Monitoring of brain interstitial total tau and beta amyloid proteins by microdialysis in patients with traumatic brain injury

Marklund, Niklas; Blennow, Kaj; Zetterberg, Henrik; Ronne-Engström, Elisabeth; Enblad, Per; Hillered, Lars

doi:10.3171/2008.9.jns08584

Cited by 127 publications

(97 citation statements)

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“…Apart from GFAP, up-regulation of total and phosphorylated Tau proteins have also been shown in the brain, CSF and blood of patients with different forms of TBI, and hence these proteins have been proposed as reliable biomarkers of outcome after TBI [11,15,20,23]. Total and phosphorylated Tau proteins in the brain were significantly increased in different animal models of TBI [7,11,22,25].…”

Section: Introductionmentioning

confidence: 90%

Distinct patterns of expression of traumatic brain injury biomarkers after blast exposure: Role of compromised cell membrane integrity

Arun

Abu-Taleb

Oguntayo

et al. 2013

Neuroscience Letters

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Madhusoodana, "Distinct patterns of expression of traumatic brain injury biomarkers after blast exposure: Role of compromised cell membrane integrity" (2013 h i g h l i g h t s• Repeated blast exposures causes acute decrease in GFAP and Tau in brain and plasma.• GFAP and Tau levels increases acutely in the liver and spleen after blast exposure.• No acute changes in GFAP and Tau mRNA levels in the liver after blast exposure.• The acute changes in GFAP and Tau suggest blast-induced cell membrane disruption. a r t i c l e i n f o a b s t r a c tGlial fibrillary acidic protein (GFAP), a protein enriched in astrocytes, and Tau, a protein abundant in neuronal microtubules, are being widely studied as biomarkers of brain injury, and persistent severitydependent increases in brain and blood have been reported. Studies on the acute changes of these proteins after blast exposure are limited. Using a mouse model of closely-coupled repeated blast exposures, we have evaluated acute changes in the levels of GFAP and total Tau by Western blotting. Brain levels of GFAP and Tau proteins decreased significantly at 6 h and increased considerably at 24 h after repeated blast exposures. Plasma samples showed a similar initial decrease and later increase over this timeframe. This biphasic pattern points to possible absorption or sequestration of these proteins from plasma immediately after repeated blast exposures. Liver and spleen tissue showed significant increases in the levels of GFAP and Tau protein at 6 and 24 h post-blast exposures whereas semi-quantitative RT-PCR analysis of liver showed no significant changes in the levels of GFAP or Tau mRNAs. These results suggest that blast exposure causes transient changes in cell membrane integrity in multiple organs leading to abnormal migration of proteins from the tissues to the plasma and vice versa. This transient changes in cell membrane permeability and subsequent bidirectional movement of molecules may contribute to the pathophysiology of TBI and polytrauma after blast exposure.

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Section: Introductionmentioning

confidence: 90%

Distinct patterns of expression of traumatic brain injury biomarkers after blast exposure: Role of compromised cell membrane integrity

Arun

Abu-Taleb

Oguntayo

et al. 2013

Neuroscience Letters

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“…24 Since β-and γ-secretase-generated Aβ forms are released into the interstitial fluid, cerebral microdialysis (MD) is a preferred sampling method for these biomarkers. 25,26 …”

