Journal of Alzheimer's Disease - Volume 60, issue 2

Authors: Kueider, Alexandra M. | An, Yang | Tanaka, Toshiko | Kitner-Triolo, Melissa H. | Studenski, Stephanie | Ferrucci, Luigi | Thambisetty, Madhav

Article Type: Research Article

Abstract: Serum uric acid (SUA) is an abundant natural antioxidant capable of reducing cellular oxidation, a major cause of neurodegenerative disease. In line with this, SUA levels are lower in Alzheimer’s disease; however, the association between SUA and cognition remains unclear. Results from studies examining the effects of SUA on cognition may be difficult to interpret in the context of normal versus pathological aging. This study examined sex-specific associations of baseline SUA with cognition during aging. Data from dementia-free participants initially aged 26–99 (N  = 1,451) recruited for the Baltimore Longitudinal Study of Aging (BLSA), were used in the current analyses. SUA …was assessed using blood samples collected during research visits. Cognition was measured using five composite scores (verbal memory, attention, executive function, language, and visuospatial ability). At the first study visit, compared with women, men were older, more likely to be White, had more years of education, higher baseline SUA levels, and higher cardiovascular risk scores. Higher baseline SUA was associated with attenuated declines in attention (β= 0.006; p  = 0.03) and visuospatial abilities (β= 0.007; p  = 0.01) in men. There was a trend to suggest higher baseline SUA in men was associated with attenuated declines in language, but this finding did not reach statistical significance (p  = 0.09). There were no significant findings with SUA and cognition in women. In this sample of cognitively healthy, community-dwelling adults, we found that higher SUA levels at baseline were associated with attenuated declines in attention and visuospatial abilities in men. SUA was not associated with cognition or change in cognition over time in women. Show more

Keywords: Aging, cognitive function, older adults, uric acid

DOI: 10.3233/JAD-170287

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 699-706, 2017

Authors: Weissberger, Gali H. | Melrose, Rebecca J. | Fanale, Candace M. | Veliz, Joseph V. | Sultzer, David L.

Article Type: Research Article

Abstract: Orientation to time, date, and place is commonly utilized in clinical settings to aid in diagnosis, staging, and monitoring of Alzheimer’s disease (AD). This study aimed to identify the cerebral metabolic correlates of orientation in patients with AD, and the degree to which regions associated with orientation overlap with memory-related structures. Eighty-five patients with a diagnosis of probable AD underwent fluorodeoxyglucose positron emission tomography (FDG-PET) and neuropsychological testing. Orientation items from the Dementia Rating Scale and recognition performance from the Consortium to Establish a Registry for AD (CERAD) Word List Learning test were correlated with cerebral glucose metabolism. Post-hoc …analyses examined neuropsychological predictors of orientation. Better orientation performance related to greater cerebral metabolism in the bilateral middle-inferior temporal lobes, bilateral middle-posterior cingulate, left angular gyrus, and left middle occipital gyrus. In comparison, higher CERAD recognition discriminability score was associated with greater metabolic activity in left medial temporal lobe regions including the hippocampal and parahippocampal gyri, and the left fusiform gyrus. Post-hoc behavioral analyses revealed multiple cognitive functions to be related to orientation, including list learning, recognition memory, visuospatial functioning, attention, and language. Findings from the present study suggest that disorientation in AD results from dysfunction of a network of structures and cognitive abilities commonly found to be implicated in AD. The study supports the notion that memory is necessary but not sufficient for successful orientation. Show more

Keywords: Alzheimer’s disease, fluorodeoxyglucose F18, memory, neuropsychology, orientation

DOI: 10.3233/JAD-170420

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 707-719, 2017

Authors: Karki, Reagon | Kodamullil, Alpha Tom | Hofmann-Apitius, Martin

Article Type: Research Article

Abstract: Background: Various studies suggest a comorbid association between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) indicating that there could be shared underlying pathophysiological mechanisms. Objective: This study aims to systematically model relevant knowledge at the molecular level to find a mechanistic rationale explaining the existing comorbid association between AD and T2DM. Method: We have used a knowledge-based modeling approach to build two network models for AD and T2DM using Biological Expression Language (BEL), which is capable of capturing and representing causal and correlative relationships at both molecular and clinical levels from various knowledge resources. …Results: Using comparative analysis, we have identified several putative “shared pathways”. We demonstrate, at a mechanistic level, how the insulin signaling pathway is related to other significant AD pathways such as the neurotrophin signaling pathway, PI3K/AKT signaling, MTOR signaling, and MAPK signaling and how these pathways do cross-talk with each other both in AD and T2DM. In addition, we present a mechanistic hypothesis that explains both favorable and adverse effects of the anti-diabetic drug metformin in AD. Conclusion: The two computable models introduced here provide a powerful framework to identify plausible mechanistic links shared between AD and T2DM and thereby identify targeted pathways for new therapeutics. Our approach can also be used to provide mechanistic answers to the question of why some T2DM treatments seem to increase the risk of AD. Show more

Keywords: Alzheimer’s disease, comorbidity, disease mechanisms, disease modeling, metformin, OpenBEL, type 2 diabetes mellitus

DOI: 10.3233/JAD-170440

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 721-731, 2017

Authors: Zhang, Li | Sun, Caixian | Jin, Yaxi | Gao, Kai | Shi, Xudong | Qiu, Wenying | Ma, Chao | Zhang, Lianfeng

Article Type: Research Article

Abstract: Dysfunctional Wnt signaling is associated with Alzheimer’s disease (AD), and activation of the Wnt signaling pathway inhibits AD development. Dickkopf 3 (Dkk3) is a modulator of the Wnt signaling pathway and is physiologically expressed in the brain. The role of Dkk3 in the pathogenesis of AD has not been evaluated. In the present study, we determined that Dkk3 expression was significantly decreased in brain tissue from AD patients and the AD transgenic mouse model APPswe/PS1dE9 (AD mice). Transgenic mice with brain tissue-specific Dkk3 expression were generated or crossed with AD mice to study the effects of Dkk3 on AD. In …AD mice, transgenic expression of Dkk3 improved abnormalities in learning, memory, and locomotor activity, reduced the accumulation of amyloid-β, and ameliorated glucose uptake deficits. Furthermore, we determined that Dkk3 downregulated GSK-3β, a central negative regulator in canonical Wnt signaling, and upregulated PKCβ1, a factor implicated in noncanonical Wnt signaling. This indicates that increased activation of GSK-3β and the inhibition of PKCβ1 in AD patients may be responsible for the dysfunctional Wnt signaling in AD. In summary, our data suggest that Dkk3 is an agonist of Wnt signaling, and the ability of transgenic expression of Dkk3 to compensate for the decrease in Dkk3 expression in AD mice, reverse dysfunctional Wnt signaling, and partially inhibit the pathological development of AD suggests that Dkk3 could serve as a therapeutic target for the treatment of AD. Show more

Keywords: Alzheimer’s disease, cognition, Dkk3, transgenic mice, Wnt signaling pathway

DOI: 10.3233/JAD-161254

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 733-746, 2017