NEURO-INFLAMMATION AND ITS EFFECTS ON COGNITION: A REVIEW OF LITERATURE
Introducere: Există din ce în ce mai multe dovezi ce sugerează o asociere pozitivă între inflamație și declinul cognitiv al vârstnicului și un posibil rol în apariția demenței. Metode: Circuitele fiziologice cu rol în conectarea sistemului imun cu sistemul nervos central cât și studiile ce arată asocierea dintre inflamație și funcția neurocognitivă sunt revizuite în cadrul acestui articol. Rezultate: Studii recente arată că inflamația apărută la vârsta mijlocie poate fi asociată cu funcția cognitivă și morfologia creierului. Rezultatele din studiile pe oameni cât și pe animale de laborator folosind diverși markeri inflamatori, metode neuroimagistice și teste cognitive, arată contribuția inflamației la declinul performanței cognitive, putând chiar depăși alți factori cum ar fi: hipertensiunea, factorii metabolici, fumatul și ateroscleroza sub-clinică. Pe de altă parte, limitările acestor studii sunt constituite de absența includerii unor factori cu posibil impact asupra mediatorilor inflamatori precum: boala inflamatorie acuta, stresul psihologic sau activitatea fizică. Concluzii: Markerii inflamatori din circulația sangvină p o t p re z i c e r i s c u l d e a p a r i ț i e a l d e c l i n u l u i cognitiv/demenței și pot contribui la mecanismul fiziopatologic al declinului cognitiv pre-clinic.
Age-related cognitive decline is characterized by the gradual and progressive deterioration of several domains of cognitive ability, including executive function, working and episodic memory, processing speed and attention (1). These declines typically begin in middle adulthood and progress at a consistent rate across the rest of life and they include worse scores on tasks involving mental flexibility, recognition and delayed recall (1, 2, 3). What is more, deterioration in cognitive function has a negative impact on quality of life and imposes significant risk for dementia, injuries, hospitalization and death(1,2,3).
Recent research (4,5,6) has focused on identifying modifiable risk factors of age-related cognitive decline and evidence suggests that systemic inflammation may also play a role in this process, in opposition with the old paradigm that the immune system and the brain functioned in isolation due to the anatomical separation of leukocytes from the central nervous system (CNS) by the blood-brain barrier (BBB). As such, impairments in cognitive function were observed in animal models following peripheral administration of endotoxin (7), findings that were also confirmed in human studies where systemic infusion of IL-1 and/or interferon alpha lead to poorer memory consolidation, decreased social exploration and suppression of food intake (8-10).
At least three distinctive molecular pathways were identified linking peripheral immune stimuli to changes in the CNS. In the first case, peripheral cytokines stimulate brain vascular endothelial cells to release secondary messengers in the CNS that, in term, promote central release of proinflammatory cytokines (11). Another pathway is represented by peripheral cytokines that activate vagal afferent nerves to stimulate the production of proinflammatory cytokines via signals form the nucleus tractus solitarus (12). The third pathway is represented by peripheral cytokines which can be actively transported in the paraventricular regions of the BBB (13) and from there into the CNS. These pathways provide a link between the peripheral expression of proinflammatory cytokines and the central immune responses which can cause neurocognitive symptoms.
The acute inflammatory response is initiated when macrophages are activated by pathogen invasion or tissue d a m a g e , r e s u l t i n g i n t h e r e l e a s e o f s e v e r a l proinflammatory cytokines such as interleukin-10 (IL- 10), IL- 6, and tumor necrosis factor-a (TNF-a). Pro- inflammatory cytokines also enter the peripheral circulatory system and cause a systemic inflammatory response characterized by hepatic synthesis and release of acute-phase proteins including C-reactive protein (CRP) (14, 15). Although TNF-a decays rapidly, IL-6 and CRP have longer half-lives and are reliably detected in human plasma serum. What is more, it has been shown that circulating levels of IL-6 and CRP increase with age and predict the risk of accelerated cognitive decline among the elderly (16). For example, transgenic mice that overexpress central levels of IL-6 show deficits in synaptic plasticity and impaired avoidance learning (17) and the administration of IL-6 receptor antagonists to normal mice prevents the decrease in hippocampal long- term potentiation (LTP), neurogenesis and the subsequent cognitive sequelae that accompany peripheral and central inflammation (18). Taken together, these findings suggest that proinflammatory cytokines play a critical role in modulating the neuro-molecular processes involved in cognitive functioning such as learning and memory.
