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

Authors: Clark, Lindsay R. | Norton, Derek | Berman, Sarah E. | Johnson, Sterling C. | Bendlin, Barbara B. | Wieben, Oliver | Turski, Patrick | Carlsson, Cynthia | Asthana, Sanjay | Gleason, Carey E. | Johnson, Heather M.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) has a higher prevalence among African Americans. Targeting cardiovascular and metabolic risk factors may be potential mechanisms to modify AD risk and address racial/ethnic disparities in AD dementia. Objective: This study investigated relationships among cardiovascular and metabolic risk factors, APOE genotype, AD biomarkers, and intracranial arterial blood flow in Whites and African Americans enriched for AD risk. Methods: 399 cognitively unimpaired adults from the Wisconsin Alzheimer’s Disease Research Center completed physical and neuroimaging examinations. A 4D Flow MRI sequence (phase-contrast vastly under sampled isotropic projection imaging) measured intracranial arterial flow in …the Circle of Willis. Linear mixed-effects regression models estimated relationships between risk factors and intracranial arterial flow and tested interactions with racial group, APOE genotype, and AD biomarkers, with separate models per risk factor. Results: Higher fasting glucose was associated with lower intracranial arterial flow; no additional relationships between flow and risk factors were observed. Main effects of racial group were observed, without an interaction, indicating lower flow in African Americans compared to Whites. In race-stratified analyses, higher glucose and triglycerides were associated with lower flow for African Americans, but not for Whites. No main effects or interactions among risk factors, APOE , or AD biomarkers, and flow were observed. Conclusion: Elevated fasting glucose and triglycerides were associated with lower intracranial arterial flow; these relationships were more prominent in African Americans. Targeting metabolic risk factors may impact intracranial arterial health. Additional research is needed to determine if this will impact disparities in dementia prevalence. Show more

Keywords: African Americans, aging, Alzheimer’s disease, Apolipoprotein E4, cerebrovascular circulation, glucose, metabolic syndrome, neuroimaging, risk factors

DOI: 10.3233/JAD-190645

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Article Type: Correction

DOI: 10.3233/JAD-199010

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

Authors: Fuchsberger, Tanja | Yuste, Raquel | Martinez-Bellver, Sergio | Blanco-Gandia, Mari-Carmen | Torres-Cuevas, Isabel | Blasco-Serra, Arantxa | Arango, Román | Miñarro, Jose | Rodríguez-Arias, Marta | Teruel-Marti, Vicent | Lloret, Ana | Viña, Jose

Article Type: Research Article

Abstract: Glutamate excitotoxicity has long been related to Alzheimer’s disease (AD) pathophysiology, and it has been shown to affect the major AD-related hallmarks, amyloid-β peptide (Aβ) accumulation and tau phosphorylation (p-tau). We investigated whether oral administration of monosodium glutamate (MSG) has effects in a murine model of AD, the double transgenic mice APP/PS1. We found that AD pathogenic factors appear earlier in APP/PS1 when supplemented with MSG, while wildtype mice were essentially not affected. Aβ and p-tau levels were increased in the hippocampus in young APP/PS1 animals upon MSG administration. This was correlated with increased Cdk5-p25 levels. Furthermore, in these mice, …we observed a decrease in the AMPA receptor subunit GluA1 and they had impaired long-term potentiation. The Hebb-Williams maze revealed that they had memory deficits. We show here for the first time that oral MSG supplementation can accelerate AD-like pathophysiology in a mouse model of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, glutamate excitotoxicity, long-term potentiation, memory, p-tau

DOI: 10.3233/JAD-190274

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2019

Authors: Schelter, Bjoern O. | Shiells, Helen | Baddeley, Thomas C. | Rubino, Christopher M. | Ganesan, Harish | Hammel, Jeffrey | Vuksanovic, Vesna | Staff, Roger T. | Murray, Alison D. | Bracoud, Luc | Riedel, Gernot | Gauthier, Serge | Jia, Jianping | Bentham, Peter | Kook, Karin | Storey, John M.D. | Harrington, Charles R. | Wischik, Claude M.

