Would Adding Low Doses of Lithium Salts and/or Prebiotic Fibre Interventions to an Effective Exercise Protocol Further Enhance Retention of Cognitive Integrity? Potential for Preventing Loss of Cognition with Aging Using Combinations of Low Cost Regimens
It is clear that loss of cognition is becoming epidemic in our aging society. Onset of dementia and diseases such as Alzheimer’s are very prevalent and the prognosis is not optimistic that numbers will decrease in the coming decades. Thus, this epidemic is impacting the quality of life of a large number of people, primarily females, as well as the health care systems of many countries. Of relevance is the fact that large clinical trials of candidate drugs to treat these conditions have not been overwhelming successes, indicating that we may need to take new directions or focus on prevention. One conservative approach in this regard has been the use of exercise protocols to both retain cognition and inhibit progression of loss. With the optimization of exercise protocols, it may be time to step back and ask “how can these successes be augmented to further inhibit risk and stabilize loss early in the development of these conditions?” An example of how this could be approached is via supplementation with low doses of minerals such as lithium salts, or supplementation of the diet with prebiotics in patients with obesity and metabolic syndrome. Regarding the former, recent epidemiological studies have indicated that the content of Li in the drinking water is associated with lower incidences of cognitive diseases/conditions. While not definitive, such clues may warrant performing controlled studies using low doses of lithium salts plus exercise to further optimize impact on retention of cognition in those at risk, or those with early disease. Similarly, patients with obesity are at higher risk to develop dementia, and prebiotics can correct some of the metabolic derangements associated with the microbiome in such patients to impact risk. Thus, multiple low cost interventions plus exercise could further enhance retention of cognitive integrity in specific populations.
References
[1]
Bellou, V., et al. (2017) Systematic Evaluation of the Associations between Environmental Risk Factors and Dementia: An Umbrella Review of Systematic Reviews and Meta-Analyses. Alzheimers Dement, 13, 406-418. https://doi.org/10.1016/j.jalz.2016.07.152
[2]
Hickman, R.A., et al. (2016) Alzheimer Disease and Its Growing Epidemic: Risk Factors, Biomarkers, and the Urgent Need for Therapeutics. Neurologic Clinics, 34, 941-953. https://doi.org/10.1016/j.ncl.2016.06.009
[3]
Barha, C.K., et al. (2017) Personalizing Exercise Recommendations for Brain Health: Considerations and Future Directions. British Journal of Sports Medicine, 51, 536-639. https://doi.org/10.1136/bjsports-2016-096710
[4]
Pike, C.J. (2017) Sex and the Development of Alzheimer’s Disease. Journal of Neuroscience Research, 95, 671-680. https://doi.org/10.1002/jnr.23827
[5]
Podcasy, J.L. and Epperson, C.N. (2016) Considering Sex and Gender in Alzheimer Disease and Other Dementias. Dialogues in Clinical Neuroscience, 18, 437-446.
[6]
Gunn-Moore, D., et al. (2017) Alzheimer’s Disease in Humans and Other Animals: A Consequence of Postreproductive Life Span and Longevity Rather Than Aging. Alzheimers Dement. [Epub ahead of Print] https://doi.org/10.1016/j.jalz.2017.08.014
[7]
Hamson, D.K., et al. (2016) Sex Hormones and Cognition: Neuroendocrine Influences on Memory and Learning. Comprehensive Physiology, 6, 1295-1337. https://doi.org/10.1002/cphy.c150031
[8]
Georgakis, M.K., et al. (2016) Age at Menopause and Duration of Reproductive Period in Association with Dementia and Cognitive Function: A Systematic Review and Meta-Analysis. Psychoneuroendocrinology, 73, 224-243. https://doi.org/10.1016/j.psyneuen.2016.08.003
[9]
