Neuronal Loss of NCLX-Dependent Mitochondrial Calcium Efflux Contributes to Age-Associated Cognitive Decline

2021 ◽  
Author(s):  
Pooja Jadiya ◽  
Devin W. Kolmetzky ◽  
Dhanendra Tomar ◽  
Henry M. Cohen ◽  
John W. Elrod
Keyword(s):  
Cognitive Decline ◽  
Neuronal Loss ◽  
Mitochondrial Calcium ◽  
Calcium Efflux

scholarly journals Computational Causal Modeling of the Dynamic Biomarker Cascade in Alzheimer’s Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Jeffrey R. Petrella ◽  
Wenrui Hao ◽  
Adithi Rao ◽  
P. Murali Doraiswamy
Keyword(s):  
Clinical Trials ◽  
Natural History ◽  
Cognitive Decline ◽  
Computational Model ◽  
Early Onset ◽  
Causal Model ◽  
Late Onset ◽  
Neuronal Loss ◽  
Prior Literature ◽  
Longitudinal Biomarker

Background. Alzheimer’s disease (AD) is a major public health concern, and there is an urgent need to better understand its complex biology and develop effective therapies. AD progression can be tracked in patients through validated imaging and spinal fluid biomarkers of pathology and neuronal loss. We still, however, lack a coherent quantitative model that explains how these biomarkers interact and evolve over time. Such a model could potentially help identify the major drivers of disease in individual patients and simulate response to therapy prior to entry in clinical trials. A current theory of AD biomarker progression, known as the dynamic biomarker cascade model, hypothesizes AD biomarkers evolve in a sequential but temporally overlapping manner. A computational model incorporating assumptions about the underlying biology of this theory and its variations would be useful to test and refine its accuracy with longitudinal biomarker data from clinical trials. Methods. We implemented a causal model to simulate time-dependent biomarker data under the descriptive assumptions of the dynamic biomarker cascade theory. We modeled pathologic biomarkers (beta-amyloid and tau), neuronal loss biomarkers, and cognitive impairment as nonlinear first-order ordinary differential equations (ODEs) to include amyloid-dependent and nondependent neurodegenerative cascades. We tested the feasibility of the model by adjusting its parameters to simulate three specific natural history scenarios in early-onset autosomal dominant AD and late-onset AD and determine whether computed biomarker trajectories agreed with current assumptions of AD biomarker progression. We also simulated the effects of antiamyloid therapy in late-onset AD. Results. The computational model of early-onset AD demonstrated the initial appearance of amyloid, followed by biomarkers of tau and neurodegeneration and the onset of cognitive decline based on cognitive reserve, as predicted by the prior literature. Similarly, the late-onset AD computational models demonstrated the first appearance of amyloid or nonamyloid-related tauopathy, depending on the magnitude of comorbid pathology, and also closely matched the biomarker cascades predicted by the prior literature. Forward simulation of antiamyloid therapy in symptomatic late-onset AD failed to demonstrate any slowing in progression of cognitive decline, consistent with prior failed clinical trials in symptomatic patients. Conclusions. We have developed and computationally implemented a mathematical causal model of the dynamic biomarker cascade theory in AD. We demonstrate the feasibility of this model by simulating biomarker evolution and cognitive decline in early- and late-onset natural history scenarios, as well as in a treatment scenario targeted at core AD pathology. Models resulting from this causal approach can be further developed and refined using patient data from longitudinal biomarker studies and may in the future play a key role in personalizing approaches to treatment.

scholarly journals Matrix Calcium Efflux via the Putative Mitochondrial Calcium-Hydrogen Exchanger: Role in mPTP Opening

