Review Article | Open Access
Is There a Causal Link between Inflammation and Dementia?
Neuroinflammation is a constant event in Alzheimer’s disease (AD), but the current knowledge is insufficient to state whether inflammation is a cause, a promoter, or simply a secondary phenomenon in this inexorably progressive ailment. In the current paper, we review research data showing that inflammation is not a prerequisite for onset of dementia, and, although it may worsen the course of the disease, recent evidence shows that chronic inhibition of inflammatory pathways is not necessarily beneficial for patients. Prospective clinical trials with anti-inflammatory drugs failed to stop disease progression, measurements of inflammatory markers in serum and cerebrospinal fluid of patients yielded contradictory results, and recent bench research proved undoubtedly that neuroinflammation has a protective side as well. Knockout animal models for TNFRs or ILRs do not seem to prevent the pathology or the cognitive decline, but quite the contrary. In AD, the therapeutic intervention on inflammatory pathways still has a research future, but its targets probably need reevaluation.
Based on current data, one cannot establish whether inflammation is a cause, a promoter, or simply a secondary phenomenon in Alzheimer’s disease (AD) , although this can be the case for other molecular mechanisms involved in the pathogenic chain of events. In this paper, we shall try to argue that neuroinflammation, although indisputably present in AD, even as an early event, is not a prerequisite for onset of dementia—a syndrome that is met at a late stage of a disease (e.g., AD or vascular dementia (VaD) or B12 deficiency). Several clinical and laboratory research results support this perspective, and below we present three main arguments for this assumption.
Argument No. 1. The AD pathology (soluble Aβ/amyloid plaques) is one of the main triggers of neuroinflammation; increased levels of proinflammatory factors, such as cytokines and chemokines, and the activation of the complement cascade are known to occur in the brains of AD patients and to contribute to the local inflammatory response , but only after they are triggered by senile plaque.
Argument No. 2. Neuroinflammation is a two-sided phenomenon, with both neurodestructive and neuroprotective facets; the hypothesis in which inflammation leads to dementia would imply a predominance of the first over the latter. Recent reports seem to indicate that, in AD brain, this is not the case, as showed further on in this review.
Argument No. 3. Even though knockout animal models and anti-inflammatory treatment alleviate AD-like pathology in laboratory experiments, clinical trials were less successful, even contradictory, some reporting potentially hazardous adverse effects. Prospective clinical trials with anti-inflammatory drugs failed as trials with drugs designed for other targets—but it might be argued that inflammation is an early event and could be targeted for prevention .
In brief, our argumentation is presented in Table 1, which includes only a part of reported data in such an extensive research field.
|Abbreviations: IL: interleukin, TNF: tumor necrosis factor, NGF: nerve growth factor, CSF: cerebrospinal fluid, and AchE: acetylcholinesterase.|
2. Neuroinflammation-Related Events in AD
There are several definitions of inflammation available on http://medical-dictionary.thefreedictionary.com/inflammation, cropped from different medical dictionaries, all of them constructed around the central idea of “response to injury”.
Inflammatory response in the CNS occurs, similar to peripheral cascade of events, in few partially overlapping steps: (i) “classical” inflammation, leading to activation of macrophages/microglia and production of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-12), chemokines, proteases, and redox proteins; (ii) alternative activation of microglia, a “repair/resolution” state, characterized by a switch in gene expression towards reconstruction and tissue repair, driven by IL-4 and IL-13 stimulation; and (iii) acquired deactivation, also an anti-inflammatory and repair functional phenotype, but this time induced by exposure of macrophages to apoptotic cells or to TGF-β and/or IL-10 . From animal models of AD [5, 6] or histochemical analysis of human brain serial sections , one may conclude that this response is triggered by amyloid plaques, and a number of studies have reported aggregation of activated microglia around amyloid plaques in animal  and human brain [8–10]. Also soluble Aβ may be involved . There are also reports of soluble Aβ-triggered neuroinflammation at BBB level , suggesting that inflammation is an early process in AD pathogeny. An increase in microglial activation has been observed in very early stages of AD and, interestingly, it is not preserved over time .
