The scales evaluating patients' neurological functions and quality of life are the basis of clinical evaluation and/or scientific research of nervous system diseases. Neurological functions of patients with spinal cord injury (SCI) are commonly assessed by using American Spinal Injury Association (ASIA) Impairment Scale or International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). Generally, the quality of life for SCI patients is evaluated by using several available evaluating scales. International Association of Neurorestoratology (IANR) Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS) was designed as one single method to assess various items of quality of life related with SCI, including male sexual function. However, in clinical practice, the ability of returning to society is an important index of quality of life after SCI. Additionally, the female patients' sexual function after SCI that has been neglected in the past should be reconsidered following neurorestorative treatments. Even more, this scale also can be applied to assess the quality of life in patients with spinal cord dysfunction due to diseases or disorders. Thus, the IANR added the ability of returning to society and female patients' sexual function in the current revised version and renamed the scale as Spinal Cord Injury or Dysfunction Quality of Life Rating Scale (SCIDQLRS) (IANR 2022 version). Hopefully, this revised scale is widely used to expand enhanced improvements of quality of life following neurorestorative treatments in patients with SCI or spinal cord dysfunction.

Cell therapy has been shown to be a crucial clinical therapeutic option for central nervous system diseases or damage. Promoting standardization of clinical cell therapy procedures is essential for professional associations devoted to cell therapy. The International Association of Neurorestoratology (IANR) and the Chinese Association of Neurorestoratology (CANR; Preparatory) collaborated to release Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017) in 2018. Due to recent advances and achievements in clinical cell therapy worldwide in recent years, IANR and CANR have renewed and updated the guidelines. Except for the requirements of equipment, personnel, and ethics, these revised guidelines include cell type nomenclature, cell quality control, cell types in clinical application, minimal suggested cellular doses, patient-informed consent, indications and contraindications for undergoing cell therapy, documentation of procedure and therapy, safety evaluation, efficacy evaluation, the policy of repeated treatments, do not charge patients for unproven therapies, basic principles of cell therapy, and publishing responsibility. IANR/CANR recommends that all clinical practitioners follow these cellular therapy guidelines. These guidelines provide references of better cell types, doses, routes, and therapeutic timing windows in different diseases.

Breakthroughs with rapid changes are the themes of the development in Neurorestoratology this year. Given the very difficult circumstances of the persistent COVID-19 pandemic, most of the colleagues in Neurorestoratology have conducted meaningful research and obtained encouraging results, as described in the 2020 Yearbook of Neurorestoratology. Neurorestorative progress during 2021 depicts recent findings on the pathogenesis of neurological diseases, neurorestorative mechanisms and clinical therapeutic achievements. The pathogenesis and risk factors of Alzheimer's disease were parts of the most prominent hot research topics. Yet, it remains controversial whether β-amyloid accumulation and tau protein deposition are the results of, or the reasons for the neurodegenerative processes. Neurogenesis is an important neurorestorative mechanism, however, it is questionable whether neural stem cells are present in the adult humans brain. Thus, neurogenesis may not derive from endogenous neural stem cells in the adult humans. Neurorestorative treatments were important areas of the 2021 research efforts and these therapies are improving the quality of life in patients with neurological diseases. There was major exploration of cell-based therapies for neurological disease and injury. However, unfortunately several multi-center, double-blind or observing-blind, placebo controlled, randomized clinical trials of mesenchymal stromal cells or products of mesenchymal stem cells failed to show positive results in ischemic stroke when employed in the sub-acute or recovery phases as there were no appreciable differences in the quality of life as compared with controls. Excitingly, increased numbers of clinical investigations of brain–computer interface (BCI) were reported that showed benefits for patients with neurological deficits. In pharmaceutical neurorestorative therapies, Aducanumab (Aduhelm) and Sodium Oligomannate are approved respectively by the United States Food and Drug Administration (USFDA) and the China National Medical Products Administration (NMPA) to treat patients with mild-to-moderate Alzheimer's disease. Although, the decisions to approve these drugs are highly contentious in the medical and scientific community because of the contradictory findings or other problems associated with the drug usage. We believe that repeating low-level evidence studies that showed negative results or scanty evidences in randomized control trials is of little significance. However, we strongly recommend conducting multi-center, double-blind, placebo controlled, randomized clinical trials for promising innovative therapeutic methods to facilitate their possible clinical translation.

Brain trauma or traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. Along with the conventional therapeutic strategies, neurorestorative treatments for TBI have been developed in recent decades. However, missing standards and guidelines has become a growing issue both in clinical practice and fundamental research. Consequently, the Chinese Association of Neurorestoratology (Preparatory; CANR) and the China Committee of International Association of Neurorestoratology (IANR-China Committee) have reached a consensus to form and approve the Guideline of Clinical Neurorestorative Treatment for Brain Trauma. This guideline addresses the common issues in the evaluation and therapies of TBI patients within the scope of Neurorestoratology, offers recommendations based on state-of-art clinical evidences, and covers cell therapies, neural stimulation therapies, and pharmaceutical therapies. Hopefully, this guideline may provide references to clinical professionals during diagnosis and treatment, maximizing the neurorestorative therapeutic efficacy.

