Journal of Alzheimer's Disease - Volume 67, issue 1

Authors: Yang, Meirong | Wang, Yan | Liang, Ge | Xu, Zhendong | Chu, Charleen T. | Wei, Huafeng

Article Type: Research Article

Abstract: Background: Disruption of intracellular Ca2+ homeostasis and associated autophagy dysfunction contribute to neuropathology in Alzheimer’s disease (AD). Objective: To study the effects of propofol on cell viability via its effects on intracellular Ca2+ homeostasis, and the impact of autophagy, in a neuronal model of presenilin-mutated familial AD (FAD). Methods: We treated PC12 cells, stably transfected with either mutated presenilin-1 (L286V) or wild type (WT) controls, with propofol at different doses and durations, in the presence or absence of extracellular Ca2+ , antagonists of inositol trisphosphate receptors (InsP3 R, xestospongin C) and/or ryanodine receptors (RYR, …dantrolene), or an inhibitor of autophagy flux (Bafilomycin). We determined cell viability, cytosolic Ca2+ concentrations ([Ca2+ ]c ), vATPase protein expression, and lysosomal acidification. Results: The propofol dose- and time-dependently decreased cell viability significantly more in L286V than WT cells, especially at the pharmacological dose (>50μ M), and together with bafilomycin (40 nM). Clinically used concentrations of propofol (<20μ M) tended to increase cell viability. Propofol significantly increased [Ca2+ ]c more in L286V than in WT cells, which was associated with decrease of vATPase expression and localization to the lysosome. Both toxicity and increased Ca2+ levels were ameliorated by inhibiting InsP3 R/RYR. However, the combined inhibition of both receptors paradoxically increased [Ca2+ ]c , by inducing Ca2+ influx from the extracellular space, causing greater cytotoxicity. Conclusion: Impairment in autophagy function acts to deteriorate cell death induced by propofol in FAD neuronal cells. Cell death is ameliorated by either RYR or InsP3 R antagonists on their own, but not when both are co-administered. Show more

Keywords: Alzheimer’s disease, anesthesia, autophagy, calcium, presenilin

DOI: 10.3233/JAD-180858

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 137-147, 2019

Authors: Strobel, Sabrina | Grünblatt, Edna | Heinsen, Helmut | Riederer, Peter | Espach, Thomas | Meder, Michael | Monoranu, Camelia-Maria

Article Type: Research Article

Abstract: Oxidative stress is implicated in the pathogenesis of neurodegenerative diseases, including sporadic Alzheimer’s disease (AD). Mitochondrial DNA (mtDNA) deletions are markers of oxidative damage with an age-dependent accumulation. In a previous study, we analyzed mtDNA levels in diverse neuronal cell types in order to unravel the impact of oxidative stress in brains of AD patients. The aim of this study was to identify possible correlations between mtDNA deletion levels of selected astrocytes and microglia from three brain regions with different vulnerability to AD pathology and different stages of disease compared to controls. Our results reflect a higher vulnerability of hippocampal …astrocytes and microglia to oxidative stress compared to other brain regions, such as cerebellum and brainstem. Show more

Keywords: Alzheimer’s disease, astrocytes, brainstem, cerebellum, hippocampus, microglia, mitochondrial DNA, oxidative stress, selective vulnerability

DOI: 10.3233/JAD-180661

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 149-157, 2019

Authors: Guven, Gamze | Bilgic, Başar | Tufekcioglu, Zeynep | Erginel Unaltuna, Nihan | Hanagasi, Hasmet | Gurvit, Hakan | Singleton, Andrew | Hardy, John | Emre, Murat | Gulec, Cagri | Bras, Jose | Guerreiro, Rita | Lohmann, Ebba

Article Type: Research Article

Abstract: Progranulin (GRN) gene mutations are a major cause of frontotemporal dementia (FTD). Most mutations identified to date are null mutations, which are predicted to cause the pathology via haploinsufficiency. Decreased peripheral progranulin protein (PGRN) levels are associated with the presence of GRN null mutations and are accepted as reliable biomarkers. In this study, our aim was to test whether the presence of specific GRN splice site mutations (c.– 8+2T>G and c.708+6_9del), could be predicted by peripheral mRNA or protein GRN levels, by studying affected and asymptomatic individuals from FTD families. We also tested four missense GRN …variants to assess if altered GRN levels depended on the type of mutation. Our results confirmed a reduction in both mRNA and protein PGRN levels in the splice site mutation carriers, which is consistent with previous reports for null mutations. Our results also suggested that both decreased peripheral GRN mRNA and serum PGRN levels indicate the presence of pathogenic mutations in affected individuals, and identify the asymptomatic individuals at risk, without previous knowledge of genetic status. Both inferences suggest a potential use of peripheral GRN mRNA or serum PGRN levels as biomarkers for families with FTD. Show more

