Journal of Alzheimer's Disease - Volume 50, issue 3

Authors: Ardekani, Babak A. | Convit, Antonio | Bachman, Alvin H.

Article Type: Research Article

Abstract: Background: Hippocampus (HC) atrophy is a hallmark of early Alzheimer’s disease (AD). Atrophy rates can be measured by high-resolution structural MRI. Longitudinal studies have previously shown sex differences in the progression of functional and cognitive deficits and rates of brain atrophy in early AD dementia. It is important to corroborate these findings on independent datasets. Objective: To study temporal rates of HC atrophy over a one-year period in probable AD patients and cognitively normal (CN) subjects by longitudinal MRI scans obtained from the Minimal Interval Resonance Imaging in AD (MIRIAD) database. Methods: We used a novel …algorithm to compute an index of hippocampal (volumetric) integrity (HI) at baseline and one-year follow-up in 43 mild-moderate probable AD patients and 22 CN subjects in MIRIAD. The diagnostic power of longitudinal HI measurement was assessed using a support vector machines (SVM) classifier. Results: The HI was significantly reduced in the AD group (p  <  10–20 ). In addition, the annualized percentage rate of reduction in HI was significantly greater in the AD group (p  <  10–13 ). Within the AD group, the annual reduction of HI in women was significantly greater than in men (p  = 0.008). The accuracy of SVM classification between AD and CN subjects was estimated to be 97% by 10-fold cross-validation. Conclusion: In the MIRIAD patients with probable AD, the HC atrophies at a significantly faster rate in women as compared to men. Female sex is a risk factor for faster descent into AD. The HI measure has potential for AD diagnosis, as a biomarker of AD progression and a therapeutic target in clinical trials. Show more

Keywords: Alzheimer’s disease, atrophy, brain, classification, hippocampus, longitudinal analysis, MRI, sex, support vector machines

DOI: 10.3233/JAD-150780

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 847-857, 2016

Authors: Shi, Shi | Liang, Dongli | Bao, Min | Xie, Yilin | Xu, Wangjie | Wang, Lianyun | Wang, Zhaoxia | Qiao, Zhongdong

Article Type: Research Article

Abstract: Recent studies have revealed that the α 7 nicotinic acetylcholine receptor (α 7 nAChR) is a critical link between inflammation and neurodegeneration, which is closely associated with Alzheimer’s disease (AD). The JAK2/STAT3 and PI3K/AKT signaling pathways contribute to the neuroprotective and anti-inflammatory effects of α 7nAChR. Our previous studies have shown that treatment with gx-50 improves cognitive function and is neuroprotective. Here, we investigated the effect of gx-50 on α 7 nAChR and Aβ-induced inflammation in microglia. First, the binding affinity of gx-50 to α 7 nAChR was examined using the fluorescence-based Octet RED system, and the expression of α …7 nAChR was detected using real-time PCR and western blotting. We also investigated downstream events of α 7 nAChR activity, including the translocation of p-STAT3 and the phosphorylation of JAK2, STAT3, PI3K, and AKT. Finally, the effect of gx-50 on Aβ-induced inflammation via α 7 nAChR-mediated signaling pathways was investigated using cytokine assays. The results showed that gx-50 is able to act as a specific ligand to activate α 7 nAChR, which then upregulates the JAK2/STAT3 and PI3K/AKT signaling pathways to inhibit the secretions of pro-inflammatory cytokines, such as IL-1β. In conclusion, the results suggest that gx-50 could inhibit the Aβ-induced inflammatory response in microglia via α 7 nAChR activity, which might be a successful therapeutic target against AD. Show more

Keywords: Alzheimer’s disease, α7 nAChR, gx-50, inflammation, JAK2/STAT3, PI3K/AKT

DOI: 10.3233/JAD-150963

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 859-871, 2016

Authors: Melah, Kelsey E. | Lu, Sharon Yuan-Fu | Hoscheidt, Siobhan M. | Alexander, Andrew L. | Adluru, Nagesh | Destiche, Daniel J. | Carlsson, Cynthia M. | Zetterberg, Henrik | Blennow, Kaj | Okonkwo, Ozioma C. | Gleason, Carey E. | Dowling, N. Maritza | Bratzke, Lisa C. | Rowley, Howard A. | Sager, Mark A. | Asthana, Sanjay | Johnson, Sterling C. | Bendlin, Barbara B.

Article Type: Research Article

Abstract: Background: The immune response in Alzheimer’s disease (AD) involves activation of microglia which may remove amyloid-β (Aβ). However, overproduction of inflammatory compounds may exacerbate neural damage in AD. AD pathology accumulates years before diagnosis, yet the extent to which neuroinflammation is involved in the earliest disease stages is unknown. Objective: To determine whether neuroinflammation exacerbates neural damage in preclinical AD. Methods: We utilized cerebrospinal fluid (CSF) and magnetic resonance imaging collected in 192 asymptomatic late-middle-aged adults (mean age = 60.98 years). Neuroinflammatory markers chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1) in CSF were utilized as markers …of neuroinflammation. Neural cell damage was assessed using CSF neurofilament light chain protein (NFL), CSF total tau (T-Tau), and neural microstructure assessed with diffusion tensor imaging (DTI). With regard to AD pathology, CSF Aβ42 and tau phosphorylated at threonine 181 (P-Tau181 ) were used as markers of amyloid and tau pathology, respectively. We hypothesized that higher YKL-40 and MCP-1 in the presence of AD pathology would be associated with higher NFL, T-Tau, and altered microstructure on DTI. Results: Neuroinflammation was associated with markers of neural damage. Higher CSF YKL-40 was associated with both higher CSF NFL and T-Tau. Inflammation interacted with AD pathology, such that greater MCP-1 and lower Aβ42 was associated with altered microstructure in bilateral frontal and right temporal lobe and that greater MCP-1 and greater P-Tau181 was associated with altered microstructure in precuneus. Conclusion: Inflammation may play a role in neural damage in preclinical AD. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid proteins, diffusion tensor imaging, inflammation,

