Journal of Alzheimer's Disease - Volume 55, issue 2

Authors: McClure, Richard | Ong, Henry | Janve, Vaibhab | Barton, Shawn | Zhu, Meiying | Li, Bo | Dawes, Mary | Jerome, W. Gray | Anderson, Adam | Massion, Pierre | Gore, John C. | Pham, Wellington

Article Type: Research Article

Abstract: We report a novel approach for the delivery of curcumin to the brain via inhalation of the aerosol for the potential treatment of Alzheimer’s disease. The percentage of plaque fraction in the subiculum and hippocampus reduced significantly when young 5XFAD mice were treated with inhalable curcumin over an extended period of time compared to age-matched nontreated counterparts. Further, treated animals demonstrated remarkably improved overall cognitive function, no registered systemic or pulmonary toxicity associated with inhalable curcumin observed during the course of this work.

Keywords: Aerosol, amyloid-β, curcumin, nebulization

DOI: 10.3233/JAD-160289

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 797-811, 2017

Authors: Lewczuk, Piotr | Matzen, Anja | Blennow, Kaj | Parnetti, Lucilla | Molinuevo, Jose Luis | Eusebi, Paolo | Kornhuber, Johannes | Morris, John C. | Fagan, Anne M.

Article Type: Research Article

Abstract: Background: Decreased concentrations of amyloid-β 1-42 (Aβ42 ) in cerebrospinal fluid (CSF) and increased retention of Aβ tracers in the brain on positron emission tomography (PET) are considered the earliest biomarkers of Alzheimer’s disease (AD). However, a proportion of cases show discrepancies between the results of the two biomarker modalities which may reflect inter-individual differences in Aβ metabolism. The CSF Aβ42/40 ratio seems to be a more accurate biomarker of clinical AD than CSF Aβ42 alone. Objective: We tested whether CSF Aβ42 alone or the Aβ42/40 ratio corresponds better with amyloid PET status …and analyzed the distribution of cases with discordant CSF-PET results. Methods: CSF obtained from a mixed cohort (n  = 200) of cognitively normal and abnormal research participants who had undergone amyloid PET within 12 months (n  = 150 PET-negative, n  = 50 PET-positive according to a previously published cut-off) was assayed for Aβ42 and Aβ40 using two recently developed immunoassays. Optimal CSF cut-offs for amyloid positivity were calculated, and concordance was tested by comparison of the areas under receiver operating characteristic (ROC) curves (AUC) and McNemar’s test for paired proportions. Results: CSF Aβ42/40 corresponded better than Aβ42 with PET results, with a larger proportion of concordant cases (89.4% versus 74.9%, respectively, p  < 0.0001) and a larger AUC (0.936 versus 0.814, respectively, p  < 0.0001) associated with the ratio. For both CSF biomarkers, the percentage of CSF-abnormal/PET-normal cases was larger than that of CSF-normal/PET-abnormal cases. Conclusion: The CSF Aβ42/40 ratio is superior to Aβ42 alone as a marker of amyloid-positivity by PET. We hypothesize that this increase in performance reflects the ratio compensating for general between-individual variations in CSF total Aβ. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarker, cerebrospinal fluid, positron emission tomography

DOI: 10.3233/JAD-160722

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 813-822, 2017

Authors: Peh, Chao Xu | Abdin, Edimansyah | Vaingankar, Janhavi A. | Verma, Swapna | Chua, Boon Yiang | Sagayadevan, Vathsala | Seow, Esmond | Zhang, YunJue | Shahwan, Shazana | Ng, Li Ling | Prince, Martin | Chong, Siow Ann | Subramaniam, Mythily

Article Type: Research Article

Abstract: Background: The latent variable δ has been proposed as a proxy for dementia. Previous validation studies have been conducted using convenience samples. It is currently unknown how δ performs in population-wide data. Objective: To validate δ in Singapore using population-wide epidemiological study data on persons aged 60 and above. Methods: δ was constructed using items from the Community Screening Instrument for Dementia (CSI’D) and World Health Organization Disability Assessment Schedule (WHODAS II). Confirmatory factor analysis (CFA) was conducted to examine δ model fit. Convergent validity was examined with the Clinical Dementia Rating scale (CDR) and GMS-AGECAT …dementia. Divergent validity was examined with GMS-AGECAT depression. Results: The δ model demonstrated fit to the data, χ2 (df ) = 249.71(55), p  < 0.001, CFI = 0.990, TLI = 0.997, RMSEA = 0.037. Latent variable δ was significantly associated with CDR and GMS-AGECAT dementia (range: β= 0.32 to 0.63), and was not associated with GMS-AGECAT depression. Compared to unadjusted models, δ model fit was poor when adjusted for age, gender, ethnicity, and education. Conclusion: The study found some support for δ as a proxy for dementia in Singapore based on population data. Both convergent and divergent validity were established. In addition, the δ model structure appeared to be influenced by age, gender, ethnicity, and education covariates. Show more