CHRONIC STRESS AND MICROGLIA
Another factor that can alter cognitive function is chronic stress (including low socioeconomic status, loneliness and caregiving for a terminally ill family member) (19) because it has been shown to increase peripheral inflammation that sensitizes or ‘primes’ a proinflammatory shift in microglial phenotype, resulting in an increase in central proinflammatory cytokines and concomitant deficits in learning and memory (20, 21). Studies on mice exposed to social isolation over a 4-week period presented elevated levels of hippocampal IL- 1F, decreased hippocampal neurogenesis and specific impairment of hippocampal-dependent memory (22). AGE The aging process is considered to be associated with a proinflammatory status giving raise to cytokine expression in the periphery (23), IL-6 in hippocampal and prefrontal brain regions (24) and activating the microglia (25). Also, receptors for proinflammatory cytokines are highly expressed on microglia found in the hippocampus and prefrontal brain regions (26-31). Animal studies suggest that age-related microglial activation results in exaggerated central responses to peripheral inflammation, which may play a role in the neurocognitive decline that accompanies the aging process (32).
I N F L A M M A T I O N V I A E N D O T O X I N ADMINISTRATION
The most used methodology in human studies involves examining changes in cognitive performance that accompanies the peripheral administration of an inflammatory stimulus. For example, a double-blind, balanced, crossover study split 20 male subjects in an intervention group (that received Salmonella endotoxin) and placebo (that received saline) (33) showing significant impairments in cognitive performance in the intervention group. Moreover, the effect was dependent on the level of the IL-6, with higher responses predicting the greatest impairments in performance. Similar results were reported in subsequent studies by Krabbe et al. (using Escherichia coli endotoxin vaccination) (23) and later confirmed by Brydon el al. (with typhoid vaccination) (34) with both studies finding inverse associations of IL-6 production and performance on declarative memory and executive function tasks. Finally, more direct evidence for a role of IL-6 comes from a study conducted by Spath Schwalbe et al. which showed that peripheral administration of recombinant IL-6 decreased self- reported attentional capacity when compared to placebo (35). While the specific assessments of cognitive ability may vary, several other studies show inverse associations of proinflammatory markers and cognitive functioning (36-39).
INFLAMMATION STATUS OF PATIENTS WITH DEMENTIA
Some insight regarding this topic comes from studies of neurodegenerative diseases that typically involve deficits in memory (including Alzheimer’s disease and vascular dementia). These syndromes are generally associated with higher than normal circulating levels of CRP, IL-6, and IL-1F (22, 40). For example, Zuliani et al. (40) showed patients diagnosed with dementia had higher levels of circulating TNF-a, IL-1B and IL-6 compared to healthy individuals. It is plausible that elevations in peripheral cytokines may reflect a consequence rather than a cause of neurodegenerative processes (41). Studies with longitudinal design showed that peripheral inflammation predicts future cognitive declines and subsequent risk for Alzheimer’s disease and other dementias (42). For example, a recent study showed that people with a chronic inflammatory condition like rheumatoid arthritis, have elevated levels of IL-6 (when compared to healthy participants) and have a 1.96-fold greater risk for developing mild cognitive impairment and a 2.43-fold increased risk for developing Alzheimer disease over a 20-year follow-up period (43). These results are confirmed by others studies that show that midlife levels of circulating CRP and peripheric production of TNF-a have been positively linked with increased risk for Alzheimer’s disease and vascular dementia in late life (44, 45). On the other hand, in the Framingham Heart Study plasma CRP levels were unrelated to dementia risk among older adults followed over a 13-year period (45).
These findings contribute to a growing data that links chronic inflammation to poor cognitive functioning. It also raises the possibility that high levels of circulating cytokines could be a biomarker of future risk for accelerated cognitive decline.
