Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Sheikh-Bahaei, Nasim | Manavaki, Roido | Sajjadi, S. Ahmad | Priest, Andrew N. | O’Brien, John T. | Gillard, Jonathan H.

Article Type: Research Article

Abstract: Background: Despite the well-documented relationship between lobar cerebral microbleeds (lCMB) and Alzheimer’s disease (AD), there is limited knowledge about the role of lCMB in AD pathology. Objective: To understand the nature of this relationship, we investigated the association between lCMB, amyloid load, perfusion, and metabolism. Methods: Participants with AD, mild cognitive impairment (MCI), and healthy controls were recruited and scanned with 11 C-Pittsburg-Compound B (PiB), Fluorodeoxyglucose (FDG) PET, and susceptibility-weighted MRI. Early PiB-PET frames were used to estimate perfusion. The association between lCMB and PET uptake in each anatomical lobe was measured using multiple regression models. …Results: The presence of lCMB predicted increased total (p  < 0.001) and regional (p  = 0.0002) PiB uptake, as well as decreased cerebral perfusion (p  = 0.03). Cases with lCMB had hypometabolism in their temporal lobe (p  = 0.04). Conclusion: There are significant relationships between lCMBs and various markers of AD pathology. lCMB has a spatial association with Aβ load and a complex effect on perfusion and metabolism. Show more

Keywords: Alzheimer’s disease, cerebral metabolism, cerebral perfusion, FDG-PET, lobar cerebral microbleeds, PiB-PET, susceptibility weighted imaging

DOI: 10.3233/JAD-180443

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Wadhawan, Abhishek | Stiller, John W. | Potocki, Eileen | Okusaga, Olaoluwa | Dagdag, Aline | Lowry, Christopher A. | Benros, Michael E. | Postolache, Teodor T.

Article Type: Review Article

Abstract: Given the increasing rate of death by suicide in the United States, it is imperative to examine specific risk factors and to identify possible etiologies of suicidal behavior in at-risk clinical subpopulations. There is accumulating evidence to support an elevated risk of death by suicide in individuals with a history of traumatic brain injury (TBI). In this review article, after defining terms used in suicidology, we discuss the associations of TBI with death by suicide, suicide attempt, and suicidal ideation. A model for repetitive TBIs, chronic traumatic encephalopathy, is also discussed as a neuroinflammatory process, with discussion about its possible …link with suicide. The review concludes with an overview of interventions to prevent suicidal behavior. Show more

Keywords: Chronic traumatic encephalopathy, death by suicide, inflammation, neuroinflammation, suicidal behavior, traumatic brain injury

DOI: 10.3233/JAD-181055

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-32, 2019

Authors: Boomsma, Jooske M.F. | Exalto, Lieza G. | Barkhof, Frederik | Berg, Esther van den | Bresser, Jeroen de | Heinen, Rutger | Leeuwis, Anna E. | Prins, Niels D. | Scheltens, Philip | Weinstein, Henry C. | van der Flier, Wiesje M. | Biessels, Geert Jan | behalf of the TRACE-VCI study group

