Biomarkers of Brain Damage and Postoperative Cognitive Disorders in Orthopedic Patients: An Update

Table 1

Summary of clinical studies on biomarkers of brain damage and their relation to orthopedic surgery and/or postoperative cognitive disorders.

Author(s)	Study design	Results	Conclusions	Reference
Anderson et al., 2001	Analysis of serum S100B concentrations for a normal population ( = 459) and multitrauma patients without head injury ( = 17).	The mean serum S100B concentration for a normal healthy population was 0.032 g/L. Among trauma patients, serum S100B levels were highest after bone fractures and thoracic contusions. Burns and minor bruises also produced increased S100B levels.	Trauma, even in the absence of head trauma, results in high serum concentrations of S100B. S100B may have a negative predictive value to exclude brain tissue damage after trauma.	[8]
Kinoshita et al., 2003	Patients ( = 14) undergoing TKA with bone cement use ( = 7) or reamed intramedullary nailing for tibial fracture ( = 7).	The serum level of S100B was increased after a pneumatic tourniquet deflation in the TKA group compared with the tibial fracture group.	In patients undergoing TKA, bone cement may transiently induce astroglial injury, although it does not alter neurological outcomes.	[9]
Pelinka et al., 2003	Bilateral femur fracture in 10 anesthetized rats.	S100B concentration was increased after bilateral femur fracture and reached a peak 30–120 minutes after fracture.	S100B is increased after bilateral femur fracture without hemorrhagic shock in rats.	[10]
Stolz et al., 2004	Patients ( = 37) undergoing aortic valve replacement.	New DWI lesions (14 patients, 3 with focal deficits) correlated with age, preexisting T2 lesion volume, and postoperative S100B concentrations after surgery. In a forward stepwise canonical discrimination model, only T2 lesion volume was a relevant variable.	The volume of preexisting T2 lesions is related to the development of perioperative DWI lesions.	[11]
Ramlawi et al., 2006	Patients ( = 40) undergoing cardiac surgery under CPB.	The incidence of NCD was 40%. Both NSE and tau protein were elevated in the presence of NCD compared with those without NCD. S100B increase was not different between the NCD and control patients. Cardiotomy suction increased S100B levels; NSE and tau were not influenced.	NSE and tau are better associated with NCD and less influenced by cardiotomy suction compared with S100B.	[12]
Stålnacke et al., 2006	Female soccer players ( = 44) before and after a competition.	Concentration of both S100B and NSE was increased after the game, with correlation between S100 concentration and both the number of head injuries and other trauma events.	S100B and NSE were increased by game activities. The increases in S100B concentration were related to the number of head injuries and other trauma events.	[13]
Taurino et al., 2008	Patients ( = 15) undergoing carotid endarteriectomy.	MMP-9 levels were higher in patients with carotid stenosis versus controls, significantly in those with cerebral lesions at neuroimaging.	MMP-9 assay could be useful in the evaluation of carotid lesions to help identify those at highest risk of a neurologic event.	[14]
van Munster et al., 2009	Patients ( = 120) aged 65 years or more with hip fracture.	The incidence of delirium was 51.7%. Delirious state, pre- or postoperative status, and type of fracture were associated with S100B levels. The highest S100B levels were found “during” delirium. No difference in S100B or NSE levels was seen regardless of subtype of delirium.	Delirium was associated with increased level of S100B.	[15]
Gaudet et al., 2010	Patients ( = 73) undergoing carotid endarteriectomy.	Approximately 19% of eligible patients developed NCD. Compared to patients without NCD, this group had both higher total and activity MMP-9 levels at baseline.		[16]
Mondello et al., 2010	Adult patients ( = 40) with severe TBI who underwent ventriculostomy.	Mean CSF levels of SBDPs were higher in TBI patients than in controls. SBDP145 provided accurate diagnoses at all time-points examined, while SBDP120 release was more accurate 24 h after injury. Within 24 h after injury, SBDP145 CSF levels correlated with GCS scores, while SBDP120 levels correlated with age. SBDP levels were higher in patients who died than in those who survived. SBDP145 levels (>6 ng/mL) and SBDP120 levels (>17.55 ng/mL) strongly predicted death.	CSF SBDP levels can predict injury severity and mortality after severe TBI and can be useful complements to clinical assessment.	[17]
