Journal of Alzheimer's Disease - Volume 58, issue 2

Authors: Vos, Stephanie J.B. | van Boxtel, Martin P.J. | Schiepers, Olga J.G. | Deckers, Kay | de Vugt, Marjolein | Carrière, Isabelle | Dartigues, Jean-François | Peres, Karine | Artero, Sylvaine | Ritchie, Karen | Galluzzo, Lucia | Scafato, Emanuele | Frisoni, Giovanni B. | Huisman, Martijn | Comijs, Hannie C. | Sacuiu, Simona F. | Skoog, Ingmar | Irving, Kate | O’Donnell, Catherine A. | Verhey, Frans R.J. | Visser, Pieter Jelle | Köhler, Sebastian

Article Type: Research Article

Abstract: Background: Recently, the LIfestyle for BRAin health (LIBRA) index was developed to assess an individual’s prevention potential for dementia. Objective: We investigated the predictive validity of the LIBRA index for incident dementia in midlife, late life, and the oldest-old. Methods: 9,387 non-demented individuals were recruited from the European population-based DESCRIPA study. An individual’s LIBRA index was calculated solely based on modifiable risk factors: depression, diabetes, physical activity, hypertension, obesity, smoking, hypercholesterolemia, coronary heart disease, and mild/moderate alcohol use. Cox regression was used to test the predictive validity of LIBRA for dementia at follow-up (mean 7.2 y, …range 1–16). Results: In midlife (55–69 y, n = 3,256) and late life (70–79 y, n = 4,320), the risk for dementia increased with higher LIBRA scores. Individuals in the intermediate- and high-risk groups had a higher risk of dementia than those in the low-risk group. In the oldest-old (80–97 y, n = 1,811), higher LIBRA scores did not increase the risk for dementia. Conclusion: LIBRA might be a useful tool to identify individuals for primary prevention interventions of dementia in midlife, and maybe in late life, but not in the oldest-old. Show more

Keywords: Aging, dementia, modifiable risk factors, prevention

DOI: 10.3233/JAD-161208

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 537-547, 2017

Authors: Li, Qian | Cui, Jing | Fang, Chen | Liu, Min | Min, Guowen | Li, Liang

Article Type: Research Article

Abstract: Oxidative stress and neuroinflammation are mainly involved in the pathogenic mechanisms of Alzheimer’s disease (AD). Amyloid-β (Aβ), the main component of senile plaques, is a kind of strong inducer of oxidative stress. Glutathione is an endogenous antioxidant protecting cells from oxidative injury. S-adenosylmethionine (SAM) produced in the methionine cycle is the primary methyl donor and the precursor of glutathione. In this study, the Aβ intrahippocampal injection rat model and cultured SH-SY5Y cells were used to explore the neuroprotective effect of SAM. We found that SAM could protect cells against Aβ-induced cellular injury by inhibition of oxidative stress and neuroinflammation. SAM …administration could increase the endogenous antioxidant glutathione and potentiate the antioxidant enzymes activities. SAM might act as an antioxidant and be a potential candidate therapy for AD patients. Show more

Keywords: Amyloid-β, glutathione, inflammation, oxidative stress, S-adenosylmethionine

DOI: 10.3233/JAD-170177

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 549-558, 2017

Authors: Maezawa, Izumi | Zou, Bende | Di Lucente, Jacopo | Cao, William S. | Pascual, Conrado | Weerasekara, Sahani | Zhang, Man | Xie, Xinmin Simon | Hua, Duy H. | Jin, Lee-Way

Article Type: Research Article

Abstract: There is an urgent unmet need for new therapeutics for Alzheimer’s disease (AD), the most common cause of dementia in the elderly. Therapeutic approaches targeting amyloid-β (Aβ) and its downstream toxicities have become major strategies in AD drug development. We have taken a rational design approach and synthesized a class of tricyclic pyrone (TP) compounds that show anti-Aβ and other neuroprotective actions. The in vivo efficacy of a lead TP named CP2 to ameliorate AD-like pathologies has been shown in mouse models. Here we report the selection and initial characterization of a new lead TP70, which exhibited an anti-Aβ …therapeutic index even higher than CP2. Moreover, TP70 was able to reduce oxidative stress, inhibit acyl-coenzyme A:cholesterol acyltransferase (ACAT), and upregulate the expression of ATP-binding cassette subfamily A, member 1 (ABCA1), actions considered neuroprotective in AD. TP70 further showed excellent pharmacokinetic properties, including brain penetration and oral availability. When administered to 5xFAD mice via intraperitoneal or oral route, TP70 enhanced the overall solubility and decreased the level of cerebral Aβ, including both fibrillary and soluble Aβ species. Interestingly, TP70 enhanced N -methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic potential (EPSP) in the hippocampal CA1 area, increased the magnitude of NMDA-dependent hippocampal long-term potentiation (LTP), a cellular model of learning and memory, and prevented the Aβ oligomer-impaired LTP. Significantly, a single dose of TP70 administered to aged 5xFAD mice was effective in mitigating the impaired LTP induction, recorded at 24 h after administration. Our results support a potential of TP70 in clinical development for AD in view of its synergistic neuroprotective actions, ability to positively modulate NMDA receptor-mediated hippocampal plasticity, and favorable pharmacokinetic properties in rodents. Show more