WHITE MATTER LEISONS AND MRI FINDINGS
Other studies have extended the assessment of inflammation-related brain structures to an examination of white matter hyperintensities (WMH), providing a marker of white matter damage and lesions (46). The older the subjects the higher the WMH value (47) and it has also been proven that this mark predicts future incidence of stroke, dementia, cognitive decline and death (48). The possibility that inflammatory processes may play a role in age related increases of WMH has been the focus of several recent investigations (49, 50). Additionally, IL-6 and, to a lesser extent, CRP were positively associated with WMH volume.
A recent study by Furney et al. (51) examined the contribution of structural MRI results of inflammation in predicting the risk for dementia. Although cytokine levels and MRI findings contributed independently to the prediction of risk, a model that combined them both accounted for greater predictability. There are many congruent proofs that inflammation plays a role in progression to dementia and these findings raise the question if the traditional structural MRI techniques may not adequately detect the entirety of inflammatory-related effects.
In addition to immune cells, adipose tissue is a key contributing source of proinflammatory mediators, including IL-6, explaining why high BMI is also associated with age-related cognitive decline (52) and risk for future dementia (53). Thus, it is plausible that interventions aimed at reducing adiposity may protect against cognitive impairment. While weight loss by dieting and bariatric surgery has been associated with reductions in peripheral inflammation (54), it is unknown whether the magnitude of these effects conveys protection against accelerated cognitive aging.
Findings also suggest that anti-inflammatory drugs can restore hippocampal neurogenesis in rats and other human epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) may slow the progression of memory loss in patients with dementia and decrease the future risk for Alzheimer’s disease. Until now, most of these clinical trials have focused on secondary prevention in elderly populations who are already diagnosed with dementia, but results from a recent study showed that anti-inflammatory drugs could protect against age-related atrophy of grey and white matter among older women (55). However, not all findings are consistent as there are clinical trials that show no benefit of NSAlDs in preventing cognitive decline in patients with dementia (56). It remains to be determined whether NSAIDs are beneficial if provided earlier in the disease course.
While some prospective longitudinal designs have been utilized, studies investigating associations of inflammation and cognitive function are largely cross- sectional, precluding causal interpretations. Animal studies support the role of inflammation in modulating cognitive performance, however the reverse is also a possibility with elevations in peripheral inflammation from neurodegenerative processes in the CNS, but this can also be a ‘spillover’ effect (57). It is also possible that associations may stem from a third factor, possibly relating to individual differences in genetics.
Another limitation of the current literature is the use of single set assessments of inflammatory markers. Evidence suggests that these markers are relatively stable over extended periods (58), however, multiple factors are known to impact circulating levels of inflammatory mediators, including acute inflammatory disease, psychological stress, and physical activity. Thus, a more reliable assessment of stable individual difference would be derived from assessing means across multiple testing occasions.
The studies overviewed in this article suggest that circulating markers of inflammation can predict the risk of cognitive decline and can possibly contribute to the pathophysiology of preclinical neurocognitive decline.
Recent human studies combining different markers of inflammation, neuroimaging methods and cognitive tests are consistent with studies on animal models showing that inflammation contributes to lowering cognitive performance. However, because inflammation varies significantly in elderly and they also have more cardiovascular risk factors, predictive factors of cognitive decline are very difficult to pin-point.
Future prospective investigations are needed, which begin in middle adulthood and examine inflammation, brain structure and cognitive function, in order to assess if variation in systemic inflammation among adults represents a risk for accelerated cognitive decline and dementia, shedding light on possible neural pathways of these processes.
1.Buckner RL: Memory and executive function in aging and AD: multiple factors that cause and reserve factors that compensate. Neuron 2004;44:195-208.
2.Salthouse TA, et al: When docs age-related cognitive decline begins? Neurobiol Aging 2009:30;500-520.
3.Barberger-Gateau, et al: Functional impairment in instrumental activities of daily living: an early clinical sign of dementia?
J Am Geriatr Soc 1994;47:450-464.
4.Yaffe K, et al: Metabolic syndrome and cognitive disorders: is the sum greater than its parts? Dis Assoc Disord 2007;21:167-170.
