Neurological Therapy Research Articles

Neuropathological comorbidity, genetics and cognition in a Chinese community-based autopsy cohort.

Neurodegenerative comorbidities are common and critical, yet data specific to the Chinese population remains limited. The study aims to investigate the prevalence and associations of neuropathologic changes and comorbidities, and their correlation with genetics and cognition in a community-dwelling autopsy cohort in China. Datasets of 610 participants were obtained from the National Human Brain Bank for Development and Function at the Chinese Academy of Medical Sciences/Peking Union Medical College. Neuropathological changes analysed included Alzheimer's disease neuropathological change (ADNC) (n = 331); α-synucleinopathies (n = 124) with 120 Lewy body disease (LBD) and 4 multiple system atrophy; limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) (n = 341); primary age-related tauopathy (PART) (n = 231); argyrophilic grain disease (AGD) (n = 107); age-related tau astrogliopathy (ARTAG) (n = 144); cerebral amyloid angiopathy (CAA) (n = 183); hippocampus sclerosis (HS) (n = 46). Frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and amygdala-predominant LBD are rare. Descriptive statistics and logistic regression models were used to assess the neuropathological associations. Increased age at death was correlated with increased severity in ADNC, LBD, and LATE-NC, as well as with a higher number of comorbidities. APOE ε4 allele frequency in the present autopsy cohort was 13.63%. The presence of the APOE ε4 allele was linked to an advanced ADNC stage and increased comorbidities. The co-pathology prevalence varied by pathologies, with notable increases in specific subgroups: within the ADNC subgroups, LBD, LATE-NC, CAA, and HS were more frequent in advanced stages; in the LATE-NC subgroups, ADNC, CAA, and ARTAG increased, while PART decreased in higher LATE-NC stages. PART cases presented the highest proportion of pure pathology (37.2%) compared to other groups. Advanced ADNC stages were significantly associated with higher LATE-NC stages, and vice versa. Neocortical LBD was correlated with elevated ADNC levels, and higher LATE-NC stages were associated with worsening LBD pathology. High level ADNC, neocortical LBD, and stage 3 of LATE-NC were identified as independent predictors of severe cognition status. Our study suggests that older age at death and APOE ε4 presence are the risk factors for neuropathologic comorbidities in Chinese people. The findings underscore the importance of considering comorbid neurologic diagnoses and therapies in clinical practice.

Focused ultrasound widely broadens AAV-delivered Cas9 distribution and activity.

Because children have little temporal exposure to environment and aging, most pediatric neurological diseases are inherent, i.e. genetic. Since postnatal neurons and astrocytes are mostly non-replicating, gene therapy and genome editing present enormous promise in child neurology. Unlike in other organs, which are highly permissive to adeno-associated viruses (AAV), the mature blood-brain barrier (BBB) greatly limits circulating AAV distribution to the brain. Intrathecal administration improves distribution but to no more than 20% of brain cells. Focused ultrasound (FUS) opens the BBB transiently and safely. In the present work we opened the hippocampal BBB and delivered a Cas9 gene via AAV9 intrathecally. This allowed brain first-pass, and subsequent vascular circulation and re-entry through the opened BBB. The mouse model used was of Lafora disease, a neuroinflammatory disease due to accumulations of misshapen overlong-branched glycogen. Cas9 was targeted to the gene of the glycogen branch-elongating enzyme glycogen synthase. We show that FUS dramatically (2000-fold) improved hippocampal Cas9 distribution and greatly reduced the pathogenic glycogen accumulations and hippocampal inflammation. FUS is in regular clinical use for other indications. Our work shows that it has the potential to vastly broaden gene delivery or editing along with clearance of corresponding pathologic basis of brain disease.

Time of the Day of Traumatic Brain Injury has Minimal Effects on Behavioral and Histological Outcomes in Mice of Both Sexes.

Transcription of > 50% of the mammalian coding genes follows circadian rhythm in an organ-specific manner. Recent findings highlighted the influence of time of the day in the progression of various neurological diseases and therapies. In the present study, we evaluated the effect of time of occurrence of traumatic brain injury (TBI) on behavioral and neuropathological outcomes in mice of both sexes. Following a controlled cortical impact injury induced between Zeitgeber time (ZT)1-4 or ZT13-16, behavioral deficits and brain damage were evaluated. There were no significant differences in post-TBI motor function between groups ZT1-4 and ZT13-16 in either male or female mice compared with the sex-matched naïve control. TBI-induced anxiety-like behavior was significantly higher in the female ZT13-16 cohort compared to the naïve cohort; but, no difference was observed between injured groups in both sexes. Similarly, spatial learning and memory were not significantly different between the ZT1-4 and ZT13-16 groups in both sexes. Post-TBI cortical lesion volume was also not significantly different between ZT1-4 and ZT-13-16 groups in both sexes. The present study observed no significant effects of occurrence time on TBI-induced brain damage or behavioral deficits in male and female mice.

Probiotics Encapsulated via Biological Macromolecule for Neurological Therapy and Functional Food: A Review.