Inflammation-related gene profiling in AD patients brain samples indicates microglia to be in an alternative, “reconstructive” activation state, rather than the classical, “destructive” state, detrimental for neuronal homeostasis , making the anti-inflammatory therapeutic intervention questionable. In the view of neuroinflammation-driven AD pathology, there are numerous attempts to identify the signaling pathways that should be blocked in order to obtain effective therapeutic intervention. Although encouraging reports have been published following animal models experiments, later clinical study experiences showed that more likely a multimodal intervention is required, with emphasis on right timing rather than specific target.
Chronic blockade of IL-1R in a mouse model of AD alters brain inflammatory responses, alleviates cognitive deficits, markedly attenuates tau pathology, and partly reduces certain fibrillar and oligomeric forms of Aβ . Unfortunately, brain-directed overexpression of human soluble IL-1 receptor antagonist in another transgenic mouse strain led to an atrophic phenotype of the brain along with modified levels of APP and PS1 . It is possible, however, that such blockade stimulates alternative pathways, as reported by Reed-Geaghan et al. . Although they reported decreased plaque burden and reduced levels of insoluble Aβ in an AD mouse model after CD14 deletion, loss of this TLR2/4 coreceptor expression was associated with increased expression of genes encoding the pro-inflammatory cytokines TNF-α and Ifnγ, decreased levels of the microglial/macrophage alternative activation markers Fizz1 and Ym1, and increased expression of the anti-inflammatory gene IL-10 .
Encouraging results were reported after deletion of the TNFR1 gene in APP23 transgenic mice, leading to diminished Aβ plaque formation, reduced beta-secretase 1 (BACE1) levels and activity, and overall unimpaired cognition . However, treatment of AD patients with an anti-TNFα drug was unexpectedly poor in results, as discussed in a following section of this paper.
CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer’s-disease-like pathogenesis in APP+PS1 double-transgenic mice, enhances neurogenesis, and inhibits spatial learning impairment . Mechanisms proposed to accomplish these effects are activation of a subset of microglia and increased expression of Aβ-degrading enzymes . AD patients chronically treated with acetylcholinesterase inhibitors have higher levels of serum IL-4 than nontreated subjects ; still, it is common knowledge that this kind of therapy does not prevent disease progression.
3. Neuroprotective Effect of Neuroinflammation
In the complex environment of neuroinflammation, there is not a clear cut between “destructive” and “regenerative” actions of microglial subpopulations. The neuroprotective effects of activated microglia in inflammatory environments are partially overlapping its phagocytotic, destructive ones and may be triggered by signaling molecules produced by degenerating neurons, such as CX3C chemokine fractalkine (FKN). Secreted from damaged neurons, FKN promotes microglial phagocytosis of neuronal debris through the release of MFG-E8 and induces the expression of the antioxidant enzyme hemeoxygenase-1 (HO-1) in microglia, resulting in neuroprotection against glutamate toxicity .
Another such trigger is phosphatidylserine—a phospholipid expressed on the surface of apoptotic neurons—that, in vitro, induces a shift in microglia expression of cytokines from deleterious inflammatory (IL-1, TNF-α, NO) to protective (TGF-β and NGF) . The deleterious effect of NO in AD was proven by Nathan et al.  in an animal model, in which deficiency of iNOS substantially protected the AD-like mice from premature mortality, cerebral plaque formation, increased Aβ levels, protein tyrosine nitration, astrocytosis, and microgliosis.