5.Yaffe K, et al. metabolic syndrome inflammation and risk of cognitive decline. JAMA 2004;292:2237.
6.Brown GC Neher JJ et al: Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Mol Neurobiol 2010;41:242-247
7.Lee JW, et al: Neuroinflammation induced by lipopolysaccharide cause cognitive impairment through enhancement of beta-amyloid. J Neuroinflammation 2008;5:37.
8.Bluthe RM. et al: Synergy between tumor necrosis factor alpha and i n t e r l e u k i n – 1 i n t h e i n d u c t i o n s i c k n e s s b e h a v i o r i n m i c e . Psychoneuroendocrinology 1994;19:197-207.
9.Rachal Pugh C, et al: The immune sptern and memory consolidation: a role for the cytokine IL-1 beta. Neurosci Biobehav Rev 2010;25:29.
10.Dantzer R, et al: Cytokine-induced sickness behavior: a neuroimmune response to activation of innate immunity. Eur J Pharmacol 2004;500:399.
11.Ek M, et al: Inflammatory pathway across blood-brain barrier. Nature 2001;410:430.
12.Tracey KJ, et al: The inflammatory reflex. Nature 2002;420:835.
13.Laflamme N et al: Effects of systemic immunogenic insults and circulating proinflammatory cytokines or, the transcription of the inhibitory factor kappaB alpha within specific cellular populations of the rat brain. J Neurochem 1999;73:309-321.
14.Heinrich et al: Interleukin-6 and the acute phase response. Biochem J 1990;256:621.
15.Bataille R. Klein B: C-reactive protein levels as a direct indicator of interleukin-6 levels in humans in vivo- Arthritis Rheum 1992;35:982.
16.Maggio M, el al: Interleukin in aging and chronic disease: a magnificent pathway. J Gerontol A Biol Sci Med Sci 2006;61:575-584.
17.Heyser CJ, et al: Progressive decline in avoidance learning paralleled by inflammatory neurodegencration in transgenic mice expressing interleukin 6 in the brain. Proc Natl Acad Sci USA 1997;94:1500.
18.Balschun D, et al: Interleukin-6: a cytokine to forget. FASEB J 2004;18:1788,
19.Kiecolt-GIaser JK, et al: Chronic stress and age-related increases in the proinflammatory cytokine 11 and 6. Proc Natl Acad sci USA
20.Frank MG, et al: Microglia serve as a neuroimmune substrate for stress induced potentiation of CNS proinflammatory cytokine responses. Brain Behav Immun 2007;21:47.
21.Perry VB. Cunningham C, Holmes C: Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 2007;7:161-167.
22.Ben Menachem-Zidon O, et al: Intrahippocampal transplantation of transgenic neural precursor cells overexpressing interleukin-1 receptor antagonist blocks chronic isolation-induced impairment in memory and neurogenesis. Neuropsychopharmacology 2008;33:2262.
23.Krabbe KS et al: Inflammatory mediators in the elderly. Exp Gerontol 2004;39:687.
24.Ye SM et al: Increased interleukins expression by neuroglia from brain of aged mice. J Neuroinnnunol 1999;93:139.
25.Perry V H , M atyszak MK. Fearn S; Altered antigen expression of microglia in the aged rodent CNS. Glia 1993;7:60-67.
26.Aloisi F. Immune function of Microglia. Glia 2001;36:165.
27.Dickson DW, et al: Micro-glia and cytokines in neurological disease, with special reference to AIDS and Alzheimer’s disease. Glia 1993;7:75.
28.Hanisch U K: Microglia as a source and target of cytokines. Glia 2002;40:140-155.
29.Gadient RA, et al: Expression of interleukin-6 (ll.-6) and interleukin-
6 receptor mRNAs in rat brain during postnatal development. Brain Res 1994;637:10-14.
30.Vallieres L et al: Reduced hippocampal neurogenesis ir adult transgenic mice With chronic astrocytic production of interleukin-6. J Neurosci 2002;22:492.
31.Vitkovic L, et al: Cytokine signals propagate through the brain. Mol Psychiatry 2000;5:604.
32.Sparkman N, et al: Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress. NeurolmmunoModulation 2008;15:323.