Keywords: ELISA, frontotemporal dementia, progranulin, serum, splice site mutation

DOI: 10.3233/JAD-180599

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 159-167, 2019

Authors: Zhang, Haibo | Wang, Ding | Gong, Ping | Lin, Aihua | Zhang, Yan | Ye, Richard D. | Yu, Yang

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by progressive loss of memory and other cognitive functions. Accumulation of amyloid-β (Aβ) and hyperphosphorylated tau are two major neuropathological features of AD. Formyl peptide receptor 2 (FPR2), contributing to innate immunity and inflammation, has been implicated in the uptake and clearance of Aβ. It remains unclear whether FPR2 affects cognition and tau phosphorylation. The effects of FPR2 in cognition and tau phosphorylation were examined using FPR2 knock-out (Fpr2 –/– ) mice receiving intracerebroventricular (ICV) injection of streptozotocin (STZ). The general behaviors and cognitive functions were evaluated using rotarod, open field test, and Morris …water maze test. The alteration in tau hyperphosphorylation and activation of astrocytes were determined by using western blotting and/or immunofluorescence staining. ICV injection of STZ impaired spatial learning and memory of mice in Morris water maze. FPR2 deficiency improved spatial learning and memory of ICV-STZ mice. In the hippocampus and cortex of ICV-STZ mice, a marked increase was observed in tau phosphorylation at Ser199, Thr205, and Ser396 compared with ICV-saline control mice. However, FPR2 deficiency attenuated the hyperphosphorylation of tau at Ser199 and Ser396. In addition, the expression of GFAP was significantly increased in hippocampus and cortex of ICV-STZ mice. FPR2 deletion reduced the increase of GFAP expression induced by ICV injection of STZ. These results indicate that FPR2 deficiency is associate with improved cognition, reduced tau hyperphosphorylation, and activation of astrocytes in the mouse AD model tested. FPR2 may be a potential target in AD prevention and therapy. Show more

Keywords: Alzheimer’s disease, astrocyte activation, formyl peptide receptor 2, tau phosphorylation

DOI: 10.3233/JAD-180823

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 169-179, 2019

Authors: Schwarz, Christopher G. | Gunter, Jeffrey L. | Lowe, Val J. | Weigand, Stephen | Vemuri, Prashanthi | Senjem, Matthew L. | Petersen, Ronald C. | Knopman, David S. | Jack Jr, Clifford R.

Article Type: Research Article

Abstract: Longitudinal PET studies in aging and Alzheimer’s disease populations rely on accurate and precise measurements of change over time from serial PET scans. Various methods for partial volume correction (PVC) are commonly applied to such studies, but existing comparisons and validations of these PVC methods have focused on cross-sectional measurements. Rate of change measurements inherently have smaller magnitudes than cross-sectional measurements, so levels of noise amplification due to PVC must be smaller, and it is necessary to re-evaluate methods in this context. Here we compare the relative precision in longitudinal measurements from serial amyloid PET scans when using geometric transfer …matrix (GTM) PVC versus the traditional two-compartment (Meltzer-style), three-compartment (Müller-Gärtner-style), and no-PVC approaches. We used two independent implementations of standardized uptake value ratio (SUVR) measurement and PVC (one in-house pipeline based on SPM12 and ANTs, and one using FreeSurfer 6.0). For each approach, we also tested longitudinal-specific variants. Overall, we found that measurements using GTM PVC had significantly worse relative precision (unexplained within-subject variability ≈4–8%) than those using two-compartment, three-compartment, or no PVC (≈2–4%). Longitudinally-stabilized approaches did not improve these properties. This data suggests that GTM PVC methods may be less suitable than traditional approaches when measuring within-person change over time in longitudinal amyloid PET. Show more

Keywords: Amyloid PET, change over time, geometric transfer matrix, partial volume correction, Pittsburgh Compound B, precision, SUVR

DOI: 10.3233/JAD-180749

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 181-195, 2019

Authors: Hvidsten, Lara | Engedal, Knut | Selbæk, Geir | Wyller, Torgeir Bruun | Benth, Jūratė Šaltytė | Kersten, Hege

