Plasma p-tau181

Plasma p-tau181

Frank et al. from the Boston University School of Medicine examined the ability of plasma hyperphosphorylated tau (p-tau)181 to detect cognitive impairment due to Alzheimer’s disease (AD) independently and in combination with plasma total tau (t-tau) and neurofilament light (NfL).

Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables.

Plasma p-tau181 discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau181 had a direct association with cognitive diagnosis in a bootstrapped GGM.

These results support plasma p-tau181 for the detection of Alzheimer’s disease dementia and the use of blood-based biomarkers for optimal disease detection 1).


Results suggest that in elderly individuals without dementia at baseline, plasma p-tau181 biomarkers were associated with greater memory decline and rates of clinical progression to dementia. Plasma p-tau181 improved prediction of memory decline above a model with currently available clinical and genetic data. While the clinical importance of this improvement in the prediction of memory decline is unknown, these results highlight the potential of plasma p-tau181 as a cost-effective and scalable Alzheimer’s disease biomarker 2)


Plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below the PET threshold of amyloid-β positivity or apparent entorhinal tau deposition. 3).


The study of Karikari et al. adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment. 4)


O’Connor et al. investigated the timing of p-tau181 changes using 153 blood samples from 70 individuals in a longitudinal study of familial AD (FAD). Plasma p-tau181 was measured, using an in-house single-molecule array assay. We compared p-tau181 between symptomatic carriers, presymptomatic carriers, and non-carriers, adjusting for age and sex. We examined the relationship between p-tau181 and neurofilament light and estimated years to/from symptom onset (EYO), as well as years to/from the actual onset in asymptomatic subgroup. In addition, we studied associations between p-tau181 and clinical severity, as well as testing for differences between genetic subgroups. Twenty-four were presymptomatic carriers (mean baseline EYO -9.6 years) while 27 were non-carriers. Compared with non-carriers, plasma p-tau181 concentration was higher in both symptomatic (p < 0.001) and presymptomatic mutation carriers (p < 0.001). Plasma p-tau181 showed considerable intra-individual variability but individual values discriminated symptomatic (AUC 0.93 [95% CI 0.85-0.98]) and presymptomatic (EYO ≥ -7 years) (AUC 0.86 [95% CI 0.72-0.94]) carriers from non-carriers of the same age and sex. From a fitted model, there was evidence (p = 0.050) that p-tau181 concentrations were higher in mutation carriers than non-carriers from 16 years prior to estimated symptom onset. Our finding that plasma p-tau181 concentration is increased in symptomatic and presymptomatic FAD suggests potential utility as an easily accessible biomarker of AD pathology. 5).


1)

Frank B, Ally M, Brekke B, Zetterberg H, Blennow K, Sugarman MA, Ashton NJ, Karikari TK, Tripodis Y, Martin B, Palmisano JN, Steinberg EG, Simkina I, Turk KW, Budson AE, O’Connor MK, Au R, Goldstein LE, Jun GR, Kowall NW, Stein TD, McKee AC, Killiany R, Qiu WQ, Stern RA, Mez J, Alosco ML. Plasma p-tau181 shows stronger network association to Alzheimer’s disease dementia than neurofilament light and total tau. Alzheimers Dement. 2021 Dec 2. doi: 10.1002/alz.12508. Epub ahead of print. PMID: 34854549.
2)

Therriault J, Benedet AL, Pascoal TA, Lussier FZ, Tissot C, Karikari TK, Ashton NJ, Chamoun M, Bezgin G, Mathotaarachchi S, Gauthier S, Saha-Chaudhuri P, Zetterberg H, Blennow K, Rosa-Neto P; Alzheimer’s Disease Neuroimaging Initiative. Association of plasma P-tau181 with memory decline in non-demented adults. Brain Commun. 2021 Jun 14;3(3):fcab136. doi: 10.1093/braincomms/fcab136. PMID: 34222875; PMCID: PMC8249102.
3)

Ashton NJ, Pascoal TA, Karikari TK, Benedet AL, Lantero-Rodriguez J, Brinkmalm G, Snellman A, Schöll M, Troakes C, Hye A, Gauthier S, Vanmechelen E, Zetterberg H, Rosa-Neto P, Blennow K. Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathol. 2021 May;141(5):709-724. doi: 10.1007/s00401-021-02275-6. Epub 2021 Feb 14. PMID: 33585983; PMCID: PMC8043944.
4)

Karikari TK, Benedet AL, Ashton NJ, Lantero Rodriguez J, Snellman A, Suárez- Calvet M, Saha-Chaudhuri P, Lussier F, Kvartsberg H, Rial AM, Pascoal TA, Andreasson U, Schöll M, Weiner MW, Rosa-Neto P, Trojanowski JQ, Shaw LM, Blennow K, Zetterberg H; Alzheimer’s Disease Neuroimaging Initiative. Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative. Mol Psychiatry. 2021 Feb;26(2):429-442. doi: 10.1038/s41380-020-00923-z. Epub 2020 Oct 26. PMID: 33106600.
5)

O’Connor A, Karikari TK, Poole T, Ashton NJ, Lantero Rodriguez J, Khatun A, Swift I, Heslegrave AJ, Abel E, Chung E, Weston PSJ, Pavisic IM, Ryan NS, Barker S, Rossor MN, Polke JM, Frost C, Mead S, Blennow K, Zetterberg H, Fox NC. Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer’s disease: a longitudinal cohort study. Mol Psychiatry. 2020 Jul 14. doi: 10.1038/s41380-020-0838-x. Epub ahead of print. PMID: 32665603.