It has been proven that bone-marrow migrated macrophages are actively involved in brain Aβ clearance . This process requires macrophage/microglial activation by chemokines and toll-like receptors. Knockout of CC chemokine receptor 2 (CCR2) in a mouse model of AD hastes the onset and worsens the cognitive impairment while compensatory increase in anti-inflammatory cytokines was noted . Chronic exposure to CCR3 increased NMDA-evoked Ca(2+) signals in the hippocampal neurons and increased NMDA receptor levels . Toll-like receptors (TLRs) are generally considered to activate pro-inflammatory pathways, and in the CNS they are upregulated in neuroinflammatory conditions such as multiple sclerosis (MS)  and its experimental animal model, experimental autoimmune encephalomyelitis (EAE) . TLR 2 and 4 are reported to be present in amyloid plaques  and involved in uptake of Aβ and other aggregated proteins, thereby promoting their clearance from the CNS . Another member of the family, TLR3, is induced on astrocytes in inflammatory conditions and, in turn, induces expression of a range of neuroprotective mediators, anti-inflammatory cytokines including IL-9, IL-10, and IL-11. In vitro, TLR3 activation enhances neuronal survival and endothelial cell growth, promoting neuroprotective responses rather than pro-inflammatory signals .
4. AD and MCI: Contradictory Data on CSF and Plasma Levels of Inflammatory Biomarkers
A meta-analysis of cytokines in serum and CSF of AD patients showed increased serum IL-6, TNF-α, IL-1β, TGF-β, and IL-12, whereas in CSF only TGF-β was increased as compared to control subjects . Since CSF mirrors brain chemistry, this result can be interpreted as a confirmation of alternative, “repair” activation state of microglial population. Why TNF-α is not increased in the CSF, although it is a well-known mediator of inflammation and an inducer of apoptosis? It could be because in AD brains TNFRI levels are increased compared to nondemented brains. Furthermore, using 125I-TNF-α binding technique, Cheng et al. found that, in AD brains, 125I-TNF-α binding affinity to TNFRI is increased ; thus, the uptake of the ligand is increased and its disponibility in CSF is low. Low levels of TNF-α in frontal cortex, the superior temporal gyrus, and the entorhinal cortex compared with non-AD subjects have been previously reported . However, in the same report, Lanzrein et al. describe no significant differences between AD subjects and controls regarding serum and CSF levels of interleukin-1 beta (IL-1β), IL-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), the soluble TNF receptors type I and II (sTNFR 1 and 2), and the acute phase protein alpha1-antichymotrypsin (α1-ACT). Diniz et al. also report no statistically significant differences in serum TNF-α, sTNFR1, and sTNFR2 between patients with MCI and AD as compared to controls. Nevertheless, patients with MCI who progressed to AD had significantly higher serum sTNFR1 levels as opposed to patients who retained the diagnosis of MCI upon followup . Another study reports higher CSF levels of TACE/ADAM17 activity and soluble TNFRs in the MCI group than those in AD patients . Buchhave et al. also report that patients with MCI who subsequently developed AD or VaD had higher levels of sTNFR1 and sTNFR2 in both CSF and plasma already at baseline when compared to age-matched controls . An even more recent report found that TNFα expression was similar in AD and control brains .
Regarding inflammation and MCI progression to AD, there are reports to indicate the predictive value of certain pro-inflammatory cytokines for conversion. We already mentioned TNFR1, with several different groups of research in consensus, but also sCD40—another member of TNFR superfamily —and IL-1β, but only for multidomain MCI, and not single-domain amnestic/nonamnestic MCI .
These data prove that there is an inflammatory process in MCI and AD, and it gets more intense as the disease advances. However, one cannot tell that the advancement is due to the inflammatory process, and recent reports for new markers for CSF diagnostic of AD may not even include any of the classical mediators of inflammation .
The panel of inflammatory cytokines and chemokines seems to be different in AD from other dementias, as MCP-1 is dramatically reduced in the grey matter in VaD and mixed dementia in comparison to controls, but not in AD. IL-6 decreases were also observed in the grey matter of VaD and mixed dementia . Frontotemporal dementia (FTD) patients showed increased CSF TNF-α and TGF-β . This kind of difference is not visible in the periphery, as already established AD and VaD cases had similar levels of TNF-α and IL-1β levels, when compared to each other and to healthy controls .