Article Type: Research Article

Abstract: Background: Cross-sectional studies of quality of life (QOL) of people with young-onset dementia show diverging results. Objective: To identify factors associated with QOL in people with young-onset Alzheimer’s (AD) and frontotemporal dementia (FTD) and explore development in QOL over a two-year period, including differences between the two subtypes. Methods: A two-year cohort study of 88 community-dwelling people with young-onset AD and FTD recruited from Nordic memory clinics. QOL was assessed using the proxy version of the Quality of Life – Alzheimer’s Disease questionnaire, dementia severity was rated with the Clinical Dementia Rating scale, depressive symptoms by …the Cornell Scale for Depression in Dementia, awareness with the Reed anosognosia scale, and needs using the Camberwell Assessment of Needs in the Elderly questionnaire. Factors associated with QOL and development in QOL over time were explored with growth mixture model trajectories and mixed model analyses. Results: We identified two groups of people following trajectories with better (n  = 35) versus poorer (n  = 53) QOL. People with more depressive symptoms at baseline had higher odds of belonging to poorer QOL group, OR 1.2 (CI 1.1; 1.5, p  = 0.011). Having Alzheimer’s disease was associated with significantly better QOL (p  = 0.047 at baseline, p  = 0.009 at T1 and p  = 0.033 at T2). Increasing number of unmet needs was significantly associated with poorer QOL at baseline (p  = 0.007), but not later in follow-up. Conclusion: Early assessment and treatment based on dementia subtype, depression, and individual needs may enhance quality of life in young-onset dementia. Show more

Keywords: Alzheimer’s disease, depression, frontotemporal dementia, quality of life, young-onset

DOI: 10.3233/JAD-180479

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 197-210, 2019

Authors: Lövheim, Hugo | Norman, Tove | Weidung, Bodil | Olsson, Jan | Josefsson, Maria | Adolfsson, Rolf | Nyberg, Lars | Elgh, Fredrik

Article Type: Research Article

Abstract: Background: Herpes simplex virus (HSV) has been suggested to play a role in Alzheimer’s disease (AD) development. Objective: The aim of the present study was to investigate the early AD-related symptom episodic memory decline in relation to HSV and carriage of allele 4 of the apolipoprotein E gene (APOE ɛ 4) in a large population-based cohort with a long follow-up time. Methods: The study included 3,413 persons, with longitudinal data available for 1,293 persons with a mean follow-up time of 11.6 years. The associations between HSV carriage, APOE ɛ 4 carriage, and episodic memory …was investigated at baseline, as well as in longitudinal analyses where individuals with and without HSV antibodies (HSV1/2 non-specific) were matched and episodic memory decline compared. Results: Cross-sectional analyses revealed an age-dependent association of HSV carriage with lower episodic memory function, particularly among APOE ɛ 4 carriers (p  = 0.008). Longitudinal analyses showed an increased risk of episodic memory decline in HSV carriers (≥65 years: p  < 0.001, all ages: non-significant), and a significant interaction between HSV and APOE ɛ 4 for episodic memory decline (p  < 0.001). Conclusion: In this large population-based cohort study, both cross-sectional and longitudinal results support an association between HSV carriage and declining episodic memory function, especially among APOE ɛ 4 carriers. The results strengthen the hypothesis that HSV is associated with AD development. Show more

Keywords: Alzheimer’s disease, APOE ɛ4, apolipoprotein E4, cognitive impairment, cohort study, dementia, epidemiological study, episodic memory, herpes simplex virus

DOI: 10.3233/JAD-171162

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 211-220, 2019

Authors: Wang, Xue-Jie | Xu, Wei | Li, Jie-Qiong | Cao, Xi-Peng | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Early-life environment is related to childhood brain development and cognitive function in later life. However, the associations of early-life risk factors with dementia and cognitive impairment were still controversial. Objective: Our study aims to investigate early-life risk factors for dementia and cognitive impairment. Methods: PubMed and Cochrane Library were searched to identify prospective cohort and retrospective case-control studies exploring early-life factors for dementia and cognitive impairment. Pooled effect estimates for each factor were calculated by random-effect model. Results: Thirty-seven studies with 46,727 participants were included. The pooled results indicated significant associations of dementia …with food deficiency (OR = 2.05, 95% CI = 1. 22–3.44), low education level (RR = 1.80, 95% CI = 1.60–2.02), and shorter leg length (OR = 1.19, 95% CI = 1.07–1.32). Other potential risk factors identified in the systematic review include rural residence, number of siblings, history of head trauma, early parental death or re-marriage, and poor learning ability. Conclusion: Early-life factors, including education level, leg length, history of childhood head trauma, family-related factors and learning ability, were associated with the risk of dementia and cognitive impairment in later life. Further high-quality longitudinal studies are needed to verify the causality between early-life risk factors and dementia and cognitive impairment. Show more