Article Type: Research Article

Abstract: Background: Memory clinic patients frequently present with different forms of vascular brain injury due to different etiologies, often co-occurring with Alzheimer’s disease (AD) pathology. Objective: We studied how cognition was affected by different forms of vascular brain injury, possibly in interplay with AD pathology. Methods: We included 860 memory clinic patients with vascular brain injury on magnetic resonance imaging (MRI), receiving a standardized evaluation including cerebrospinal fluid (CSF) biomarker analyses (n  = 541). The cognitive profile of patients with different forms of vascular brain injury on MRI (moderate/severe white matter hyperintensities (WMH) (n  = 398), microbleeds (n  = 368), …lacunar (n  = 188) and non-lacunar (n  = 96) infarct(s), macrobleeds (n  = 16)) was assessed by: 1) comparison of all these different forms of vascular brain injury with a reference group (patients with only mild WMH (n  = 205) without other forms of vascular brain injury), using linear regression analyses also stratified for CSF biomarker AD profile and 2) multivariate linear regression analysis. Results: The cognitive profile was remarkably similar across groups. Compared to the reference group effect sizes on all domains were <0.2 with narrow 95% confidence intervals, except for non-lacunar infarcts on information processing speed (age, sex, and education adjusted mean difference from reference group (β : – 0.26, p  = 0.05). Results were similar in the presence (n  = 300) or absence (n  = 241) of biomarker co-occurring AD pathology. In multivariate linear regression analysis, higher WMH burden was related to a slightly worse performance on attention and executive functioning (β : – 0.08, p  = 0.02) and working memory (β : – 0.08, p  = 0.04). Conclusion: Although different forms of vascular brain injury have different etiologies and different patterns of cerebral damage, they show a largely similar cognitive profile in memory clinic patients regardless of co-occurring AD pathology. Show more

Keywords: Cerebral small vessel diseases, cerebrovascular disorders, cognitive disorders, neuropsychological test

DOI: 10.3233/JAD-180696

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Bohlken, Jens | Kostev, Karel

Article Type: Short Communication

Abstract: Little is known about the diagnostic methods currently used in routine care for patients with mild cognitive impairment (PwMCI). We estimated the frequency of diagnostic procedures in incident PwMCI compared to incident patients with dementia (PwD) in 2016-2017. The study is based on the Disease Analyzer database. After matching by age and sex, 4,700 PwMCI and 4,700 PwD were available. The diagnostic procedures were identified on the basis of the related medical fee schedule items. All diagnostic procedures were used more frequently in PwMCI than in PwD. The drafting of a practice-oriented MCI guideline is an important task for the future.

Keywords: Alzheimer’s disease, mild cognitive impairment, preclinical dementia, prevalence, real-world data

DOI: 10.3233/JAD-190012

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2019

Authors: Cao, Long-Long | Guan, Pei-Pei | Liang, Yun-Yue | Huang, Xue-Shi | Wang, Pu

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is reported to be associated with the accumulation of calcium ions (Ca2+ ), which is responsible for the phosphorylation of tau. Although a series of evidence have demonstrated this phenomenon, the inherent mechanisms remain unknown. Using tauP301S and cyclooxygenase-2 (COX-2) transgenic mice and neuroblastoma (n)2a cells as in vivo and in vitro experimental models, we found that Ca2+ stimulates the phosphorylation of tau by activating COX-2 in a prostaglandin (PG) E2 -dependent EP receptor-activating manner. Specifically, Ca2+ incubation stimulated COX-2 and PGE2 synthase activity, microsomal PGE synthase 1 and the synthesis …of PGE2 by activating the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells in n2a cells. Elevated levels of PGE2 were responsible for phosphorylating tau in an EP-1, -2, and -3 but not EP4-dependent glycogen synthase kinase 3-activating manner. These observations were corroborated by results that showed tau was phosphorylated when it colocalized with activated COX-2 in tauP301S and COX-2 transgenic mice or n2a cells. To further validate these observations, treatment of mice with the COX-2 inhibitor rofecoxib decreased the phosphorylation of tau via EP1-3 but not EP4. Collectively, our observations fill the gaps between Ca2+ and the phosphorylation of tau in a COX-2-dependent mechanism, which potentially provides therapeutic targets for combating AD. Show more

Keywords: Alzheimer’s disease, cyclooxygenase-2, EP receptors, prostaglandin E2 , tau

