Cited by 501Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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Intrathecal inflammation precedes development of Alzheimer's disease

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Tarkowski, E·2003·Journal of Neurology, Neurosurgery & Psychiatry

DOI 10.1136/jnnp.74.9.1200PMC PMC1738668

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Abstract

OBJECTIVES: To analyse the cerebrospinal fluid (CSF) values of the proinflammatory cytokines, interleukin 1beta (IL1beta), tumour necrosis factor alpha (TNFalpha), GM-CSF, of the anti-inflammatory cytokine TGFbeta, of tau protein, a marker for neurodegeneration, and of beta amyloid (Abeta), a protein involved in the formation of senile plaques, in prospectively followed up patients with mild cognitive impairment (MCI). METHODS: Analyses of CSF levels of TNFalpha, IL1beta, GM-CSF, TGFbeta, betaa, and tau protein were performed using ELISA in 56 patients with MCI who were followed up prospectively and in 25 age matched, healthy controls. RESULTS: Patients with MCI displayed significantly higher levels of TNFalpha and tau protein and significantly lower levels of TGFbeta and Abeta compared with the healthy controls. After nine months of follow up, 25 patients still displayed MCI while the remaining 31 patients had progressed to Alzheimer's disease (AD). Only MCI patients who progressed to AD at follow up, showed significantly higher CSF levels of TNFalpha than controls. In addition, reduced CSF-Abeta42 levels were only found in MCI patients that progressed to AD, further supporting the notion that disturbed metabolism of Abeta is an early finding in AD. CONCLUSIONS: These results demonstrate increased production of the proinflammatory cytokine, TNFalpha and decreased production of the anti-inflammatory cytokine TGFbeta in patients with MCI at risk to develop AD, suggesting a propensity towards inflammation in this patient group and indicating that CNS inflammation is a early hallmark in the pathogenesis of AD.

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The role of aluminum and copper on neuroinflammation and Alzheimer's disease
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“It has been found that cerebrospinal fluid levels of pro-inflammatory factors such as IL-1 β , IL-6, and TNF-α are high in AD patients and increase with disease progression (114, 115).”
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Presenilin 2 Is the Predominant γ-Secretase in Microglia and Modulates Cytokine Release
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“The latter cytokine is associated with the development of AD (Tarkowski et al. 2003) and may stimulate myeloperoxidase expression in microglia since the expression of myeloperoxidase in atheroma reflects the activated state of macrophages in these lesions.”
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Perispinal etanercept for neuroinflammatory disorders
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“64 Tarkowski, E. et al. (2003) Intrathecal inflammation precedes development of Alzheimer’s disease.”
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Serum Hepcidin Levels, Iron Dyshomeostasis and Cognitive Loss in Alzheimer’s Disease
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Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice
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“Indeed, increased TNF-α in serum is associated with a worsen cognitive decline in AD [21] and elevated concentrations of TNF-α in CSF increase the probability to evolve from a mild cognitive impairment (MCI) stage to dementia [42].”
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Retracted: Aging is associated with altered inflammatory, arachidonic acid cascade, and synaptic markers, influenced by epigenetic modifications, in the human frontal cortex
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“Some of the molecular and epigenetic modifications observed during aging might result in MCI and later evolve as AD (Tarkowski et al. 2003; Galimberti et al. 2008).”
Background
Retracted
The Role of Neutrophil Extracellular Traps in Central Nervous System Diseases and Prospects for Clinical Application
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“Thus, expression and release of TNF- from early recruited microglia could participate in a first wave of signals complemented by the co-release of other factors like for example ATP and reactive oxygen species that help to initiate reactive pathways in neighboring astrocytes.”
BackgroundInfluential
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“Consistent with these findings, individuals with mild cognitive impairment (MCI) and early AD have been found to have higher levels of inflammatory markers in blood and in cerebral spinal fluid (CSF) (Janelidze et al., 2018; Tarkowski et al., 2003).”
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Transcription factor p53 influences microglial activation phenotype
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“sclerosis (ALS), Parkinson disease (PD) and Alzheimer disease (AD) (Henkel et al. 2004; Imamura et al. 2003; Moreau et al. 2005; Nagatsu and Sawada 2005; Tarkowski et al. 2003; Tarkowski et al. 1997).”
Background
The Association between TNF-alpha, IL-1 alpha and IL-10 with Alzheimer's Disease
Čuljak, M., Perković, M. N., Uzun, S., Štrac, D. Š., Erjavec, G. N., Leko, M. B., Šimić, G., Tudor, L., Konjevod, M., Kozumplik, O., et al. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666201130092427 · Cited by 52
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“2008) Higher plasma CCL2, TNF-α, IL-6, MCP-1, quinolinic acid (Galimberti et al. 2006; Liao et al. 2016; Streit et al. 2004; Tarkowski et al. 2003)”
BackgroundInfluential
Soluble TREM2 and Inflammatory Proteins in Alzheimer’s Disease Cerebrospinal Fluid
Rauchmann, B., Sadlon, A., Perneczky, R., & Initiative, A. D. N. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-191120 · Cited by 49
Cerebrospinal Fluid Cytokine Dynamics Differ Between Alzheimer Disease Patients and Elderly Controls
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Background
Extracellular Vesicles from Mesenchymal Stem Cells Exert Pleiotropic Effects on Amyloid‐β, Inflammation, and Regeneration: A Spark of Hope for Alzheimer's Disease from Tiny Structures?
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TNF-α–mediated reduction in inhibitory neurotransmission precedes sporadic Alzheimer’s disease pathology in young Trem2 rats
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Bettcher, B. M., & Kramer, J. H. (2012) · Neurocase · doi:10.1080/13554794.2011.654227 · Cited by 49
“…correlate with global cognitive performance in AD patients (i.e., MMSE), suggesting that worse overall cognition is associated with higher levels of peripheral inflammatory markers (Bonotis et al., 2008; Bossu et al., 2008; Forlenza et al., 2009; Licastro et al., 2000; Tarkowski et al., 2003).”
Disease-modifying benefit of Fyn blockade persists after washout in mouse Alzheimer's model
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“This stands in stark contrast to the pathology observed in human patients in which clinical symptoms are not apparent until amyloidosis has plateaued, neuroinflammation is ongoing, and neurodegeneration is well established (Morris and Price, 2001; Perrin et al., 2009; Shi et al., 2009; Tarkowski et al., 2003; Xiang et…”
Systemic Tumor Necrosis Factor-Alpha Trajectories Relate to Brain Health in Typically Aging Older Adults
Lindbergh, C. A., Casaletto, K. B., Staffaroni, A. M., Elahi, F. M., Walters, S. M., You, M. Y., Neuhaus, J. M., Contreras, W. R., Wang, P., Karydas, A., et al. (2019) · The Journals of Gerontology Series A · doi:10.1093/gerona/glz209 · Cited by 47
“For example, cerebrospinal fluid levels of TNF‐α are increased 25-fold in Alzheimer's disease patients relative to healthy controls and correlate with clinical decline (10,11).”
Background
The diagnostic role of serum inflammatory and soluble proteins on dementia subtypes: Correlation with cognitive and functional decline
Öztürk, C., Özge, A., Yalın, O. Ö., Yılmaz, İ. A., Delialioglu, N., Yıldız, Ç., Tesdelen, B., & Kudiaki, C. (2007) · Behavioural Neurology · doi:10.1155/2007/432190 · Cited by 46
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The Role of Pro-inflammatory Cytokines in Memory Processes and Neural Plasticity
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Amelioration of Age Associated Neuroinflammation on Long Term Bacosides Treatment
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“Inflammation in the central nervous system (CNS) is an early pathological change in the brains of Alzheimer’s disease (AD) patients (Golde, 2002; Tarkowski et al., 2003), and increasing evidence suggests that abnormalities in the cholesterol metabolism could play an important role in the pathogenesis of AD (Kivipelto…”
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Potential Mechanisms Underlying Resistance to Dementia in Non-Demented Individuals with Alzheimer’s Disease Neuropathology
Kok, F. K., van Leerdam, S., & de Lange, E. C. M. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-210607 · Cited by 46
“More504 over, results from a cell culture study indicated 505 that microglia, when activated by A , release 506 reactive oxygen species and also TNF- , creat507 ing a positive feedback loop of enhanced A and 508 microglial induced inflammation [125].”