Korczyn, A.D. (2012) Why Have We Failed to Cure Alzheimer’s Disease? Journal of Alzheimers Disease, 29, 275-282. https://doi.org/10.1016/j.neurobiolaging.2012.01.061
[10]
Hung, S.Y. and Fu, W.M. (2017) Drug Candidates in Clinical Trials for Alzheimer’s Disease. Journal of Biomedical Science, 24, 47. https://doi.org/10.1186/s12929-017-0355-7
[11]
Hampel, H., et al. (2017) A Precision Medicine Initiative for Alzheimer’s Disease: The Road Ahead to Biomarker-Guided Integrative Disease Modeling. Climacteric, 20, 107-118. https://doi.org/10.1080/13697137.2017.1287866
[12]
DiMarco, L.Y., et al. (2015) Vascular Dysfunction in the Pathogenesis of Alzheimer’s Disease—A Review of Endothelium-Mediated Mechanisms and Ensuing Vicious Circles. Neurobiology of Disease, 82, 593-606. https://doi.org/10.1016/j.nbd.2015.08.014
[13]
Eichenbaum, H. (2017) On the Integrations of Space, Time, and Memory. Neuron, 95, 1007-1018. https://doi.org/10.1016/j.neuron.2017.06.036
[14]
Canevelli, M., et al. (2017) Sex and Gender Differences in the Treatment of Alzheimer’s Disease: A Systematic Review of Randomized Controlled Trials. Pharmacological Research, 115, 218-223. https://doi.org/10.1016/j.phrs.2016.11.035
[15]
Bolos, M., et al. (2017) Alzheimer’s Disease as an Inflammatory Disease. Biomolecular Concepts, 8, 37-43. https://doi.org/10.1515/bmc-2016-0029
[16]
Bagyinszky, E., et al. (2017) Role of Inflammatory Molecules in Alzheimer’s Disease Progression and Diagnosis. Journal of the Neurological Sciences, 376, 242-254. https://doi.org/10.1016/j.jns.2017.03.031
[17]
Albanese, E., et al. (2015) Overweight and Obesity in Midlife and Brain Structure and Dementia 26 Years Later: The AGES-Reykjavik Study. American Journal of Epidemiology, 181, 672-679. https://doi.org/10.1093/aje/kwu331
[18]
Wang, M., et al. (2016) Metabolic, Inflammatory, and Microvascular Determinants of White Matter Disease and Cognitive Decline. American Journal of Neurodegenerative Disease, 5, 171-177.
[19]
Albanese, E., et al. (2017) Body Mass Index in Midlife and Dementia: Systematic Review and Meta-Regression Analysis of 589,649 Men and Women Followed in Longitudinal Studies. Alzheimer’s & Dementia, 8, 165-178. https://doi.org/10.1016/j.dadm.2017.05.007
[20]
Moser, V.A. and Pike, C.J. (2016) Obesity and Sex Interact in the Regulation of Alzheimer’s Disease. Neuroscience & Biobehavioral Reviews, 67, 102-118. https://doi.org/10.1016/j.neubiorev.2015.08.021
[21]
Sample, C.H. and Davidson, T.L. (2017) Considering Sex Differences in the Cognitive Controls of Feeding. Physiology & Behavior. https://doi.org/10.1016/j.physbeh.2017.11.023
[22]
Kiliaan, A.J., et al. (2014) Adipokines: A Link between Obesity and Dementia? The Lancet Neurology, 13, 913-923. https://doi.org/10.1016/S1474-4422(14)70085-7
[23]
Arnoldussen, J.A., et al. (2014) Obesity and Dementia: Adipokines Interact with the Brain. European Neuropsychopharmacology, 24, 1982-1999. https://doi.org/10.1016/j.euroneuro.2014.03.002
[24]
Zanini, P., et al. (2017) Diet-Induced Obesity Alters Memory Consolidation in Female Rats. Physiology & Behavior, 180, 91-97. https://doi.org/10.1016/j.physbeh.2017.08.011
[25]
Collins, K.H., et al. (2015) Relationship between Inflammation, the Gut Microbiota, and Metabolic Osteoarthritis Development: Studies in a Rat Model. Osteoarthritis Cartilage, 23, 1989-1998. https://doi.org/10.1016/j.joca.2015.03.014
[26]
Collins, K.H., et al. (2016) A High-Fat High-Sucrose Diet Rapidly Alters Muscle Integrity, Inflammation and Gut Microbiota in Male Rats. Scientific Reports, 6, Article No. 37278. https://doi.org/10.1038/srep37278
[27]
Van der Wardt, V., et al. (2017) Adherence Support Strategies for Exercise Interventions in People with Mild Cognitive Impairment and Dementia: A Systematic Review. Preventive Medicine Reports, 7, 38-45. https://doi.org/10.1016/j.pmedr.2017.05.007
[28]
Chieffi, S., et al. (2017) Neuroprotective Effects of Physical Activity: Evidence from Human and Animal Studies. Frontiers in Neurology, 8, 188.