DOI: 10.3233/JAD-181066

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2019

Authors: Rosen, Allyson C. | Toy, Leslie | Langston, Ashley

Article Type: Research Article

Abstract: The potential for successful disease modifying treatments for Alzheimer’s disease (AD) opens up the possibility that there will be a large cohort of patients living with late-stage dementia and poor quality of life. There must thus be a parallel effort to leverage restorative therapies that improve quality of life in these patients. With the potential for stopping the onset of new patients with AD must come a commitment to those patients living with this chronic disability for many more years than first thought. Legal and ethical implications surrounding who makes decisions and equity in receiving care will become increasingly important …if AD is no longer a terminal illness. Show more

Keywords: Alzheimer’s disease, dementia, end of life, hospice, neuroethics, therapy

DOI: 10.3233/JAD-181193

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2019

Authors: Strunz, Maximilian | Jarrell, Juliet T. | Cohen, David S. | Rosin, Eric R. | Vanderburg, Charles R. | Huang, Xudong

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is an age-related progressive form of dementia that features neuronal loss, intracellular tau, and extracellular amyloid-β (Aβ) protein deposition. Neurodegeneration is accompanied by neuroinflammation mainly involving microglia, the resident innate immune cell population of the brain. During AD progression, microglia shift their phenotype, and it has been suggested that they express matricellular proteins such as secreted protein acidic and rich in cysteine (SPARC) and Hevin protein, which facilitate the migration of other immune cells, such as blood-derived dendritic cells. We have detected both SPARC and Hevin in postmortem AD brain tissues and confirmed significant alterations in transcript …expression using real-time qPCR. We suggest that an infiltration of myeloid-derived immune cells occurs in the areas of diseased tissue. SPARC is highly expressed in AD brain and collocates to Aβ protein deposits, thus contributing actively to cerebral inflammation and subsequent tissue repair, and Hevin may be downregulated in the diseased state. However, further research is needed to reveal the exact roles of SPARC and Hevin proteins and associated signaling pathways in AD-related neuroinflammation. Nevertheless, normalizing SPARC/Hevin protein expression such as interdicting heightened SPARC protein expression may confer a novel therapeutic opportunity for modulating AD progression. Show more

Keywords: Alzheimer’s disease, amyloid-β , dendritic cells, Hevin/SPARCL1 protein, macrophages, microglia, SPARC protein

DOI: 10.3233/JAD-181032

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Zhou, Sheng-Lan | Tan, Chen-Chen | Hou, Xiao-He | Cao, Xi-Peng | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: TREM2 (triggering receptor expressed on myeloid cells 2) gene variants were reported to increase the risk of Alzheimer’s disease (AD) and even other neurodegenerative diseases (frontotemporal dementia (FTD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS)), but so far, no definite conclusion has been drawn. The aim of our systematic review and meta-analysis was to investigate the role of TREM2 variants in neurodegenerative diseases. A total of 39 papers (including 26 case-control studies and 13 case reports) were retrieved from PubMed, MEDLINE, EMBASE, and the Cochrane library in this study. A fixed effect model was used to pool …results in the analysis. Three variants in TREM2 (rs75932628 (R47H), rs2234255 (H157Y), and rs143332484 (R62H)) were significantly associated with AD risk, but the similar associations between rs104894002 (Q33X), rs2234253 (T96K), rs142232675 (D87N), rs2234256 (L211P), and AD were not proven. Rs75932628 also increased risk of PD in North Americans and FTD, but not PD in Europeans or ALS. In the systematic review, 12 biallelic TREM2 mutations (e.g., rs104894002, rs201258663 (T66M), and rs386834144, etc.) have been described to cause Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL) in 14 families. And homozygous mutations also have been reported to cause FTD without typical bone phenotypes in 7 families. This study demonstrates that multiple variants in TREM2 have association with the onset of AD, FTD, and PD in North Americans and also play a key role in the phenotypes of the rare familial genetic disorder. Show more

Keywords: Meta-analysis, neurodegenerative diseases, PLOSL, TREM2 , variant

DOI: 10.3233/JAD-181038

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Lee, Sung | Parekh, Trusha | King, Sarah M. | Reed, Bruce | Chui, Helena C. | Krauss, Ronald M. | Yassine, Hussein N.