Intradiscal Platelet-Rich Plasma

Intradiscal Platelet-Rich Plasma

Akeda et al. demonstrated that intradiscal injection of autologous Platelet-Rich Plasma PRP releasate in patients with low back pain was safe, with no adverse events observed during follow-up. Future randomized controlled clinical studies should be performed to systematically evaluate the effects of this therapy 1).

Systemic Reviews

A systematic review was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Level I-IV investigations of intradiscal PRP injections in DDD were sought in multiple databases. The Modified Coleman Methodology Score (MCMS) was used to analyze the methodological quality of the study. Only the outcome measurements used by more than 50% of the studies were included in the data analysis. The study heterogeneity and nature of evidence (mostly retrospective, non-comparative) precluded meta-analysis. Pre and post-injection pain visual analog scales (VAS) were compared using two sample Z-tests. Five articles (90 subjects, mean age 43.6 ± 7.7 years, mean follow-up 8.0 ± 3.6 months) were analyzed. Four articles were level IV evidence and one article was level II. Mean MCMS was 56.0 ± 10.3. There were 43 males and 37 females (10 unidentified). Pain VAS significantly improved following lumbar intradiscal PRP injection (69.7 mm to 43.3 mm; p<0.01). Two patients (2.2%) experienced lower extremity paresthesia after treatment. One patient (1.1%) underwent re-injection. No other complications were reported. In conclusion, intradiscal injection of PRP for degenerative discs resulted in statistically significant improvement in VAS with low re-injection and complication rates in this systematic review. It is unclear whether the improvements were clinically significant given the available evidence. The low level of evidence available (level IV) does not allow for valid conclusions regarding efficacy; however, the positive results suggest that further higher-quality studies might be of value 2).

Critical reviews

In 2019 Although there was only one double-blind randomized controlled trial, all the studies reported that PRP was safe and effective in reducing back pain. While the clinical evidence of tissue repair of IVDs by PRP treatment is currently lacking, there is a great possibility that the application of PRP has the potential to lead to a feasible intradiscal therapy for the treatment of degenerative disc diseases. Further large-scale studies may be required to confirm the clinical evidence of PRP for the treatment of discogenic LBP 3).


In 2018, Mohammed and Yu reviewed the current literature on PRP therapy and its potential use in the treatment of chronic discogenic low back pain, with a focus on evidence from clinical trials 4).

Clinical trials

A trial demonstrates encouraging preliminary 6 month findings, using strict categorical success criteria, for intradiscal PRP as a treatment for presumed discogenic low back pain. Randomized placebo controlled trials are needed to further evaluate the efficacy of this treatment 5).

Case reports

Intradiscal Platelet-Rich Plasma for Discogenic Low Back Pain Owing to a Degenerated and Previously Discectomized L5-S1 Disc 6).

References

1)

Akeda K, Ohishi K, Masuda K, et al. Intradiscal Injection of Autologous Platelet-Rich Plasma Releasate to Treat Discogenic Low Back Pain: A Preliminary Clinical Trial. Asian Spine J. 2017;11(3):380-389. doi:10.4184/asj.2017.11.3.380
2)

Hirase T, Jack Ii RA, Sochacki KR, Harris JD, Weiner BK. Systemic Review: Is an Intradiscal Injection of Platelet-Rich Plasma for Lumbar Disc Degeneration Effective?. Cureus. 2020;12(6):e8831. Published 2020 Jun 25. doi:10.7759/cureus.8831
3)

Akeda K, Yamada J, Linn ET, Sudo A, Masuda K. Platelet-rich plasma in the management of chronic low back pain: a critical review. J Pain Res. 2019;12:753-767. Published 2019 Feb 25. doi:10.2147/JPR.S153085
4)

Mohammed S, Yu J. Platelet-rich plasma injections: an emerging therapy for chronic discogenic low back pain. J Spine Surg. 2018;4(1):115-122. doi:10.21037/jss.2018.03.04
5)

Levi D, Horn S, Tyszko S, Levin J, Hecht-Leavitt C, Walko E. Intradiscal Platelet-Rich Plasma Injection for Chronic Discogenic Low Back Pain: Preliminary Results from a Prospective Trial. Pain Med. 2016;17(6):1010-1022. doi:10.1093/pm/pnv053
6)

Karamanakos PN, Manousakis E, Rozakis D, Kämäräinen OP, Oikonomi E, Panteli ES. Intradiscal Platelet-Rich Plasma for Discogenic Low Back Pain Owing to a Degenerated and Previously Discectomized L5-S1 Disc [published online ahead of print, 2020 Aug 12]. Pain Med. 2020;pnaa241. doi:10.1093/pm/pnaa241

Prophylactic plasma transfusion

Prophylactic plasma transfusion

Review findings show uncertainty for the utility and safety of prophylactic FFP use. This is due to predominantly very low-quality evidence that is available for its use over a range of clinically important outcomes, together with lack of confidence in the wider applicability of study findings, given the paucity or absence of study data in settings such as major body cavity surgery, extensive soft tissue surgery, orthopaedic surgery, or neurosurgery. Therefore, from the limited RCT evidence, we can neither support nor oppose the use of prophylactic FFP in clinical practice 1).