Tomaszewski et al., 2010	Patients ( = 60) undergoing THA with ( = 30) or without ( = 30) bone cement use.	Following surgery, the S100B levels were increased in both groups. However, S100B concentration in the cement group was higher and its normalization was slower, in comparison to the noncement group. No clear changes in neuropsychological tests between both groups were observed.	There was a relationship between bone cement implantation and elevated S100B postoperatively; however, neuropsychological test results did not reflect this.	[18]
Witlox et al., 2011	Participants ( = 77) aged 75 and older admitted for surgical repair of acute hip fracture.	Postoperative delirium occurred in 39.5%. Preoperative CSF A1-42, tau, and P-Tau levels were not different between participants who did and did not develop delirium.	CSF markers for plaque and tangle formation are not strongly associated with delirium risk in older adults with hip fracture.	[19]
Jones et al., 2012	Participants ( = 68) over 60 years old following major surgery.	Baseline NSE and the change in NSE levels between baseline and 24 h were correlated with the change in CAMCOG score between baseline and 52 weeks.	NSE may be a useful predictor of individuals at risk of more severe long-term cognitive decline.	[20]
Mondello et al., 2012	Patients ( = 16) with severe TBI (GCS  ≤  8) 6 months after injury and in 16 controls.	Severe TBI patients had higher serum MAP-2 concentrations than controls with no history of TBI at 6 months after injury. MAP-2 levels correlated with the GOSE and LCFS at month 6. Lower serum levels of MAP-2 were observed in VS patients compared to non-VS patients.	Severe TBI results in a chronic release of MAP-2 in patients with higher levels of consciousness, suggesting that remodeling of synaptic junctions and neuroplasticity processes occur several months after injury. The data indicate MAP-2 as a potential marker for emergence to higher levels of cognitive function.	[21]
Papa et al., 2012	Adult patients ( = 96) with blunt head trauma.	Mean UCH-L1 levels in patients with positive CT scans were higher in comparison to those with negative CT.	UCH-L1 is detectable in serum within an hour of injury and is associated with measures of injury severity including the GCS score, CT lesions, and NSI.	[22]
Ji et al., 2013	Patients ( = 83) older than 65 years undergoing elective THA.	POCD occurred in 24.6% at 7 days after surgery.; Patients with POCD had significantly higher IL-1, Tau/A1-42, P-Tau/A1-42, and a lower level of A1-42 in CSF when compared with the non-POCD group. There were no differences in preoperative CSF levels of Tau, IL-6, and P-Tau as well as plasma levels of IL-1, IL-6, BDNF, and CRP between POCD and non-POCD groups.	The POCD patients were associated with higher postoperative plasma levels of MDA and higher IL-1 and lower A1-42 levels in preoperative CSF that might predispose the development of POCD in aged patients following THA with spinal anesthesia.	[23]
Xie et al., 2013	Patients ( = 136) undergoing THA/TKA.	Preoperative CSF A-42/tau ratio was associated with postoperative Hopkins Verbal Learning Test Retention and the Benton Judgment of Line Orientation. A-40/tau ratio was associated with Brief Visuospatial Memory Test Total Recall.	Preoperative CSF A/tau ratio is associated with postoperative changes. The presence of biomarkers, specifically the A/tau ratio, may identify patients at higher risk for cognitive changes after surgery.	[24]
Anckarsäter et al., 2014	Patients ( = 35) undergoing TKA under spinal anesthesia.	CSF T-Tau concentrations increased during and after surgery and were correlated with the administered doses of bupivacaine. P-Tau, A-42, and NFL remained unchanged, while the mean GFAP level increased with a large standard deviation. CSF T-Tau and P-Tau correlated with the CSF/serum albumin ratios.	Bupivacaine may be involved in impaired cortical axonal integrity during nonneurological surgery.	[25]
Gempp et al., 2014	Divers ( = 59) with neurological DCS and 37 asymptomatic divers.	NSE, but not S100B protein, was higher in the DCS group than in controls.	NSE was found to be useful for the diagnosis of neurological DCS. Reliability of S100B was not demonstrated.	[26]

BNDF: brain-derived neurotrophic factor; CAMCOG score: Cambridge Assessment for Mental Disorder in the Elderly; CPB: cardiopulmonary bypass; CRP: C reactive protein; CSF: cerebrospinal fluid; CT: computer tomography; DCS: decompression sickness; DWI: diffusion-weighted imaging; GCS: Glasgow Coma Scale; GFAP: glial fibrillary acidic protein; GOSE: Glasgow Outcome Scale; LCFS: Level of Cognitive Function Scale; NCD: neurocognitive decline; NFL: neurofilament light; NSE: neuron-specific enolase; NSI: neurosurgical intervention; POCD: postoperative cognitive dysfunction; SBDPs: αII-spectrin breakdown products; TBI: traumatic brain injury; THA: total hip arthroplasty; TKA: total knee arthroplasty; UCH: ubiquitin C-terminal hydrolase; VS: vegetative state.