Keywords: Cognitive impairment, dementia, early-life, meta-analysis, risk factors, systematic review

DOI: 10.3233/JAD-180856

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 221-229, 2019

Authors: El Bitar, Fadia | Qadi, Najeeb | Al Rajeh, Saad | Majrashi, Amna | Abdulaziz, Sara | Majrashi, Nada | Al Inizi, Maznah | Taher, Asma | Al Tassan, Nada

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a chronic neurological disorder associated with mental decline and dementia. Several studies focused on investigating the molecular basis of the disease that led to the identification of several causative genes and risk associated alleles. Replication of these studies and findings from different populations is very important. Objective: Molecular assessment of a cohort of 117 familial and sporadic AD cases from Saudi Arabia. Methods: Comprehensive screening for point mutations was carried out by direct sequencing of coding regions in the three known AD causative genes: PSEN1, PSEN2 , APP , as well …as the AD associated gene SORL1. All patients were also genotyped for APOE alleles. In silico 3D protein structure analysis was performed for two novel SORL1 variants. Results: We identified a total of eight potential pathogenic missense variants in all studied genes. Five of these variants were not previously reported including four in SORL1 (p.Val297Met, p.Arg1084Cys, p.Asp1100Asn, and p.Pro1213Ser) and one in APP (p.Glu380Lys). The frequency of APOE- ɛ 4 allele was 21.37% of total investigated cases. In silico 3D protein structure analysis of two SORL1 novel missense variants (p.Pro1213Ser and p.Arg1084Cys) suggested that these variants may affect the folding of the proteins and disturb their structure. Conclusions: Our comprehensive analysis of the open reading frame of the known genes have identified potential pathogenic rare variants in 18/117 cases. We found that point mutations in AD main genes (PSEN1, PSEN2 , and APP ) were underrepresented in our cohort of patients. Our results confirm involvement of SORL1 in familial and sporadic AD cases. Show more

Keywords: Alzheimer’s disease, familial, gene, novel variants, sporadic

DOI: 10.3233/JAD-180415

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 231-242, 2019

Authors: Bonvicini, Cristian | Scassellati, Catia | Benussi, Luisa | Di Maria, Emilio | Maj, Carlo | Ciani, Miriam | Fostinelli, Silvia | Mega, Anna | Bocchetta, Martina | Lanzi, Gaetana | Giacopuzzi, Edoardo | Ferraboli, Sergio | Pievani, Michela | Fedi, Virginia | Defanti, Carlo Alberto | Giliani, Silvia | Alzheimer’s Disease Neuroimaging Initiative | Frisoni, Giovanni Battista | Ghidoni, Roberta | Gennarelli, Massimo

Article Type: Research Article

Abstract: Background: Early onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia. Objective: To identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E (APOE ) and prion protein (PRNP ) genes were also assessed. Methods: We studied 22 EOD patients recruited in Memory Clinics, in the context of studies investigating genetic forms of dementia. Two methodological approaches were applied for the target-Next Generation …Sequencing (NGS) analysis of these patients. In addition, we performed progranulin plasma dosage, C9Orf72 hexanucleotide repeat expansion analysis, and APOE genotyping. Results: We detected three rare known pathogenic mutations in the GRN and PSEN2 genes and eleven unknown-impact mutations in the GRN , VCP , MAPT , FUS, TREM2, and NOTCH3 genes. Six patients were carriers of only common risk variants (APOE and PRNP ), and one did not show any risk mutation/variant. Overall, 69% (n  = 9) of our early onset Alzheimer’s disease (EAOD) patients, compared with 34% (n  = 13) of sporadic late onset Alzheimer’s disease (LOAD) patients and 27% (n  = 73) of non-affected controls (ADNI, whole genome data), were carriers of at least two rare/common risk variants in the analyzed candidate genes panel, excluding the full penetrant mutations. Conclusion: This study suggests that EOD patients without full penetrant mutations are characterized by higher probability to carry polygenic risk alleles that patients with LOAD forms. This finding is in line with recently reported evidence, thus suggesting that the genetic risk factors identified in LOAD might modulate the risk also in EOAD. Show more

Keywords: Alzheimer’s disease, common variants, early onset dementia, frontotemporal dementia, Lewy body dementia, next generation sequencing, rare mutations

DOI: 10.3233/JAD-180482

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 243-256, 2019