Authors: Tarkowski, E.
Affiliations: University of Gothenburg (SE)
Corresponding author: Tarkowski, E
Venue: Journal of Neurology, Neurosurgery & Psychiatry
Publisher: BMJ
Published: 2003-09-01
Volume: 74
Issue: 9
Pages: 1200-1205
ISSN: 0022-3050 (ISSN-L)
DOI: 10.1136/jnnp.74.9.1200
PMC: PMC1738668
OpenAlex: W2071728536
Cited by: 501
References: 53
Citations by year: 2026: 16 · 2025: 17 · 2024: 45 · 2023: 28 · 2022: 43 · 2021: 51 · 2020: 23 · 2019: 30 · 2018: 32 · 2017: 23 · 2016: 18 · 2015: 16 · 2014: 14 · 2013: 13 · 2012: 18
FWCI: 6.52
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Neurology Neurosurgery & Psychiatry (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Rune och Ulla Amlövs Stiftelse för Neurologisk och Reumatologisk Forskning
Hjärt-Lungfonden
Göteborgs Läkaresällskap
Svenska Läkaresällskapet
Stiftelsen Konung Gustaf V:s 80-årsfond
Medical Research Council
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: Alzheimer's disease, mild cognitive impairment, cerebrospinal fluid biomarkers, intrathecal inflammation, inflammatory cytokines, TNF-α, IL-1β, GM-CSF, TGF-beta, tau protein, amyloid-beta, amyloid metabolism, neuroinflammation, disease progression
MeSH terms: Aged, Aged, 80 and over, Alzheimer Disease, Central Nervous System, Cognition Disorders, Female, Humans, Inflammation, Interleukin-1, Male, Middle Aged, Prospective Studies, Risk Factors, Tumor Necrosis Factor-alpha, Granulocyte-Macrophage Colony-Stimulating Factor, Amyloid beta-Peptides, tau Proteins, Plaque, Amyloid

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Intrathecal inflammation precedes development of Alzheimer's disease

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