Journal of Alzheimer's Disease - Volume 72, issue 3

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. 72, no. 3, pp. 911-918, 2019

Authors: Clark, Lindsay R. | Norton, Derek | Berman, Sara 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. 72, no. 3, pp. 919-929, 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, hydromethylthionine

DOI: 10.3233/JAD-190772

Citation: Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 931-946, 2019

Authors: Huang, Nayan | Li, Wenjie | Rong, Xiangjiang | Champ, Mei | Wei, Lian | Li, Mo | Mu, Haiyan | Hu, Yueqing | Ma, Zongjuan | Lyu, Jihui

Article Type: Research Article

Abstract: Background: Tai Chi exercise is a non-pharmacological therapy that has received increased attention in recent years. A Tai Chi program has been specifically modified for older people with cognitive impairments by the research team. Objective: We aim to assess the effects of this Tai Chi program on mild dementia. Methods: Eighty older people with mild dementia were recruited and randomly assigned to a Tai Chi group or a control group. The Tai Chi group practiced the Tai Chi program three times a week for 10 months, while the control group continued receiving routine treatments. All participants …were assessed for cognitive function, behavior/mood, and activities of daily living at baseline, 5 months, and 10 months. Results: The Tai Chi group performed better than the control group. Repeated measures ANOVA revealed a significant group×time interaction in the Montreal Cognitive Assessment (MoCA). Further analysis of sub-items of the MoCA showed a significant time effect in naming and abstraction. It was statistically significant in both main effect of time and group×time interaction in the Neuropsychiatric Inventory (NPI) and Geriatric Depression Scale (GDS). Paired sample t test showed the Tai Chi group scored lower at 5 and 10 months in the NPI and at 10 months in the GDS compared with baseline. The Tai Chi group scored lower than the control group at 10 months in the NPI and GDS. Conclusion: The results suggest this Tai Chi program may help improve cognitive function and mental well-being for older adults with mild dementia. Show more

Keywords: Behavioral and psychological symptoms, cognitive function, dementia, depressive mood, Tai Chi

DOI: 10.3233/JAD-190487

Citation: Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 947-956, 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. 72, no. 3, pp. 957-975, 2019