RESUMO
Phosphorylated microtubule-associated protein tau (tau) aggregates are a pathological hallmark of various neurodegenerative diseases, including chronic traumatic encephalopathy and amyotrophic lateral sclerosis with cognitive impairment. While there are many residues phosphorylated on tau, phosphorylation of threonine 175 (pThr175 tau) has been shown to initiate fibril formation in vitro and is present in pathological tau aggregates in vivo. Given this, preventing Thr175 tau phosphorylation presents a potential approach to reduce fibril formation; however, the kinase(s) acting on Thr175 are not yet fully defined. Using a single controlled cortical impact rodent model of traumatic brain injury (TBI), which rapidly induces Thr175 tau phosphorylation, we observed an upregulation and alteration in subcellular localization of leucine-rich repeat kinase 2 (LRRK2), a kinase that has been implicated in tau phosphorylation. LRRK2 upregulation was evident by one-day post-injury and persisted to day 10. The most notable changes were observed in microglia at the site of injury in the cortex. To determine if the appearance of pThr175 tau was causally related to the upregulation of LRRK2 expression, we examined the ability of LRRK2 to phosphorylate Thr175in vitro by co-transfecting 2N4R human WT-tau with either LRRK2-WT, constitutively-active LRRK2-G2019S or inactive LRRK2-3XKD. We found no significant difference in the level of pThr175 tau between the overexpression of LRRK2-WT, -G2019S or -3XKD, suggesting LRRK2 does not phosphorylate tau at Thr175. Further, downstream events known to follow Thr175 phosphorylation and known to be associated with pathological tau fibril formation (pSer9-GSK3ß and pThr231 tau induction) also remained unchanged. We conclude that while LRRK2 expression is altered in TBI, it does not contribute directly to pThr175 tau generation.
RESUMO
PURPOSE: Subchondroplasty® is a novel minimally invasive procedure for painful subchondral bone marrow lesions (BMLs). The aim of this systematic review was to characterize the clinical outcomes of the Subchondroplasty® procedure, a novel minimally invasive procedure for the treatment of BMLs. The hypothesis tested was that patients experience improvements in pain and functional outcomes following the Subchondroplasty® procedure. METHODS: MEDLINE, Embase, Web of Science, and Clinicaltrials.gov were searched from database inception to search date (June 10, 2020) for all clinical studies which discussed Subchondroplasty®. Two reviewers independently screened 45 unique results and 17 studies were included in the final analysis. Data were collected regarding patient demographics, indications, pain, functional scores, conversion to TKA, and complications of the procedure. RESULTS: All but one study were level IV evidence; the mean MINORS score was 9 ± 2. There were 756 patients included, 45.1% were female, and the mean age was 54 years (range 20-85). Thirteen studies investigated the effect Subchondroplasty® to the knee, while four studied the impact on the foot and ankle. Median length of follow-up was 12 months. The most common indication for Subchondroplasty® was joint pain with corresponding BML. Major contraindications to Subchondroplasty® included severe OA, joint instability, and malalignment. Mean pain score on visual analogue scale (VAS) prior to Subchondroplasty® was 7.8 ± 0.6, but decreased to 3.4 ± 0.7 postoperatively. All studies investigating functional scores reported improvement following Subchondroplasty® (IKDC 31.7 ± 1.9-54.0 ± 4.2 and KOOS 38.1 ± 0.6-70.0 ± 4.1). There were consistently high levels of patient satisfaction; 87 ± 8% of patients would be willing to undergo the procedure again. Seven cases of complications were reported, most seriously osteomyelitis and avascular necrosis. Conversion to knee arthroplasty ranged from 12.5 to 30% with length of follow-up ranging from 10 months to 7 years. CONCLUSIONS: Existing low-quality studies show Subchondroplasty® to benefit patients with BMLs through reduction in pain and improvement in function, along with a high degree of satisfaction following the procedure. The low short-to-medium term conversion rate to arthroplasty suggests that Subchondroplasty® may play a role in delaying more invasive and expensive procedures in patients with BMLs. Subchondroplasty® is a novel procedure that has promising initial findings, but requires further high-quality, comparative studies with long-term follow-up to better understand the outcomes of the procedure and impact clinical practice recommendations. LEVEL OF EVIDENCE: Systematic Review of Level III and IV Studies, Level IV.