Article Type: Research Article

Abstract: Background: Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer’s disease (AD) comparing doses in the range 150–250 mg/day with 8 mg/day intended as a control. Objective: To determine how drug exposure is related to treatment response. Methods: A sensitive plasma assay for the drug was used in a population pharmacokinetic analysis of samples from 1,162 of the 1,686 patients who participated in either of the Phase III trials with available samples and efficacy outcome data. Results: There are steep concentration-response …relationships for steady state plasma levels in the range 0.3–0.8 ng/ml at the 8 mg/day dose. Using a threshold based on the lower limit of quantitation of the assay on Day 1, there are highly significant differences in cognitive decline and brain atrophy in patients with above threshold plasma levels, both for monotherapy and add-on therapy, but with effect sizes reduced by half as add-on. Plasma concentrations in the range 4–21 ng/ml produced by the high doses are not associated with any additional benefit. Conclusions: Hydromethylthionine has pharmacological activity on brain structure and function at the 8 mg/day dose as monotherapy or as add-on to symptomatic treatments. This combined with a plateau at higher doses is consistent with the lack of dose-response seen in the Phase III trials. Treatment benefit is predicted to be maximal at 16 mg/day as monotherapy. A placebo-controlled trial in mild/moderate AD is now ongoing to confirm efficacy at this dose. Show more

Keywords: Acetylcholinesterase inhibitor, Alzheimer’s disease, clinical trials, drug interaction, leucomethylthioninium, population pharmacokinetics

DOI: 10.3233/JAD-190772

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

Article Type: Correction

DOI: 10.3233/JAD-199009

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

Authors: Ji, Yangfei | Wang, Dan | Zhang, Boai | Lu, Hong

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is the second most prevalent progressive neurodegenerative disease with motor disorders and cognitive impairment. Bergenin (Berg), extracted from the herb of Saxifrage stolonifera Curt. (Hu-Er-Cao), has anti-tumor, anti-inflammation, anti-oxidative stress, and neuroprotective properties. Objective: In this study, we wanted to investigate the effects of Berg on PD and the underlying mechanisms. Methods: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to introduce PD symptoms in mice. The expression levels of tyrosine hydroxylase, dopamine, and Iba-1 were examined. The levels of a series of inflammatory mediators were measured by qPCR. In addition, the PI3K/Akt signaling pathway …was investigated to illustrate the underlying mechanism. In vitro , PC12 cells subjected to lipopolysaccharide (LPS) were treated with Berg. Results: We found that MPTP injection introduced motor deficits, apoptosis of neurons and inflammation, as well as inhibited the PI3K/Akt signaling pathway. However, Berg treatment suppressed the MPTP-induced alterations. In vitro , Berg attenuated the cytotoxic effects on PC12 cells induced by the culture supernatants derived from LPS-induced microglial cells. Conclusion: Berg attenuated the PD symptoms via activating the PI3K/Akt signaling pathway in vivo and in vitro . Show more

Keywords: Bergenin, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), Parkinson’s disease, PI3K/Akt signaling pathway

DOI: 10.3233/JAD-190870

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Geier, David A. | Kern, Janet K. | Homme, Kristin G. | Geier, Mark R.

Article Type: Research Article

Abstract:  Cognitive health is an emerging public health concern for the aging American population. Mercury (Hg) is a toxic element that can cause nervous system damage. This hypothesis-testing study evaluated the relationship between blood ethyl-Hg levels and cognitive decline in an older adult and elderly American population. A total of 1,821,663 weighted-persons between 60–80 years old with detectable blood ethyl-Hg levels within the 2011–2012 National Health and Nutritional Survey were examined. Those persons with blood ethyl-Hg levels greater than the median were deemed the higher ethyl-Hg exposure group and those with ethyl-Hg levels less than the median were deemed the lower …ethyl-Hg exposure group. Three tests were utilized to measure cognitive function: 1) Consortium to Establish a Registry for Alzheimer’s Disease – Word List Learning (CERAD W-L) delayed recall test, 2) animal fluency test, and 3) Digit Symbol Substitution Test. Each cognitive test score was categorized as higher for those with scores greater than the median and lower for those with scores less than the median. Survey logistic regression modeling with covariates was used to analyze the data for the relationship between blood ethyl-Hg levels and cognitive function scores. Significantly increased risks for lower animal fluency test (odds ratio (OR) = 13.652, p  = 0.0029) and CERAD W-L delayed recall test (OR = 6.401, p  = 0.0433) scores were observed among the higher ethyl-Hg exposure group as compared to the lower ethyl-Hg exposure group. This study supports the hypothesis that increased ethyl-Hg exposure is associated with significant cognitive decline in older adult and elderly Americans. Show more