Section: Introductionmentioning

confidence: 98%

Monitoring of β-Amyloid Dynamics after Human Traumatic Brain Injury

Marklund

Farrokhnia

Hånell

et al. 2014

Journal of Neurotrauma

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Epidemiological evidence links severe or repeated traumatic brain injury (TBI) to the development of Alzheimer's disease (AD). Accumulation of amyloid precursor protein (APP) occurs with high frequency after TBI, particularly in injured axons, and APP may be cleaved to amyloid-β (Aβ) peptides playing key pathophysiological roles in AD. We used cerebral microdialysis (MD) to test the hypothesis that interstitial Aβ levels are altered following TBI and are related to the injury type, cerebral energy metabolism, age of the patient, and level of consciousness. In the present report, we evaluated 10 mechanically ventilated patients (7 male, 3 female, ages 18-76 years) with a severe TBI, who had intracranial pressure and MD monitoring. Each MD sample was analyzed for hourly routine energy metabolic biomarkers (MD-lactate, MD-pyruvate, MD-glucose, and MD-lactate/pyruvate ratio), cellular distress biomarkers (MD-glutamate, MD-glycerol), and MD-urea. The remaining MD samples were analyzed for Aβ1-40 (Aβ40; n=765 samples) and Aβ1-42 (Aβ42; n=765 samples) in pooled 2 h fractions up to 14 days post-injury, using the Luminex xMAP technique, allowing detection with high temporal resolution of the key Aβ peptides Aβ40 and Aβ42. Data are presented using medians and 25th and 75th percentiles. Both Aβ40 and Aβ42 were consistently higher in patients with predominately diffuse axonal injury compared with patients with focal TBI at days 1-6 post- injury, Aβ42 being significantly increased at 113-116 h post-injury (p<0.05). The Aβ levels did not correlate with the interstitial energy metabolic situation, age of the patient, or the level of consciousness. These results support that interstitial generation of potentially toxic Aβ species may occur following human TBI, particularly related to axonal injury.

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“…The two characteristic neuropathologies of Alzheimer's disease are the abnormal accumulation and deposition of amyloid-␤ peptides and tau proteins in the brain. Evidence from humans [40][41][42] and experimental animal models [43] has also revealed abnormal accumulations of amyloid-␤ peptides and tau proteins in the brain and in cerebrospinal fluid following TBI. Interestingly, elevation of plasma tau levels has been associated with increasingly severe outcomes of TBI [44].…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of Olfactory Receptors in Response to Traumatic Brain Injury Promotes Risk for Alzheimer's Disease

Pasinetti¹

2013

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATEOct PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERIcahn School of Medicine at Mount Sinai 1 Gustave L. Levy Place New York, NY 10029 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTTraumatic Brain Injury (TBI) is a risk factor for subsequent development of Alzheimer's disease (AD). Abnormal tau processing is a common pathological feature of TBI and AD and tau neuropathology plays a key role in both TBI complications and AD dementia. This study is based on our recent findings of aberrant down-regulation of specific olfactory receptors (OR) as biological indices for TBI and down-regulation of OR TBI biomarkers following TBI might contribute to TBI-related tau neuropathology. We propose that down-regulation of select OR TBI biomarkers in the brain may contribute to the elevation of tau neuropathological phenotypes, thereby promoting the development of AD dementia among Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) veterans with exposure to TBI. In Year 1, we found that activation of OR4M1 by a low affinity ligand resulted in reduced tau phosphorylation via JNK signaling pathway and a manuscript was published based on this finding. We constructed a virtual 3D structure model for OR4M1 to screen high affinity ligands. Fifty Seven (57) compounds were identified and clustered into 32 clusters based on their structure similarities. We found significant decrease of the blood OR contents in a rat model of TBI. Outcomes from our study will provide a better understanding of TBI complications and how it is related to AD. (Zhao et al., 2013). In addition, we found down-regulation of these ORs is significantly correlated with the severity of brain injury and TBI-specific symptoms, and a two-biomarker panel, comprised of OR11H1 and OR4M1, provides the best criterion for segregating the ...

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Monitoring of brain interstitial total tau and beta amyloid proteins by microdialysis in patients with traumatic brain injury

Abstract: These results suggest that monitoring of interstitial T-tau and Abeta42 by using microdialysis may be an important tool when evaluating the presence and role of axonal injury following TBI.

Cited by 127 publications

References 76 publications

Distinct patterns of expression of traumatic brain injury biomarkers after blast exposure: Role of compromised cell membrane integrity

Distinct patterns of expression of traumatic brain injury biomarkers after blast exposure: Role of compromised cell membrane integrity

Monitoring of β-Amyloid Dynamics after Human Traumatic Brain Injury

Down-Regulation of Olfactory Receptors in Response to Traumatic Brain Injury Promotes Risk for Alzheimer's Disease

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