of myocardial ischemia; thus, in this study, we tested the hypothesis that the administration of HNG during cardiac I/R injury has therapeutic potential for brain protection. Thirty-six male Wistar rats were divided into two groups: a cardiac I/R group (n  = 30), and a sham group (n  = 6). …The I/R rats were then divided into five subgroups to receive: 1) vehicle; 2) HNG (84 μg/kg); 3) HNG (168 μg/kg); 4) HNG (252 μg/kg) intravenously administered during the cardiac-ischemia; and 5) HNG at 252 μg/kg given at the onset of reperfusion. At the end of treatment, brains were removed for determination of blood-brain barrier (BBB) breakdown, oxidative stress, brain mitochondrial function, brain mitochondrial dynamics, p-tau, amyloid-β (Aβ) and apoptosis. HNG at a dose of 168 and 252 μg/kg administered during ischemia, and 252 μg/kg given at the onset of reperfusion effectively attenuated the brain mitochondrial dysfunction, tau hyperphosphorylation and Aβ accumulation, and apoptosis, without reducing BBB breakdown, brain oxidative stress, or mitochondrial dynamics, caused by cardiac I/R injury. In conclusion, humanin exerted neuroprotection during induced cardiac I/R injury via improvement in brain mitochondrial function, and the reduction of Alzheimer’s disease pathology and apoptosis. Show more

Keywords: Alzheimer’s disease, brain, ischemia reperfusion injury, mitochondria, oxidative stress, pathology

DOI: 10.3233/JAD-170708

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1343-1353, 2018