DOI: 10.3233/JAD-150897

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 873-886, 2016

Authors: Chatterjee, Pratishtha | Lim, Wei L.F. | Shui, Guanghou | Gupta, Veer B. | James, Ian | Fagan, Anne M. | Xiong, Chengjie | Sohrabi, Hamid R. | Taddei, Kevin | Brown, Belinda M. | Benzinger, Tammie | Masters, Colin | Snowden, Stuart G. | Wenk, Marcus R. | Bateman, Randall J. | Morris, John C. | Martins, Ralph N.

Article Type: Research Article

Abstract: Background and Objective: Aberrant lipid metabolism has been implicated in sporadic Alzheimer’s disease (AD). The current study investigated plasma phospholipid and sphingolipid profiles in individuals carrying PSEN1 mutations responsible for autosomal dominant AD (ADAD). Methods: Study participants evaluated were from the Perth and Melbourne sites of the Dominantly Inherited Alzheimer Network (DIAN) study. Plasma phospholipid and sphingolipid profiles were measured using liquid chromatography coupled with mass spectrometry in 20 PSEN1 mutation carriers (MC; eight of whom were symptomatic and twelve asymptomatic, based on Clinical Dementia Rating scores) and compared with six non carriers (NC) using linear …mixed models. Further, AD gold standard biomarker data obtained from the DIAN database were correlated with lipid species significantly altered between MC and NC, using Spearman’s correlation coefficient. Results: One-hundred and thirty-nine plasma phospholipid and sphingolipid species were measured. Significantly altered species in MC compared to NC primarily belonged to choline and ethanolamine containing phospholipid classes and ceramides. Further phosphatidylcholine species (34:6, 36:5, 40:6) correlated with cerebrospinal fluid tau (p  <  0.05), and plasmalogen ethanolamine species (34:2, 36:,4) correlated with both cerebrospinal fluid tau and brain amyloid load within the MC group (p  <  0.05). Conclusion: These findings indicate altered phospholipid and sphingolipid metabolism in ADAD and provide insight into the pathomolecular changes occurring with ADAD pathogenesis. Further, findings reported in this study allow comparison of lipid alterations in ADAD with those reported previously in sporadic AD. The findings observed in the current pilot study warrant validation in the larger DIAN cohort. Show more

Keywords: Alzheimer’s disease, biomarkers, familial Alzheimer’s disease, phospholipids, sphingolipids

DOI: 10.3233/JAD-150948

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 887-894, 2016

Authors: Porter, Tenielle | Bharadwaj, Prashant | Groth, David | Paxman, Adrian | Laws, Simon M. | Martins, Ralph N. | Verdile, Giuseppe

Article Type: Research Article

Abstract: Latrepirdine (Dimebon™) has been demonstrated to be a neuroprotective and cognition improving agent in neurodegenerative diseases that feature protein aggregation and deposition, such as Alzheimer’s disease (AD). The accumulation of amyloid-β (Aβ) protein aggregates is a key event in the neurodegenerative process in AD. This study explores if latrepirdine modulation of protein aggregation contributes to its neuroprotective mechanism of action. Assessment of neuronal cell death showed that there was a significant reduction in lactate dehydrogenase release at an equimolar ratio of Aβ:latrepirdine and with lower concentrations of latrepirdine. The ability of latrepirdine to alter the formation of Aβ42 aggregates …was assessed by thioflavin-T fluorescence, western immunoblotting and atomic force microscopy (AFM). Despite showing a reduction in thioflavin-T fluorescence with latrepirdine treatment, indicating a decrease in aggregation, immunoblotting and AFM showed a modest increase in both the formation and size of Aβ aggregates. The discrepancies between thioflavin-T and the other assays are consistent with previous evidence that cyclic molecules can interfere with thioflavin-T binding of amyloid protein preparations. The ability of latrepirdine to modulate Aβ aggregation appears to be independent of its neuroprotective effects, and is unlikely to be a mechanism by which latrepirdine offers protection. This study investigates the effect of latrepirdine on Aβ aggregation, and presents evidence suggesting that caution should be applied in the use of thioflavin-T fluorescence based assays as a method for screening compounds for protein aggregation altering properties. Show more

Keywords: Alzheimer’s disease, amyloid-beta, latrepirdine, neurotoxicity, Thiofavin T

DOI: 10.3233/JAD-150790

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 895-905, 2016

Article Type: Other

DOI: 10.3233/JAD-151107

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 907-911, 2016