5. Inflammation-Mediators-Targeted Clinical Trials in AD
As previously stated, inflammation is an important factor in AD pathogenesis; thus, the anti-inflammatory drugs were expected to have disease-modifying effects. Surprisingly, “classical” anti-inflammatory therapies failed to prevent dementia progression, as briefly discussed below.
5.1. Classical Therapies
Although both steroidal and nonsteroidal anti-inflammatory products were extensively tested, randomized clinical trials failed to demonstrate efficacy in AD . Used for its antioxidant effects, vitamin E, alone  or in combination with other antioxidants (vitamin C, alpha-lipoic acid) , showed no improvement on cognition or CSF biomarkers of AD patients, but it raised questions regarding the safety of long-term administration [49, 50]. Peroxisome proliferator-activated receptor-gamma agonists, used for their anti-inflammatory effect (pioglitazone, rosiglitazone), provided contradictory data, with further need to assess safety issues . Omega-3 fatty acids for 6 months did not influence inflammatory or biomarkers in CSF or plasma of patients with mild to moderate AD .
5.2. Molecular Therapies
IL-R antagonists are not yet used in clinical trials for neurodegenerative disorders, except for acute stroke  possibly because of putative beneficial role of neuroinflammation. A number of reports have provided evidence that activation of microglia and subsequent degradation of amyloid plaques may underlie this phenomenon (reviewed in ).
In 2011, an oral inhibitor of receptor for advanced glycation end products (RAGE), PF-04494700, was tested for ten weeks in patients with mild to moderate AD and showed good tolerability and no serious adverse effects. However, no consistent effect on plasma levels of Aβ, inflammatory biomarkers, or secondary cognitive outcomes were reported .
Reports regarding pro- and anti-inflammatory cytokines in brains, serum, and CSF of AD patients are controversial. More useful in assessing the neuroinflammation role in cognitive decline and onset of dementia seems to be the study of inflammation markers in MCI patients. From the large panel of chemokines, cytokines, and cytokines receptors, CSF TNFR seem to correlate with progression from MCI to AD and show a rationale for anti-inflammatory treatment. Although CSF markers are intensively studied, they seem to be less useful as conversion predictors than neuropsychological and functional measures .
A reliable proof of inflammation as cause for dementia still lacks, and therefore its mandatory involvement in progression from MCI to AD remains questionable. However, inflammation is only one facet of the neuropathological profile of MCI, along with plaque and tangle formation, vascular pathologies, neurochemical deficits, cellular injury, oxidative stress, mitochondrial changes, changes in genomic activity, synaptic dysfunction, disturbed protein metabolism, and disrupted metabolic homeostasis .
Conflict of Interests
The authors declare that they have no conflict of interests.
This paper is supported by the Sectoral Operational Programme Human Resources Development (SOP HRD), financed by the European Social Fund and by the Romanian Government under Contract no. POSDRU/89/1.5/S/64109, by the Executive Unit for Financing Higher Education, Research, Development, and Innovation—Romania (UEFISCDI)—and by Program 4 (Partnerships in Priority Domains) Grant no. 41-013/2007. This work was first presented, as a lecture, at the 6th World Congress on Controversies in Neurology (CONy),Vienna, Austria, March 8-11, 2012.
- T. Wyss-Coray and J. Rogers, “Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature,” Cold Spring Harbor Perspectives in Medicine, vol. 2, Article ID a006346, 2012.
- M. Schultzberg, C. Lindberg, Å. F. Aronsson, E. Hjorth, S. D. Spulber, and M. Oprica, “Inflammation in the nervous system—physiological and pathophysiological aspects,” Physiology and Behavior, vol. 92, no. 1-2, pp. 121–128, 2007.
- J. J. Hoozemans, R. Veerhuis, J. M. Rozemuller, and P. Eikelenboom, “Soothing the inflamed brain: effect of non-steroidal anti-inflammatory drugs on Alzheimer's disease pathology,” CNS & Neurological Disorders Drug Targets, vol. 10, no. 1, pp. 57–67, 2011.