Prophylactic transfusion of plasma in severe traumatic brain injury without intracranial hemorrhage has not been demonstrated to improve outcome. In all situations of product transfusion, patients should be closely observed for signs of volume overload and the development of transfusion-related acute lung injury. The benefit of product transfusion should always be weighed against the risk of a transfusion-related complication 2).


West et al. in 2011 reviewed the literature in an attempt to clarify best clinical practice with regard to this issue. Although the activated partial thromboplastin time and prothrombin time-INR are useful laboratory tests to measure specific clotting factors in the coagulation cascade, in the absence of active bleeding or a preexisting coagulopathy, their utility as predictors of overall bleeding risk is limited. Several studies have shown an imperfect correlation between mild elevations in the INR and subsequent bleeding tendency. Furthermore, FFP transfusion is not always sufficient to achieve normal INR values in patients who have mild elevations (< 2) to begin with. Finally, there are risks associated with FFP transfusion, including potential transfusion-associated [disease] exposures as well as the time delay imposed by laboratory testing and transfusion administration prior to initiation of procedures. The authors propose that the current concept of a “normal” INR value warrants redefinition to make it a more meaningful clinical tool. Based on their review of the literature, the authors suggest that in a hemodynamically stable patient population there is a range of mildly prolonged INR values for which FFP transfusion is not beneficial, and is potentially harmful. 3)

In 2006 a paper presented the recommendations of the Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSaPS; French Safety Agency for Health Products). A panel of experts reviewed and graded the literature on platelet transfusions; recommendations were formulated. Threshold platelet counts (PC) for transfusions in the perioperative context have not been clearly defined and should be determined by the existence of hemorrhagic risk factors. In the case of commonly practiced invasive procedures, the recommendation is to transfuse in order to achieve PC > 50,000 x microL-1. In the absence of platelet dysfunction, regardless of the type of surgery, the standard hemorrhagic risk threshold for surgery is 50,000 x microL-1. It has not been proven that the risk threshold is different according to the type of surgery. For neurosurgery and ophthalmologic surgery involving the posterior segment of the eye, a PC of 100,000 x microL-11 is required. For axial regional anesthesia, a PC of 50,000 x microL-11 is sufficient for spinal anesthesia; a PC of 80,000 x microL-11 has been proposed for epidurals. During massive transfusion, prophylactic platelet infusion cannot be recommended beyond a loss of two blood volumes in less than 24 h (Professional Consensus). As for the therapeutic transfusion of plasma and/or platelets, as much as possible, platelet deficit should be documented with test results (PC and fibrinogen) before transfusing. In the event of bleeding, platelet transfusion may precede plasma infusion. However, although this recommendation has been the subject of several professional consensus agreements, it is not based on any randomized studies. Threshold PC for perioperative transfusions have not been clearly defined and most recommendations are the result of a professional consensus 4)5).

References

1)

Huber J, Stanworth SJ, Doree C, Fortin PM, Trivella M, Brunskill SJ, Hopewell S, Wilkinson KL, Estcourt LJ. Prophylactic plasma transfusion for patients without inherited bleeding disorders or anticoagulant use undergoing non-cardiac surgery or invasive procedures. Cochrane Database Syst Rev. 2019 Nov 28;11:CD012745. doi: 10.1002/14651858.CD012745.pub2. Review. PubMed PMID: 31778223.
2)

Reddy GD, Gopinath S, Robertson CS. Transfusion in Traumatic Brain Injury. Curr Treat Options Neurol. 2015 Nov;17(11):46. doi: 10.1007/s11940-015-0379-9. PubMed PMID: 26407615.
3)

West KL, Adamson C, Hoffman M. Prophylactic correction of the international normalized ratio in neurosurgery: a brief review of a brief literature. J Neurosurg. 2011 Jan;114(1):9-18. doi: 10.3171/2010.7.JNS091857. Epub 2010 Sep 3. Review. PubMed PMID: 20815695.
4)

Samama CM, Djoudi R, Lecompte T, Nathan N, Schved JF; French Health Products Safety Agency (AFSSAPS) Expert Group. Perioperative platelet transfusion. Recommendations of the French Health Products Safety Agency (AFSSAPS) 2003. Minerva Anestesiol. 2006 Jun;72(6):447-52. PubMed PMID: 16682914.
5)

Samama CM, Djoudi R, Lecompte T, Nathan-Denizot N, Schved JF; Agence Française de Sécurité Sanitaire des Produits de Santé expert group. Perioperative platelet transfusion: recommendations of the Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSaPS) 2003. Can J Anaesth. 2005 Jan;52(1):30-7. PubMed PMID: 15625253.
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