[29]
Bherer, L., et al. (2013) A Review of the Effects of Physical Activity and Exercise on Cognitive and Brain Functions in Older Adults. Journal of Aging Research, 2013, Article ID: 657508. https://doi.org/10.1155/2013/657508
[30]
Barha, C.K., et al. (2017) Sex Differences in Exercise Efficacy to Improve Cognition: A Systematic Review and Meta-Analysis of Randomized Controlled Trials in Older Humans. Frontiers in Neuroendocrinology, 46, 71-85. https://doi.org/10.1016/j.yfrne.2017.04.002
[31]
Barha, C.K., et al. (2017) Sex Differences in Aerobic Exercise Efficacy to Improve Cognition: A Systematic Review and Meta-Analysis of Studies in Older Rodents. Frontiers in Neuroendocrinology, 46, 86-105. https://doi.org/10.1016/j.yfrne.2017.06.001
[32]
Bryan, M.T., et al. (2014) Mechanoresponsive Networks Controlling Vascular Inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology, 34, 2199-2205. https://doi.org/10.1161/ATVBAHA.114.303424
[33]
Vivar, C. and van Praag, H. (2017) Running Changes the Brain: The Long and the Short of It. Physiology (Bethesda), 32, 410-424. https://doi.org/10.1152/physiol.00017.2017
[34]
Hart, D.A. and Scott, A. (2012) Getting the Dose Right When Prescribing Exercise for Connective Tissue Conditions: The Yin and the Yang of Tissue Homeostasis. British Journal of Sports Medicine, 46, 696-698. https://doi.org/10.1136/bjsports-2011-090083
[35]
Kessing, L.V., et al. (2008) Lithium Treatment and Risk of Dementia. Arch Gen Psychiatry, 65, 1331-1335. https://doi.org/10.1001/archpsyc.65.11.1331
[36]
Kessing, L.V., et al. (2010) Does Lithium Protect against Dementia? Bipolar Disorders, 12, 87-94. https://doi.org/10.1111/j.1399-5618.2009.00788.x
[37]
Mauer, S., et al. (2014) Standard and Trace-Dose Lithium: A Systematic Review of Dementia Prevention and Other Behavioral Benefits. Australian & New Zealand Journal of Psychiatry, 48, 809-818. https://doi.org/10.1177/0004867414536932
[38]
Matsunga, S., et al. (2015) Lithium as a Treatment for Alz-heimer’s Disease: A Systematic Review and Meta-Analysis. Journal of Alzheimer’s Disease, 48, 403-410. https://doi.org/10.3233/JAD-150437
[39]
Kessing, L.V., et al. (2017) Association of Lithium in the Drinking Water with the Incidence of Dementia. JAMA Psychiatry, 74, 1005-1010. https://doi.org/10.1001/jamapsychiatry.2017.2362
[40]
Cade, J.F. (1949) Lithium Salts in the Treatment of Psychotic Excitement. The Medical Journal of Australia, 2, 349-352.
[41]
Hart, D.A. (1988) Immunopharmacologic Aspects of Lithium: One Aspect of a General Role as a Modulator of Homeostasis. In: Lithium: Inorganic Pharmacology and Psychiatric Use, IRL Press, Oxford, 99-102.
[42]
Hart, D.A. (1991) Lithium, Lymphocytes and Laby-rinths: Insights into Biological Regulation and Diversity. In: Birch, N.J., Ed., The Pharmacology of Inorganic Lithium, Academic Press, New York, 289-315. https://doi.org/10.1016/B978-0-12-099300-0.50020-7
[43]
Hart, D.A. (1991) Lithium, Lymphocyte Stimulation and the Neuroimmune Interface. In: Galliccho, V., Ed., Lithium and the Blood, Karger, Basel, 68-78.
[44]
Hart, D.A., et al. (1999) Genes and Gender in Lithium Responsiveness: Parallels between Mouse and Man. In: Lucas, K.C., Becker, R.W. and Galliccho, V., Eds., Lithium-50 Years: Recent Advances in Biology and Medicine, Weider Publishing, Cheshire, 161-174.