2018 ◽  
Vol 114 (3) ◽  
pp. 658a
Author(s):  
Lyall Glait ◽  
Jyotsna Mishra ◽  
James S. Heisner ◽  
David F. Stowe ◽  
Amadou K.S. Camara ◽  
...  
Keyword(s):  
Mitochondrial Calcium ◽  
Calcium Efflux ◽  
Mptp Opening

scholarly journals Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Pooja Jadiya ◽  
Devin W. Kolmetzky ◽  
Dhanendra Tomar ◽  
Antonio Di Meco ◽  
Alyssa A. Lombardi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Mitochondrial Calcium ◽  
Calcium Efflux

scholarly journals Benzo(a)pyrene exposure induced neuronal loss, plaque deposition, and cognitive decline in APP/PS1 mice

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Dan Liu ◽  
Yujia Zhao ◽  
Yuze Qi ◽  
Yun Gao ◽  
Dezhen Tu ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Neuronal Loss ◽  
Plaque Deposition

scholarly journals Aging Brain: Prevention of Oxidative Stress by Vitamin E and Exercise

2009 ◽  
Vol 9 ◽  
pp. 366-372 ◽  
Author(s):  
Sambe Asha Devi
Keyword(s):  
Oxidative Stress ◽  
Vitamin E ◽  
Cognitive Decline ◽  
Middle Age ◽  
Neuronal Loss ◽  
Aging Brain ◽  
Key Factors ◽  
Esterase Inhibitors ◽  
The Brain ◽  
And Oxidative Stress

With aging, the brain undergoes neuronal loss in many areas. Although the loss of cells in the cerebral cortex, in particular the frontal cortex, has been recognized with aging, the influence of synaptic losses has a larger impact on cognitive decline. Much of the recent research on animals, as well as humans, has been aimed at slowing the cognitive decline through enrichment, and it has been found that the key factors are antioxidants and exercise. Several reports support the concept that regular supplementation of vitamin E and physical activity from as early as middle age can slow the cognitive decline observed during the later years. A few studies have also suggested that exercise is analogous to acetylcholine esterase inhibitors that are also used extensively to treat cognitive impairment and dementia in Alzheimer's disease. In addition, reports also support that vitamin E and exercise may act synergistically to overcome free radical injury and oxidative stress in the aging brain.

scholarly journals Advantaged socioeconomic conditions in childhood are associated with higher cognitive functioning but stronger cognitive decline in older age

2019 ◽  
Vol 116 (12) ◽  
pp. 5478-5486 ◽  
Author(s):  
Marja J. Aartsen ◽  
Boris Cheval ◽  
Stefan Sieber ◽  
Bernadette W. Van der Linden ◽  
Rainer Gabriel ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Cognitive Functioning ◽  
Cognitive Aging ◽  
Cognitive Reserve ◽  
Longitudinal Design ◽  
Neuronal Loss ◽  
Later Life ◽  
Older Age ◽  
Socioeconomic Conditions ◽  
Partner Status

Cognitive aging is characterized by large heterogeneity, which may be due to variations in childhood socioeconomic conditions (CSC). Although there is substantial evidence for an effect of CSC on levels of cognitive functioning at older age, results on associations with cognitive decline are mixed. We examined by means of an accelerated longitudinal design the association between CSC and cognitive trajectories from 50 to 96 years. Cognition included two functions generally found to decline with aging: delayed recall and verbal fluency. Data are from six waves of the Survey of Health, Aging, and Retirement in Europe (SHARE), conducted between 2004 and 2015 (n= 24,066 at baseline; 56% female, age 50+). We found a consistent CSC pattern in levels of cognitive functioning in later life. Older people with disadvantaged CSC had lower levels of cognitive functioning than those with more advantaged CSC. We also find that decline is almost 1.6 times faster in the most advantaged group compared with the most disadvantaged group. The faster decline for people with more advantaged CSC becomes less pronounced when we additionally control for adulthood socioeconomic conditions and current levels of physical activity, depressive symptoms, and partner status. Our findings are in line with the latency, pathway, and cumulative model and lend support to theories of cognitive reserve, stating that neuronal loss can no longer be repaired in people with more cognitive reserve once the underlying pathology is substantial and speed of decline is accelerated.

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