Spinal cord injury (SCI) is catastrophic damage for patients, their family, and society. Researchers and clinicians have been trying to find neurorestorative methods to recover their injured functions and structures. Cell therapy is one of the effective therapeutic strategies for SCI. And it can partially restore their neurological functions, which are once thought as permanent neurological deficits. Currently, cells being used therapeutically in clinic include olfactory ensheathing cells (OECs), mononuclear cells (MNCs), mesenchymal stromal cells (MSCs), Schwann cells, and hematopoietic stem cells, cell products differentiated from embryonic stem cells, mesenchymal stem cells, induced pluripotent stem cells, and neural stem cells as well as other kinds of cells. Real world data from these cell therapies showed some benefits in some patients with SCI. Due to being affected by many factors, the therapeutic results of some kinds of cells are contradictory and it is hard to compare effects among different types of cells. According to the data of cell therapies, OEC, MNC and MSC transplantation are applied for patients in majority percentage of cases, and OEC transplantation had a higher percentage of benefits. In next step, under the unified standard of cell preparation and quality control as well as the guidelines of clinical cell application, each kind of cells including OECs should be studied using prospective, multicenter, double-blind or observing-blind, placebo-control, randomized studies for SCI patients with different level of injury and chronicity.

Currently, most cellular therapeutic effects for nervous diseases cannot be proven in a multicenter, randomized, double-blind placebo-control clinical trials, except for a few kinds of cells such as olfactory ensheathing cells. These cells show significant improvements in functional recovery and quality of life for patients with chronic ischemic stroke. Also, olfactory neuron transplantation has promising neurorestorative effects on patients with vascular dementia. Human olfactory neuroepithelium can spontaneously and sustainably regenerate or produce new olfactory neurons and glial cell types for decades or a lifetime. The neurorestorative mechanisms of olfactory ensheathing cells are well known; however, little is known about the neurorestorative mechanisms of olfactory neurons. Therefore, I hypothesize that the neurorestorative mechanisms of olfactory neurons after transplantation: (1) can well migrate where they are needed and become local functional neurons, as they need to compensate or replace; (2) must be regulated by some special molecular factors to elongate their axons, modulate or direct synapses to correctly recognize and connect the target cells, and integrate functions. Based on olfactory neuroepithelium cells displaying the special characterization, neurorestorative mechanisms, clinical therapeutic achievements, and hypotheses of effective mechanisms, they (olfactory ensheathing cells and olfactory neurons) may be the most efficient instruments of neurorestoration.

Alzheimer’s disease (AD) is a neurodegenerative disease dominated by progressive cognitive dysfunction causing significant social, economic, and medical crises. Cell therapy has demonstrated favorable effects for AD. This pilot study examined the safety and neurorestorative effects of the olfactory ensheathing cell (OEC), olfactory neuron (ON), and Schwann cell (SC) on patients with AD. Seven patients with AD were enrolled in this two-center, randomized, double-blind, and placebo- controlled cell therapy study with a subsequent 12-month follow-up. We randomly assigned one or two participants in OEC, ON, and SC therapy or OEC combined with ON and placebo control. All enrolled patients were injected cells or medium into the olfactory sub-mucosa. They got an assessment of Mini-Mental State Examination, Montreal Cognitive Assessment, and Clinical Dementia Rating before treatment and 1, 3, 6, 12 months after treatment. We performed MRI or CT scans before treatment and 12 months after treatment. After integrating the results from the three evaluation methods, all cell types showed better results than a placebo control. ON and SC seem to exhibit more vital potential neurorestorative ability to enhance or convert the neurological functions of patients with AD, and OEC may help AD patients keep neurological functions stable. In this pilot study, there was no adverse or side-effect event. The results of this study strongly suggest conducting a phase II clinical trial of ON, SC, and OEC therapy to prove their neurorestorative effect on patients with AD.

Currently, there are many different standards for the quality control of olfactory ensheathing cell (OEC) culture prepared from human olfactory bulb and mucosa. It is challenging to compare the clinical results of OEC treatment from different hospitals. Based on various standards, the Chinese Association of Neurorestoratology (CANR; Preparatory) and China Committee of International Association of Neurorestoratology (IANR-China Committee) organized professional experts in this field to evaluate the data and develop a standard for clinical applications, including donor evaluation, sample collection, cell culture, cell testing, packaging labels, storage, transportation, and quality control of intermediate/finished cell products, as well as training and management procedures for laboratory operators, the use and management of materials and equipment, and routine maintenance of a clean environment. These standards apply to the quality and control of OEC culture using human olfactory bulb and mucosa as the sample source for the member units of the CANR (Preparatory) and IANR-China Committee. It serves as a reference for physicians around the world who perform OEC clinical applications. This standard represents the minimum required standards for quality control when performing clinical-grade OEC cultures in clinical neurorestorative treatments.

Olfactory ensheathing cells (OECs) have shown promising results for patients with neurologic diseases in non-double-blind, placebo control studies. Thirty patients with a unilateral ischemic stroke of more than a year were enrolled in a phase 2, multicenter, randomized, double-blind, and placebo-controlled cell therapy trial with a subsequent 12-month follow-up. The primary therapeutic objective has shown that after 12 months, there were significant differences in National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) assessment scores among the OEC group, Schwann cell group and placebo medium group at one-year follow-up. The second therapeutic objective found that there were significant differences in NIHSS, mRS, and BI assessment scores when comparing the endpoint data with the baseline data in the OEC group. There was neither hypersensitivity reaction nor adverse event. The results of this multicenter, randomized, double-blind, and placebo-controlled study indicate that injecting OECs into the olfactory sub-mucosa have neurorestorative effects, which can improve the quality of life for patients with chronic ischemic strokes without serious side effects.