- C. A. Colton, “Heterogeneity of microglial activation in the innate immune response in the brain,” Journal of Neuroimmune Pharmacology, vol. 4, no. 4, pp. 399–418, 2009.
- J. Apelt and R. Schliebs, “β-amyloid-induced glial expression of both pro- and anti-inflammatory cytokines in cerebral cortex of aged transgenic Tg2576 mice with Alzheimer plaque pathology,” Brain Research, vol. 894, no. 1, pp. 21–30, 2001.
- Y. Matsuoka, M. Picciano, B. Maleste et al., “Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease,” American Journal of Pathology, vol. 158, no. 4, pp. 1345–1354, 2001.
- M. R. D'Andrea, P. A. Reiser, N. A. Gumula, B. M. Hertzog, and P. Andrade-Gordon, “Application of triple immunohistochemistry to characterize amyloid plaque-associated inflammation in brains with Alzheimer's disease,” Biotechnic and Histochemistry, vol. 76, no. 2, pp. 97–106, 2001.
- I. Tooyama, H. Kimura, H. Akiyama, and P. L. McGeer, “Reactive microglia express class I and class II major histocompatibility complex antigens in Alzheimer's disease,” Brain Research, vol. 523, no. 2, pp. 273–280, 1990.
- L. S. Perlmutter, S. A. Scott, E. Barron, and H. C. Chui, “MHC class II-positive microglia in human brain: association with Alzheimer lesions,” Journal of Neuroscience Research, vol. 33, no. 4, pp. 549–558, 1992.
- T. Uchihara, H. Akiyama, H. Kondo, and K. Ikeda, “Activated microglial cells are colocalized with perivascular deposits of amyloid-β protein in Alzheimer's disease brain',” Stroke, vol. 28, no. 10, pp. 1948–1950, 1997.
- M. T. Heneka, M. Sastre, L. Dumitrescu-Ozimek et al., “Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice,” Journal of Neuroinflammation, vol. 2, article 22, 2005.
- V. Vukic, D. Callaghan, D. Walker et al., “Expression of inflammatory genes induced by beta-amyloid peptides in human brain endothelial cells and in Alzheimer's brain is mediated by the JNK-AP1 signaling pathway,” Neurobiology of Disease, vol. 34, no. 1, pp. 95–106, 2009.
- A. K. Vehmas, C. H. Kawas, W. F. Stewart, and J. C. Troncoso, “Immune reactive cells in senile plaques and cognitive decline in Alzheimer's disease,” Neurobiology of Aging, vol. 24, no. 2, pp. 321–331, 2003.
- C. A. Colton, R. T. Mott, H. Sharpe, Q. Xu, W. E. van Nostrand, and M. P. Vitek, “Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD,” Journal of Neuroinflammation, vol. 3, article 27, 2006.
- M. Kitazawa, D. Cheng, M. R. Tsukamoto et al., “Blocking IL-1 signaling rescues cognition, attenuates Tau pathology, and restores neuronal -βcatenin pathway function in an Alzheimer's disease model,” Journal of Immunology, vol. 187, no. 12, pp. 6539–6549, 2011.
- M. Oprica, E. Hjorth, S. Spulber et al., “Studies on brain volume, Alzheimer-related proteins and cytokines in mice with chronic overexpression of IL-1 receptor antagonist,” Journal of Cellular and Molecular Medicine, vol. 11, no. 4, pp. 810–825, 2007.
- E. G. Reed-Geaghan, Q. W. Reed, P. E. Cramer, and G. E. Landreth, “Deletion of CD14 attenuates Alzheimer's disease pathology by influencing the brain's inflammatory milieu,” Journal of Neuroscience, vol. 30, no. 46, pp. 15369–15373, 2010.