Keywords: Ethylmercury, merthiolate, methylmercury, thiomersal

DOI: 10.3233/JAD-190894

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

Authors: Chen, Bing | Zheng, Weiming

Article Type: Research Article

Abstract: Upregulation of Rho-associated protein kinase 2 (ROCK2) hallmarks the progression of neurodegenerative diseases. However, the molecular mechanisms underlying the regulation of ROCK2 expression are not clear and thus addressed in the current study. We generated a subacute model of Parkinson’s disease in mice with a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) method. The MPTP model was validated by impaired rotational behavior of the mice upon apomorphine exposure, astrocytic activation, and reduction in tyrosine-hydroxylase-positive neurons in the mouse striatum. Moreover, MPTP induced increases in ROCK2 protein but not in ROCK2 mRNA. Further analysis showed that MPTP inhibited the expression of microRNA-291 (miR-291), which suppressed ROCK2 …mRNA via 3’-UTR-binding in neuronal cells to increase ROCK2 protein. Intracranial injection of miR-291 four days before MPTP alleviated the impaired rotational behavior of the mice upon apomorphine exposure, MPTP-induced astrocytic activation, and the reduction in tyrosine-hydroxylase-positive neurons in the mouse striatum. Together, these data suggest that miR-291 has a protective role in neurodegeneration, likely through regulation of ROCK2. Show more

Keywords: MicroRNA-291, neurodegenerative disease, ROCK2

DOI: 10.3233/JAD-190832

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

Authors: Richards, Emma | Bayer, Antony | Hanley, Claire | Norris, Jade E. | Tree, Jeremy | Tales, Andrea

Article Type: Research Article

Abstract: Slowed behavioral reaction time is associated with pathological brain changes, including white matter lesions, the common clinical characteristic of subcortical ischemic vascular cognitive impairment (SIVCI). In the present study, reaction time (RT) employing Trails B of the Trail Making Test, with responses capped at 300 s, was investigated in SIVCI (n  = 27) compared to cognitively healthy aging (CH) (n  = 26). RT was significantly slowed in SIVCI compared to CH (Cohen’s d effect size = 1.26). Furthermore, failure to complete Trails B within 300 s was also a characteristic of SIVCI although some ostensibly cognitively healthy older adults also failed to complete within this time …limit. Within the SIVCI group, RT did not differ significantly with respect to whether the patients were classified as having moderate/severe or mild, periventricular white matter changes visible on their diagnostic CT/MRI scans. This, together with the high degree of overlap in RT between the two SIVCI subgroups, raises the possibility that using visible ratings scales in isolation may lead to the underestimation of disease level. Show more

Keywords: Methodology, reaction time, subcortical ischemic vascular cognitive impairment, Trail Making Test

DOI: 10.3233/JAD-190823

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019

Authors: Boccardi, Virginia | Paolacci, Lucia | Remondini, Daniel | Giampieri, Enrico | Poli, Giulia | Curti, Nico | Cecchetti, Roberta | Villa, Alfredo | Ruggiero, Carmelinda | Brancorsini, Stefano | Mecocci, Patrizia

Article Type: Research Article

Abstract: Background: Elevated peripheral levels of different cytokines and chemokines in subjects with Alzheimer’s disease (AD), as compared with healthy controls (HC), have emphasized the role of inflammation in such a disease. Considering the cross-talking between the central nervous system and the periphery, the inflammatory analytes may provide utility as biomarkers to identify AD at earlier stages. Objective: Using an advanced statistical approach, we can discriminate the interactive network of cytokines/chemokines and propose a useful tool to follow the progression and evolution of AD, also in light of sex differences. Methods: A cohort of 289 old-age subjects …was screened for cytokine and chemokine profiling, measured in plasma, after a thorough clinical and neuropsychological evaluation. A custom algorithm based on Fisher linear discriminant analysis was applied to ascertain a classification signature able to discriminate HC from mild cognitive impairment (MCI) and AD. Results: We observed that a joint expression of three proteins (a “signature” composed by IFN-α 2, IL-1α , TNFα ) can discriminate HC from AD with an accuracy of 65.24%. Using this signature on MCI samples, 84.93% of them were classified as “non-HC”. Stratifying MCI samples by sex, we observed that 87.23% of women were classified as “non-HC”, and only 57.69% of males. Indeed, in a scatter plot of IFN-α 2 and IL-1α , the HC group was better separated from MCI and AD in women as compared with men. Conclusion: These findings suggest that AD is accompanied by a peripheral inflammatory response that can already be present in MCI subjects, thus providing a mean for detecting this at-risk status and allow an anticipated intervention. Show more

Keywords: Cytokines, dementia, inflammation, markers, sex

DOI: 10.3233/JAD-190480

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