Abstract
Study design:
This study was a randomized, parallel-group, controlled clinical trial.
Objectives:
The purpose of this study was to examine the efficacy of targeting inflammation as a means of improving cognitive function in individuals with spinal cord injury.
Setting:
Participants were recruited from the Niagara region of Ontario Canada and all testing occurred on-site at Brock University.
Methods:
Indices of memory and verbal learning were assessed by means of the California Verbal Learning Test (CVLT). Inflammation and concentrations of neuroactive compounds related to the kynurenine pathway were assessed via a number of pro- and anti-inflammatory cytokines, as well as tryptophan, kynurenine and several large neutral amino acids. All assessments were performed at baseline as well as at 1 month and 3 months during a 3-month intervention by means of an anti-inflammatory diet.
Results:
Despite a reduction in inflammation, all measures of the CVLT, including list A, trial 1 (P=0.48), learning slope (P=0.46), long delay free recall (P=0.83), intrusions (P=0.61) and repetitions (P=0.07), showed no significant group × time interaction.
Conclusion:
It may be possible that the reduction in inflammation achieved in the current study was insufficient to induce substantial changes in indices of verbal learning and memory. Alternatively, as these participants likely underwent years of previous chronic inflammation, the underlying hippocampal damage may have negated potential improvements induced by acute reductions in inflammation.
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References
Davidoff G, Morris J, Roth E, Bleiberg J . Cognitive dysfunction and mild closed head injury in traumatic spinal cord injury. Arch Phys Med Rehabil 1985; 66: 489–491.
Davidoff G, Thomas P, Johnson M, Berent S, Dijkers M, Doljanac R . Closed head injury in acute traumatic spinal cord injury: incidence and risk factors. Arch Phys Med Rehabil 1988; 69: 869–872.
Richards JS, Brown L, Hagglund K, Bua G, Reeder K . Spinal cord injury and concomitant traumatic brain injury. Results of a longitudinal investigation. Arch Phys Med Rehabil 1988; 67: 211–216.
Wilmot CB, Cope DN, Hall KM, Acker M . Occult head injury: its incidence in spinal cord injury. Arch Phys Med Rehabil 1985; 66: 227–231.
Davidoff G, Roth E, Thomas P, Doljanac R, Dijkers M, Berent S et al. Depression and neuropsychological test performance in acute spinal cord injury patients: lack of correlation. Arch Clin Neuropsychol 1990; 5: 77–88.
Davidoff GN, Roth EJ, Haughton JS, Ardner MS . Cognitive dysfunction in spinal cord injury patients: sensitivity of the Functional Independence Measure subscales vs neuropsychologic assessment. Arch Phys Med Rehabil 1990; 71: 326–329.
Papanicolaou AC, Simos PG, Castillo EM, Breier JI, Katz JS, Wright AA . The hippocampus and memory of verbal and pictorial material. Learn Mem 2002; 9: 99–104.
Wecht JM, Rosado-Rivera D, Jegede A, Cirnigliaro CM, Jensen MA, Kirshblum S et al. Systemic and cerebral hemodynamics during cognitive testing. Clin Auton Res 2012; 22: 25–33.
Davies AL, Hayes KC, Dekaban GA . Clinical correlates of elevated serum concentrations of cytokines and autoantibodies in patients with spinal cord injury. Arch Phys Med Rehabil 2007; 88: 1384–1393.
Hayes KC, Hull TCL, Delaney GA, Potter PJ, Sequeira KAJ, Campbell K et al. Elevated serum titers of proinflammatory cytokines and CNS autoantibodies in patients with chronic spinal cord injury. J Neurotrauma 2002; 19: 753–761.
Tobinick EL, Gross H . Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflammation 2008; 5: 2.
Allison DJ, Ditor DS . The common inflammatory etiology of depression and cognitive impairment: a therapeutic target. J Neuroinflammation 2014; 11: 151.
Kato A, Suzuki Y, Suda T, Suzuki M, Fujie M, Takita T et al. Relationship between an increased serum kynurenine/tryptophan ratio and atherosclerotic parameters in hemodialysis patients. Hemodial Int 2010; 14: 418–424.
Nisapakultorn K, Makrudthong J, Sa-Ard-Iam N, Rerkyen P, Mahanonda R, Takikawa O . Indoleamine 2,3-dioxygenase expression and regulation in chronic periodontitis. J Periodontol 2009; 80: 114–121.
Oxenkrug GF . Tryptophan kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: the serotonin hypothesis revisited 40 years later. Isr J Psychiatry Relat Sci 2010; 47: 56–63.
Bender DA, McCreanor GM . Kynurenine hydroxylase: a potential rate-limiting enzyme in tryptophan metabolism. Biochem Soc Trans 1985; 13: 441–443.
Potter MC, Elmer GI, Bergeron R, Albuquerque EX, Guidetti P, Wu H-Q et al. Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior. Neuropsychopharmacology 2010; 35: 1734–1742.