- P. He, Z. Zhong, K. Lindholm et al., “Deletion of tumor necrosis factor death receptor inhibits amyloid β generation and prevents learning and memory deficits in Alzheimer's mice,” Journal of Cell Biology, vol. 178, no. 5, pp. 829–841, 2007.
- T. Kiyota, S. Okuyama, R. J. Swan, M. T. Jacobsen, H. E. Gendelman, and T. Ikezu, “CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer's disease-like pathogenesis in APP+PS1 bigenic mice,” The FASEB Journal, vol. 24, no. 8, pp. 3093–3102, 2010.
- E. Shimizu, K. Kawahara, M. Kajizono, M. Sawada, and H. Nakayama, “IL-4-induced selective clearance of oligomeric β-amyloid peptide 1–42 by rat primary type 2 microglia,” Journal of Immunology, vol. 181, no. 9, pp. 6503–6513, 2008.
- A. Lugaresi, A. Di Iorio, C. Iarlori et al., “IL-4 in vitro production is upregulated in Alzheimer's disease patients treated with acetylcholinesterase inhibitors,” Experimental Gerontology, vol. 39, no. 4, pp. 653–657, 2004.
- T. Mizuno, “The biphasic role of microglia in Alzheimer's disease,” International Journal of Alzheimer's Disease, vol. 2012, Article ID 737846, 9 pages, 2012.
- R. de Simone, M. A. Ajmone-Cat, P. Tirassa, and L. Minghetti, “Apoptotic PC12 cells exposing phosphatidylserine promote the production of anti-inflammatory and neuroprotective molecules by microglial cells,” Journal of Neuropathology and Experimental Neurology, vol. 62, no. 2, pp. 208–216, 2003.
- C. Nathan, N. Calingasan, J. Nezezon et al., “Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase,” Journal of Experimental Medicine, vol. 202, no. 9, pp. 1163–1169, 2005.
- M. Yamamoto, T. Kiyota, S. M. Walsh, and T. Ikezu, “Kinetic analysis of aggregated amyloid-β peptide clearance in adult bone-marrow-derived macrophages from APP and CCL2 transgenic mice,” Journal of Neuroimmune Pharmacology, vol. 2, no. 2, pp. 213–221, 2007.
- G. Naert and S. Rivest, “CC chemokine receptor 2 deficiency aggravates cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease,” Journal of Neuroscience, vol. 31, no. 16, pp. 6208–6220, 2011.
- M. Kuijpers, K. L. I. van Gassen, P. N. E. de Graan, and D. Gruol, “Chronic exposure to the chemokine CCL3 enhances neuronal network activity in rat hippocampal cultures,” Journal of Neuroimmunology, vol. 229, no. 1-2, pp. 73–80, 2010.
- C. Jack, F. Ruffini, A. Bar-Or, and J. P. Antel, “Microglia and multiple sclerosis,” Journal of Neuroscience Research, vol. 81, no. 3, pp. 363–373, 2005.
- M. Marta, “Toll-like receptors in multiple sclerosis mouse experimental models,” Annals of the New York Academy of Sciences, vol. 1173, pp. 458–462, 2009.
- E. Okun, K. J. Griffioen, J. D. Lathia, S. Tang, M. P. Mattson, and T. V. Arumugam, “Toll-like receptors in neurodegeneration,” Brain Research Reviews, vol. 59, no. 2, pp. 278–292, 2009.
- S. Amor, F. Puentes, D. Baker, and P. van der Valk, “Inflammation in neurodegenerative diseases,” Immunology, vol. 129, no. 2, pp. 154–169, 2010.
- M. Bsibsi, C. Persoon-Deen, R. W. H. Verwer, S. Meeuwsen, R. Ravid, and J. M. van Noort, “Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators,” GLIA, vol. 53, no. 7, pp. 688–695, 2006.
- W. Swardfager, K. Lanctt, L. Rothenburg, A. Wong, J. Cappell, and N. Herrmann, “A meta-analysis of cytokines in Alzheimer's disease,” Biological Psychiatry, vol. 68, no. 10, pp. 930–941, 2010.