Keywords: Alzheimer’s disease, amyloid, hippocampus, neuroprotection, neurotoxicity, NMDA

DOI: 10.3233/JAD-161175

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 559-574, 2017

Authors: Malek-Ahmadi, Michael | Lu, Sophie | Chan, YanYan | Perez, Sylvia E. | Chen, Kewei | Mufson, Elliott J.

Article Type: Research Article

Abstract: Within neuropsychology, the term dispersion refers to the degree of variation in performance between different cognitive domains for an individual. Previous studies have demonstrated that cognitively normal individuals with higher dispersion are at an increased risk for progressing to mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Therefore, we determined 1) whether increased dispersion in older adults was associated with amyloid plaques and neurofibrillary tangles (NFTs) and 2) whether increased cognitive dispersion accurately differentiated MCI and AD from non-cognitively impaired (NCI) individuals. The intra-subject standard deviation (ISD) was used to quantify cognitive dispersion, and receiver operator characteristic (ROC) analysis determined …whether ISD differentiated MCI and AD from NCI. Neuropathological scores for diffuse plaques (DPs), neuritic plaques (NPs), and NFTs were used as outcome measures in a series of negative binomial regression models. Regression analyses found that increased ISD was associated with increased NFT pathology (β= 10.93, SE = 3.82, p  = 0.004), but not with DPs (β= 1.33, SE = 8.85, p  = 0.88) or NPs (β= 14.64, SE = 8.45, p  = 0.08) after adjusting for age at death, gender, education, APOE ɛ 4 status, and clinical diagnosis. An interaction term of ISD with age at death also showed a significant negative association (β= –0.13, SE = 0.04, p  = 0.004), revealing an age-dependent association between ISD with NFTs. The ISD failed to show an acceptable level of diagnostic accuracy for MCI (AUC = 0.60). These findings suggest that increased cognitive dispersion is related to NFT pathology where age significantly affects this association. Show more

Keywords: Aging, Alzheimer’s disease, cognition, dispersion, mild cognitive impairment, neuropathology

DOI: 10.3233/JAD-161233

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 575-583, 2017

Authors: de Eulate, Reyes García | Goñi, Irene | Galiano, Alvaro | Vidorreta, Marta | Recio, Miriam | Riverol, Mario | Zubieta, José L. | Fernández-Seara, María A.

Article Type: Research Article

Abstract: There is increasing evidence of a vascular contribution to Alzheimer’s disease (AD). In some cases, prior work suggests that chronic brain hypoperfusion could play a prime pathogenic role contributing to the accumulation of amyloid-β,while other studies favor the hypothesis that vascular dysfunction and amyloid pathology are independent, although synergistic, mechanisms contributing to cognitive impairment. Vascular dysfunction can be evaluated by assessing cerebral blood flow impairment. Phase contrast velocity mapping by MRI offers a non-invasive means of quantifying the total inflow of blood to the brain. This quantitative parameter could be a sensitive indicator of vascular disease at early stages of …AD. In this work, phase contrast MRI was used to evaluate cerebral hemodynamics in patients with subjective memory complaints, amnestic mild cognitive impairment, and mild to moderate AD, and compare them with control subjects. Results showed that blood flow and velocity were decreased in the patients with cognitive dysfunction and the decrease correlated with the degree of cognitive impairment as assessed by means of neuropsychological tests. Total cerebral blood flow measurements were clearly reduced in AD patients, but more importantly appeared to be sensitive enough to distinguish between healthy subjects and those with mild cognitive impairment. A quantitative measurement of total brain blood flow could potentially predict vascular dysfunction and compromised brain perfusion in early stages of AD. Show more

Keywords: Alzheimer’s disease, cerebral blood flow, cognitive impairment, magnetic resonance imaging

DOI: 10.3233/JAD-161222

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 585-595, 2017