33.Reichenberg A, et al: Cytokine associated with emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001:58:445.
34.Brydon L, et al: Synergistic of psychological and immune stressors on cytokine and sickness responses in humans. Brain Behav 2009;23:217- 224.
35.Spath- Schwalbc E, et al: Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men. J Clin Endocrinol Metab 1998;83:1573.
36.Teunissen CE, et al: Inflammation markers in relation to cognition in a healthy aging population. J NeurImmunol 2003;134:142-147.
37.Tilvis R.S. et al: Predictors Of cognitive decline and mortality of people over a 10-ycar period. J Gerontol A Biol Sci Med Sci 2004;59:268.
38.Weaver JD, et al, Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology 2002;59:731-380.
39.Yaffe K, el al, Inflammatory markers and cognition in well- functioning Afro-American and while elders. Neurology 2003;61:76-80.
40.Zuliani G, et al: Plasma cytokines profile in older subjects with late onset Alzheimer’s disease or vascular dementia J Psychiatr Res
41.Licastro F, et al: Increased plasma levels of IL-I, IL-6 and α1 antichymotrypsin in patients with Alchemies’ disease: peripheral inflammation or signals from the brain? J Neuroimmunol 2000;103:97-102.
42.Engelhart MJ, et al: Inflammatory proteins in plasma and the risk of dementia: the Roterdam study. Arch Neurol 2004;61668-672.
43.Wallin K. et al: Midlife arthritis increases the risk of cognitive impairment two decades later: a population based study. Alzheimers Dis2012;31:669-676
44.Schmidt R, et al: Early inflammation and dementia: a 25-year follow- up Of the Honolulu-Asia Aging Study. Ann Neurol 2002;52:168.
45.van Himbergen TM, et al: Biomarkers for insulin resistance and inflammation and the risk for all-cause dementia and Alzheimer disease results from the Framingham Heart Study. Arch Neurol 2012;69:595- 600.
46.Fazekas F, et al; Pathologic correlates of incidental MRI White matter signal hyperintensities. Neurology 193;43:1683-1689.
47.Gunning-Dixon FM, et al: Aging of cerebral white matter: a review Of MRI findings. Int J Geriatr Psychiatry 2009;24:109-118.
48.Debette S, Markus HS: Clinical importance of white matter hyperintense sites on brain magnetic imaging: systematic review and metanalysis. BMJ 2010;341:3666
49.Banne BTs et al: Association between cytokines and cerebral MRI changes in the aging J Geriatr Psychiatry Neurol 2009;22:23-34.
50.Miralbell J, et al: Structural brain changes and cognition in relation to markers of vascular dysfunction. Neurobiol Aging 2012;33:22.
51.Furney SJ, et al: Combinatorial markers of mild cognitive impairment conversion to Alzheimer’s disease- cytokines and MRI measures together predict disease progression. J Alzheimer’s Dis 2011:3:395-405.
52.Fitzpatrick AL, et al: Midlife and late-life obesity and the risk of dementia: cardiovascular health study. Arch Neurol 2009;66:336-342.
53.Ward MA, et al: „fie effect of body mass index on global brain volume in middle-aged adults: a cross sectional study. BMC Neurol 2005;5:23.
54.Forsythe LK, Wallace JM, Livingstone MB: Obesity and inflammation: the effects of weight loss. Nutr Res Rev 2008;21:117-133.
55.Walther K, et al: Anti-inflammatory drugs reduce age-related decreases in brain volume in cognitively normal older adults. Neurobiol Aging 2011;32:497-505.
56.Jaturapatporn D, et al: Aspirin, steroidal and non-steroidal anti- inflammatory drugs for the treatment of Alzheimer’s disease. Cochrane Database Syst Rev 2012;2:cd006378.
57.Meyer JS, et al: Risk factors for cerebral hypoperfusion, mild cognitive impairment, and dementia. Neurobiol Aging 2000;21:161- 169.
58.Rao KM, et al: Variability of plasma IL-6 and crosslinked fibrin dimers over time in community dwelling elderly subjects. Am J Clin Pathol 1994;102:802.