- X. Cheng, L. Yang, P. He, R. Li, and Y. Shen, “Differential activation of tumor necrosis factor receptors distinguishes between brains from Alzheimer's disease and non-demented patients,” Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 621–630, 2010.
- A. Lanzrein, C. M. Johnston, V. H. Perry, K. A. Jobst, E. M. King, and A. D. Smith, “Longitudinal study of inflammatory factors in serum, cerebrospinal fluid, and brain tissue in Alzheimer disease: interleukin-1β, interleukin-6, interleukin-1 receptor antagonist, tumor necrosis factor-α, the soluble tumor necrosis factor receptors I and II, and α1-antichymotrypsin,” Alzheimer Disease and Associated Disorders, vol. 12, no. 3, pp. 215–227, 1998.
- B. S. Diniz, A. L. Teixeira, E. B. Ojopi et al., “Higher serum sTNFR1 level predicts conversion from mild cognitive impairment to Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1305–1311, 2010.
- H. Jiang, H. Hampel, D. Prvulovic et al., “Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease,” Molecular Neurodegeneration, vol. 6, no. 1, article 69, 2011.
- P. Buchhave, H. Zetterberg, K. Blennow, L. Minthon, S. Janciauskiene, and O. Hansson, “Soluble TNF receptors are associated with Aβ metabolism and conversion to dementia in subjects with mild cognitive impairment,” Neurobiology of Aging, vol. 31, no. 11, pp. 1877–1884, 2010.
- D. Culpan, P. G. Kehoe, and S. Love, “Tumour necrosis factor-α (TNF-α) and miRNA expression in frontal and temporal neocortex in Alzheimer's disease and the effect of TNF-α on miRNA expression in vitro,” International Journal of Molecular Epidemiology and Genetics, vol. 2, no. 2, pp. 156–162, 2011.
- P. Buchhave, S. Janciauskiene, H. Zetterberg, K. Blennow, L. Minthon, and O. Hansson, “Elevated plasma levels of soluble CD40 in incipient Alzheimer's disease,” Neuroscience Letters, vol. 450, no. 1, pp. 56–59, 2009.
- O. V. Forlenza, B. S. Diniz, L. L. Talib et al., “Increased serum IL-1β level in Alzheimer's disease and mild cognitive impairment,” Dementia and Geriatric Cognitive Disorders, vol. 28, no. 6, pp. 507–512, 2009.
- R. Craig-Schapiro, M. Kuhn, C. Xiong et al., “Multiplexed immunoassay panel identifies novel CSF biomarkers for alzheimer's disease diagnosis and prognosis,” PLoS ONE, vol. 6, no. 4, article e18850, 2011.
- E. Mulugeta, F. Molina-Holgado, M. S. Elliott et al., “Inflammatory mediators in the frontal lobe of patients with mixed and vascular dementia,” Dementia and Geriatric Cognitive Disorders, vol. 25, no. 3, pp. 278–286, 2008.
- M. Sjögren, S. Folkesson, K. Blennow, and E. Tarkowski, “Increased intrathecal inflammatory activity in frontotemporal dementia: pathophysiological implications,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 75, no. 8, pp. 1107–1111, 2004.
- C. Yasutake, K. Kuroda, T. Yanagawa, T. Okamura, and H. Yoneda, “Serum BDNF, TNF-α and IL-1β levels in dementia patients: comparison between Alzheimer's disease and vascular dementia,” European Archives of Psychiatry and Clinical Neuroscience, vol. 256, no. 7, pp. 402–406, 2006.
- P. S. Aisen, J. Cummings, and L. S. Schneider, “Symptomatic and nonamyloid/tau based pharmacologic treatment for Alzheimer disease,” Cold Spring Harbor Perspectives in Medicine, vol. 2, Article ID a006395, 2012.