Keywords: Cognition, dementia, functional status, Singapore, validation studies

DOI: 10.3233/JAD-160575

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 823-833, 2017

Authors: Shen, Yijun | Xia, Yiling | Meng, Shiquan | Lim, Nastasia K.H. | Wang, Wenan | Huang, Fude

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by deficits in learning and memory abilities, as well as pathological changes of amyloid-β (Aβ) plaque and neurofibrillary tangle formation in the brain. Insulin has been identified as a modulator of the neuronal pathways involved in learning and memory, and is also implicated as a modulator of Aβ and tau metabolism. Disrupted insulin signaling pathways are evident in AD patients and it is understood that type 2 diabetes can increase the risk of developing AD, suggesting a possible link between metabolic disorders and neurodegeneration. SH2B1 is a key protein in the insulin signaling pathway involved …in regulating the activity of the insulin receptor. To further identify the role of the insulin signaling pathway in the pathology of AD, SH2B (dSH2B homologue in flies) in neurons was partially knocked out or overexpressed in an AD Drosophila model expressing Aβ42 . Partial knockout of neuronal SH2B in the Aβ42 -expressing Drosophila had a detrimental effect on mobility and neurotransmission, and increased levels and intraneuronal accumulation of Aβ42 , as assessed by ELISA and immunostaining. Alternatively, partial overexpression of neuronal SH2B in the Aβ42 -expressing Drosophila improved lifespan, mobility, and neurotransmission, as well as decreased levels and intraneuronal accumulation of Aβ42 . Thus, SH2B1 may be an upstream modulator of Aβ metabolism, acting to inhibit Aβ accumulation, and has a role in the pathogenesis of AD. SH2B1 may therefore have potential as a therapeutic target for this common form of dementia. Show more

Keywords: Alzheimer’s disease, amyloid-β accumulation, diabetes, SH2B1 protein

DOI: 10.3233/JAD-160233

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 835-847, 2017

Authors: de la Monte, Suzanne M. | Tong, Ming | Schiano, Irio | Didsbury, John

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is associated with progressive impairments in brain insulin, insulin-like growth factor (IGF), and insulin receptor substrate (IRS) signaling through Akt pathways that regulate neuronal growth, survival, metabolism, and plasticity. The intracerebral streptozotocin (i.c. STZ) model replicates the full range of abnormalities in sporadic AD. T3D-959, an orally active PPAR-delta/gamma agonist remediates neurocognitive deficits and AD neuropathology in the i.c. STZ model. Objective: This study characterizes the effects of T3D-959 on AD biomarkers, insulin/IGF/IRS signaling through Akt pathways, and neuroinflammation in an i.c. STZ model. Methods: Long Evans rats were treated with …i.c. STZ or saline, followed by daily oral doses of T3D-959 (1 mg/kg) or saline initiated 1 day (T3D-959-E) or 7 days (T3D-959-L) later through Experimental Day 28. Protein and phospho-protein expression and pro-inflammatory cytokine activation were measured in temporal lobe homogenates by duplex or multiplex bead-based ELISAs. Results: i.c. STZ treatments caused neurodegeneration with increased pTau, AβPP, Aβ42 , ubiquitin, and SNAP-25, and reduced levels of synaptophysin, IGF-1 receptor (R), IRS-1, Akt, p70S6K, mTOR, and S9 -GSK-3β. i.c. STZ also broadly increased neuroinflammation. T3D-959 abrogated or reduced most of the AD neuropathological and biomarker abnormalities, increased/normalized IGF-1R, IRS-1, Akt, p70S6K, and S9 -GSK-3β, and decreased expression of multiple pro-inflammatory cytokines. T3D-959-E or -L effectively restored insulin/IGF signaling, whereas T3D-959-L more broadly resolved neuroinflammation. Conclusion: AD remediating effects of T3D-959 are potentially due to enhanced expression of key insulin/IGF signaling proteins and inhibition of GSK-3β and neuroinflammation. These effects lead to reduced neurodegeneration, cognitive impairment, and AD biomarker levels in the brain. Show more

Keywords: Alzheimer’s disease, cytokines, insulin resistance, neurodegeneration, PPAR delta, rat model, T3D-959

DOI: 10.3233/JAD-160656

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 849-864, 2017