[45]
Prosser, J.M. and Fieve, R.R. (2016) Patients Receiving Lithium Therapy Have a Reduced Prevalence of Neurological and Cardiovascular Disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 71, 39-44. https://doi.org/10.1016/j.pnpbp.2016.06.006
[46]
Hart, D.A. (2016) Sex-Specific Effects of LiCl Treatment on Preservation of Renal Function and Extended Lifespan in Murine Models of SLE: Perspectives on Insights into the Potential Basis for Survivorship in NZB/NZW Female Mice. Biology of Sex Differences, 7, 31.
[47]
Bosche, B., et al. (2016) Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner. Frontiers in Physiology, 7, 593.
[48]
Reimer, R.A., et al. (2017) Inulin-Type Fructans and Whey Protein Both Modulate Appetite by Only Fructans Alter Gut Micro-biota in Adults with Overweight/Obesity: A Randomized Controlled Trial. Molecular Nutrition & Food Research, 61. https://doi.org/10.1002/mnfr.201700484
[49]
Parnell, J.A., et al. (2017) Oligofructose Decreases Serum Lipo-polysaccharide and Plasminogen Activator Inhibito-1 in Adults with Overweight/Obesity. Obesity (Silver Spring), 25, 510-513. https://doi.org/10.1002/oby.21763
[50]
Nicolucci, A.C. and Reimer, R.A. (2017) Prebiotics as a Modulator of Gut Microbiota in Paediatric Obesity. Pediatric Obesity, 12, 265-273. https://doi.org/10.1111/ijpo.12140
[51]
Nicolucci, A.C., et al. (2017) Prebiotics Reduce Body Fat and Alter Intestinal Microbiota in Children Who Are Overweight or with Obesity. Gastroenterology, 153, 711-722. https://doi.org/10.1053/j.gastro.2017.05.055
[52]
Puertollano, E., et al. (2014) Biological Significance of Short-Chain Fatty Acid Metabolism by the Intestinal Microbiome. Current Opinion in Clinical Nutrition & Metabolic Care, 17, 139-144. https://doi.org/10.1097/MCO.0000000000000025
[53]
He, M. and Shi, B. (2017) Gut Mi-crobiota as a Potential Target of Metabolic Syndrome: The Role of Probiotics and Prebiotics. Cell & Bioscience, 7, 54. https://doi.org/10.1186/s13578-017-0183-1
[54]
O’Connor, S., et al. (2017) Prebiotics in the Management of Components of the Metabolic Syndrome. Maturitas, 104, 11-18. https://doi.org/10.1016/j.maturitas.2017.07.005
[55]
Dinan, T.G. and Cryan, J.F. (2017) The Microbiome-Gut-Brain Axis in Health and Disease. Gastroenterology Clinics of North America, 46, 77-89. https://doi.org/10.1016/j.gtc.2016.09.007
[56]
Lambert, J.E., et al. (2015) Exercise Training Modifies Gut Microbiota in Normal and Diabetic Mice. Applied Physiology, Nutrition, and Metabolism, 40, 749-752. https://doi.org/10.1139/apnm-2014-0452
[57]
Nasr, A. and Breckwoldt, M. (1998) Estrogen Replacement Therapy and Cardiovascular Protection: Lipid Mechanisms Are the Tip of an Iceberg. Gynecological Endocrinology, 12, 43-59. https://doi.org/10.3109/09513599809024970
[58]
Bani, D. (2008) Relaxin as a Natural Agent for Vascular Health. Vascular Health and Risk Management, 4, 515-524. https://doi.org/10.2147/VHRM.S2177
[59]
Baskaran, A., et al. (2014) Sex Differences in Rates of Obesity in Bipolar Disorder: Postulated Mechanisms. Bipolar Disorder, 16, 83-92. https://doi.org/10.1111/bdi.12141
[60]
Goodrich, D.E., et al. (2016) Sex Differences in Weight Loss among Veterans with Serious Mental Illness: Observational Study of a National Weight Management Program. Women’s Health Issues, 26, 410-419. https://doi.org/10.1016/j.whi.2016.05.001