- M. G. E. K. N. Isaac, R. Quinn, and N. Tabet, “Vitamin E for Alzheimer's disease and mild cognitive impairment,” Cochrane Database of Systematic Reviews, no. 3, Article ID CD002854, 2008.
- D. R. Galasko, E. Peskind, C. M. Clark et al., “Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures,” Archives of Neurology, vol. 69, no. 7, pp. 836–841, 2012.
- L. A. Boothby and P. L. Doering, “Vitamin C vitamin E for Alzheimer's disease,” Annals of Pharmacotherapy, vol. 39, no. 12, pp. 2073–2080, 2005.
- A. Lloret, M. Badía, N. J. Mora, F. V. Pallardó, M. Alonso, and J. Viña, “Vitamin e paradox in alzheimer's disease: it does not prevent loss of cognition and may even be detrimental,” Journal of Alzheimer's Disease, vol. 17, no. 1, pp. 143–149, 2009.
- B. W. Miller, K. C. Willett, and A. R. Desilets, “Rosiglitazone and pioglitazone for the treatment of Alzheimer's disease,” Annals of Pharmacotherapy, vol. 45, no. 11, pp. 1416–1424, 2011.
- Y. Freund-Levi, E. Hjorth, C. Lindberg et al., “Effects of omega-3 fatty acids on inflammatory markers in cerebrospinal fluid and plasma in alzheimer's disease: the omegad study,” Dementia and Geriatric Cognitive Disorders, vol. 27, no. 5, pp. 481–490, 2009.
- E. L. Tobinick and H. Gross, “Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease,” BMC Neurology, vol. 8, article 27, 2008.
- E. Tobinick, “Perispinal etanercept for treatment of Alzheimer's disease,” Current Alzheimer Research, vol. 4, no. 5, pp. 550–552, 2007.
- H. C. A. Emsley, C. J. Smith, R. F. Georgiou et al., “A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 76, no. 10, pp. 1366–1372, 2005.
- S. S. Shaftel, W. S. Griffin, and M. K. O'Banion, “The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective,” Journal of Neuroinflammation, vol. 5, article 7, 2008.
- M. N. Sabbagh, A. Agro, J. Bell, P. S. Aisen, E. Schweizer, and D. Galasko, “PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease,” Alzheimer Disease and Associated Disorders, vol. 25, no. 3, pp. 206–212, 2011.
- Y. Cui, B. Liu, S. Luo et al., “Identification of conversion from mild cognitive impairment to alzheimer's disease using multivariate predictors,” PLoS ONE, vol. 6, no. 7, article e21896, 2011.
- M. E. Bamberger, M. E. Harris, D. R. McDonald, J. Husemann, and G. E. Landreth, “A cell surface receptor complex for fibrillar β-amyloid mediates microglial activation,” Journal of Neuroscience, vol. 23, no. 7, pp. 2665–2674, 2003.
- J. Koenigsknecht-Talboo and G. E. Landreth, “Microglial phagocytosis induced by fibrillar β-amyloid and IgGs are differentially regulated by proinflammatory cytokines,” Journal of Neuroscience, vol. 25, no. 36, pp. 8240–8249, 2005.
- K. Heese, C. Hock, and U. Otten, “Inflammatory signals induce neurotrophin expression in human microglial cells,” Journal of Neurochemistry, vol. 70, no. 2, pp. 699–707, 1998.
- S. L. Montgomery, M. A. Mastrangelo, D. Habib et al., “Ablation of TNF-RI/RII expression in Alzheimer's disease mice leads to an unexpected enhancement of pathology: implications for chronic pan-TNF-α suppressive therapeutic strategies in the brain,” American Journal of Pathology, vol. 179, no. 4, pp. 2053–2070, 2011.
- B. C. M. Stephan, S. Hunter, D. Harris et al., “The neuropathological profile of mild cognitive impairment (MCI): a systematic review,” Molecular Psychiatry, vol. 17, no. 11, pp. 1056–1076, 2012.
Copyright © 2013 Ana-Maria Enciu and Bogdan O. Popescu. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.