Article Type: Research Article

Abstract: Cerebral beta-amyloidosis (CA) is a condition in which amyloid-β (Aβ) proteins are deposited in the cerebral cortex and is a predictor of Alzheimer’s disease (AD). The Aging Brain Study (ABS) investigated risk factors for CA in persons with diabetes and dyslipidemia. In the ABS, we identified that greater levels of LDL cholesterol and lower level of HDL cholesterol were associated with increased CA. Low-density lipoprotein (LDL) particles comprise multiple species of varying size, density, and protein composition. For example, within a lipoprotein profile characteristic for persons with obesity and diabetic dyslipidemia, larger LDL particles have a greater ApoE to ApoB …ratio, enhancing their binding affinity to LDL receptors. The goal of this study was to identify LDL particles that associate with CA in ABS. LDL particle size fractions were measured by ion mobility in plasma samples of 58 participants (40 women and 18 men). CA was assessed using Pittsburgh Compound B index-Positron Emission Tomography (PiB-PET) imaging. Among the LDL subfractions, greater plasma levels of large LDL particles were significantly associated with greater cerebral amyloidosis and lower hippocampal volumes independent of LDL cholesterol or triglyceride levels. Since Aβ is cleared by the LDL receptor family, such as lipoprotein-like receptor 1 (LRP1), one potential mechanism for our findings is competition between ApoE enriched larger LDL particles and brain-derived Aβ on hepatic Aβ clearance and degradation. We conclude that assessing larger LDL particles in persons with atherogenic dyslipidemia may provide a mechanistic biomarker for the extent of CA. Show more

Keywords: Alzheimer’s disease, apolipoproteins lipids, lipoproteins, receptors

DOI: 10.3233/JAD-181252

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Wang, Ya-Juan | Wan, Yu | Wang, Hui-Fu | Tan, Chen-Chen | Li, Jie-Qiong | Yu, Jin-Tai | Tan, Lan | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Two CD33 common variants, rs3826656 and rs3865444, have been identified to be correlated with Alzheimer’s disease (AD). Our study examined the effects of the two AD-related CD33 common variants (rs3826656 and rs3865444) on the chosen AD-related brain regions (including hippocampus, amygdala, parahippocampus, middle temporal, entorhinal cortex, and total brain volume) in non-demented elders recruited from the Alzheimer’s Disease Neuroimaging Initiative database at baseline and during four-year follow-up. We further tested the effects in an Aβ-positive group (including preclinical and prodromal stage of AD) and an Aβ-negative group. In the total non-demented elderly population, no associations reached significant levels …after FDR correction. In the Aβ-positive group, we found that rs3826656 was associated with hippocampal and amygdala volumes (Hippocampus-R: pc  = 0.0022; Amygdala-L: pc  = 0.0044; Amygdala-R: pc  = 0.0066), and rs3865444 was associated with right entorhinal volume (pc  = 0.0286). The associations of rs3826656 with hippocampal and amygdala volumes in the Aβ-positive group were successfully replicated in the prodromal AD group (Hippocampus-R: pc  = 0.0022; Amygdala-L: pc  = 0.0022; Amygdala-R: pc  = 0.0088). These changes became more obvious over time during four-year follow-up. No associations were found between the two CD33 variants and neuroimaging biomarkers in the Aβ-negative and preclinical AD groups after FDR correction. These results suggested that the two CD33 common variants (rs3826656 and rs3865444) influenced volumes and atrophy rates of AD-related brain regions in non-demented elders. Subgroup analyses showed the effects mainly existed in the Aβ-positive group instead of the Aβ-negative group, and the effects began in the prodromal AD stage. Show more

Keywords: Alzheimer’s disease, brain structure, CD33, neuroimaging, non-demented elders, polymorphism

DOI: 10.3233/JAD-181062

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019