Rassoulpour A, Wu H-Q, Ferre S, Schwarcz R . Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum. J Neurochem 2005; 93: 762–765.
Zmarowski A, Wu H-Q, Brooks JM, Potter MC, Pellicciari R, Schwarcz R et al. Astrocyte-derived kynurenic acid modulates basal and evoked cortical acetylcholine release. Eur J Neurosci 2009; 29: 529–538.
Wu H-Q, Pereira EFR, Bruno JP, Pellicciari R, Albuquerque EX, Schwarcz R . The astrocyte-derived alpha7 nicotinic receptor antagonist kynurenic acid controls extracellular glutamate levels in the prefrontal cortex. J Mol Neurosci 2010; 40: 204–210.
Chess AC, Simoni MK, Alling TE, Bucci DJ . Elevations of endogenous kynurenic acid produce spatial working memory deficits. Schizophr Bull 2007; 33: 797–804.
Chess AC, Bucci DJ . Increased concentration of cerebral kynurenic acid alters stimulus processing and conditioned responding. Behav Brain Res 2006; 170: 326–332.
Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T et al. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 1999; 20: 106–118.
Gulaj E, Pawlak K, Bien B, Pawlak D . Kynurenine and its metabolites in Alzheimer’s disease patients. Adv Med Sci 2010; 55: 204–211.
Tobinick E, Gross H, Weinberger A, Cohen H . TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study. MedGenMed 2006; 8: 25.
Panza F, Solfrizzi V, Colacicco AM, D’Introno A, Capurso C, Torres F et al. Mediterranean diet and cognitive decline. Public Health Nutr 2004; 7: 959–963.
Kalmijn S, van Boxtel MP, Ocké M, Verschuren WMM, Kromhout D, Launer LJ . Dietary intake of fatty acids and fish in relation to cognitive performance at middle age. Neurology 2004; 62: 275–280.
Spencer JPE . The impact of fruit flavonoids on memory and cognition. Br J Nutr 2010; 104 (Suppl 3): S40–S47.
Groah SL, Nash MS, Ljungberg IH, Libin A, Hamm LF, Ward E et al. Nutrient intake and body habitus after spinal cord injury: an analysis by sex and level of injury. J Spinal Cord Med 2009; 32: 25–33.
Levine AM, Nash MS, Green BA, Shea JD, Aronica MJ . An examination of dietary intakes and nutritional status of chronic healthy spinal cord injured individuals. Paraplegia 1992; 30: 880–889.
Allison DJ, Ditor DS . Targeting inflammation to influence mood following spinal cord injury: a randomized clinical trial. J Neuroinflammation 2015; 12: 204.
Woods SP, Delis DC, Scott JC, Kramer JH, Holdnack JA . The California Verbal Learning Test—second edition: test-retest reliability, practice effects, and reliable change indices for the standard and alternate forms. Arch Clin Neuropsychol 2006; 21: 413–420.
Stegen S, Stepanov I, Cookfair D, Schwartz E, Hojnacki D, Weinstock-Guttman B et al. Validity of the California Verbal Learning Test-II in multiple sclerosis. Clin Neuropsychol 2010; 24: 189–202.
Okuda S, Nishiyama N, Saito H, Katsuki H . 3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J Neurochem 2002; 70: 299–307.
Braidy N, Grant R, Adams S, Guillemin GJ . Neuroprotective effects of naturally occurring polyphenols on quinolinic acid-induced excitotoxicity in human neurons. FEBS J 2010; 277: 368–382.
Shah PJ, Ebmeier KP, Glabus MF, Goodwin GM . Cortical grey matter reductions associated with treatment-resistant chronic unipolar depression. Controlled magnetic resonance imaging study. Br J Psychiatry 1998; 172: 527–532.
Noonan VK, Fingas M, Farry A, Baxter D, Singh A, Fehlings MG et al. Incidence and prevalence of spinal cord injury in Canada: a national perspective. Neuroepidemiology 2012; 38: 219–226.
Gibson AE, Buchholz AC, Martin Ginis KA . C-Reactive protein in adults with chronic spinal cord injury: increased chronic inflammation in tetraplegia vs paraplegia. Spinal Cord 2008; 46: 616–621.
Manns PJ, McCubbin JA, Williams DP . Fitness, inflammation, and the metabolic syndrome in men with paraplegia. Arch Phys Med Rehabil 2005; 86: 1176–1181.
Acknowledgements
This study was supported by the Ontario Neurotrauma Foundation. We thank Now, CanPrev, AOR and Progressive for providing the supplements utilized in the dietary intervention.
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Allison, D., Josse, A., Gabriel, D. et al. Targeting inflammation to influence cognitive function following spinal cord injury: a randomized clinical trial. Spinal Cord 55, 26–32 (2017). https://doi.org/10.1038/sc.2016.96
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DOI: https://doi.org/10.1038/sc.2016.96
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