Probiotics are live microorganisms that confer health benefits to humans, offering significant potential for preventing and treating various diseases. Neurological disorders, driven by multifaceted factors and linked to high disability rates, have become a growing global concern, particularly in the context of an aging population. Recent studies emphasize a strong connection between dysbiosis of the gut microbiota and neurological disorders. Probiotics have emerged as promising therapeutic interventions due to their ability to modulate the gut microbiota and influence the production of key metabolites, such as short-chain fatty acids and neurotransmitters, crucial for neurological health. However, probiotic viability is often compromised, limiting their therapeutic efficacy. We propose that developing high-activity probiotic formulations, coupled with innovative delivery strategies, holds considerable promise for advancing neurological treatments. Encapsulation systems have proven effective in enhancing probiotic stability and efficacy. This review discusses advances in probiotic delivery using biological macromolecule-based encapsulation, addressing key challenges in maintaining viability during production, storage, and digestion. It also highlights emerging delivery systems, such as microencapsulation, aimed at improving stability and therapeutic effectiveness. Additionally, the review explores the potential of functional foods enriched with probiotics for neurological health. Future research should explore clinical applications of encapsulated probiotics and support the development of functional foods to enhance neurological health.

Advancing neurological disorders therapies: Organic nanoparticles as a key to blood-brain barrier penetration.

The blood-brain barrier (BBB) plays a vital role in protecting the central nervous system (CNS) by preventing the entry of harmful pathogens from the bloodstream. However, this barrier also presents a significant obstacle when it comes to delivering drugs for the treatment of neurodegenerative diseases and brain cancer. Recent breakthroughs in nanotechnology have paved the way for the creation of a wide range of nanoparticles (NPs) that can serve as carriers for diagnosis and therapy. Regarding their promising properties, organic NPs have the potential to be used as effective carriers for drug delivery across the BBB based on recent advancements. These remarkable NPs have the ability to penetrate the BBB using various mechanisms. This review offers a comprehensive examination of the intricate structure and distinct properties of the BBB, emphasizing its crucial function in preserving brain balance and regulating the transport of ions and molecules. The disruption of the BBB in conditions such as stroke, Alzheimer's disease, and Parkinson's disease highlights the importance of developing creative approaches for delivering drugs. Through the encapsulation of therapeutic molecules and the precise targeting of transport processes in the brain vasculature, organic NP formulations present a hopeful strategy to improve drug transport across the BBB. We explore the changes in properties of the BBB in various pathological conditions and investigate the factors that affect the successful delivery of organic NPs into the brain. In addition, we explore the most promising delivery systems associated with NPs that have shown positive results in treating neurodegenerative and ischemic disorders. This review opens up new possibilities for nanotechnology-based therapies in cerebral diseases.

The Effectiveness of Neurological Rehabilitation Therapy in Improving Motor Function and Daily Living Abilities in Stroke Patients with Hemiplegia

Objective: To explore the effects of neurological rehabilitation therapy on motor function and daily living abilities in stroke patients with hemiplegia. Methods: Fifty stroke patients with hemiplegia admitted to the hospital were randomly divided into an observation group and a control group, with 25 patients in each group. The control group received conventional rehabilitation therapy, while the observation group underwent additional neurological rehabilitation therapy. The therapeutic effects were compared between the two groups. Results: Post-treatment results showed that the observation group achieved significantly better recovery in motor function, balance ability, and daily living abilities compared to the control group, with a lower incidence of complications during the rehabilitation period. Conclusion: Adding neurological rehabilitation therapy during the rehabilitation period of stroke patients with hemiplegia can effectively enhance recovery outcomes.

Arriba y Adelante: Looking Outward and Moving Ahead.

Judith E. Deutsch, PT, PhD, FAPTA, the 55th McMillan Lecturer, is professor and director of the Research in Virtual Environments and Rehabilitation Sciences (Rivers) Lab in the Doctoral Programs in Physical Therapy in the School of Health Professions at Rutgers University. Her current research includes the development and testing of virtual reality, serious games to improve mobility and fitness of individuals with neurologic health conditions, and knowledge translation to strengthen evidence-based practice. Her research has been funded by the National Institutes of Health, the National Science Foundation, and the American Hospital Association. She also has longstanding interest and scholarship in integrating complementary therapies into physical therapy. Dr Deutsch has been recognized with awards for teaching, research, mentoring, service and publications from the American Physical Therapy Association (APTA), Academy of Neurologic Physical Therapy, the New Jersey chapter of APTA, the International Society for Virtual Rehabilitation, the Kessler Institute for Rehabilitation, the University of Southern California, and Rutgers University.

Nanomaterial‐Mediated Modulation of TRPV1 Ion Channels for Biomedical Applications

AbstractTransient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cation channel involved in various physiological processes such as pain perception, thermoregulation, and inflammatory responses. Nanomaterials have emerged as precise tools to modulate TRPV1 activity, offering high spatiotemporal resolution and specificity. These nanomaterials act as transducers, responding to internal or external stimuli such as pH, light, electric, and magnetic fields to deliver modulatory agents like agonists, antagonists, heat, reactive species, and mechanical forces to TRPV1 channels. This strategy enables non‐invasive and targeted therapeutic interventions for diseases associated with TRPV1 dysfunction. In this review, recent advances are highlighted in nanomaterial‐mediated TRPV1 modulation and its biomedical applications. The TRPV1 structure and activation mechanisms, the integration of nanomaterials for effective TRPV1 modulation, and the required material properties are covered. Moreover, biomedical applications are discussed, including neurostimulation, neurological disorder therapies, cancer therapies, metabolic disease treatments, and cardiovascular disease interventions. Future research directions and challenges in this field are also proposed.

Applying normative atlases in deep brain stimulation: a comprehensive review.

Deep brain stimulation (DBS) has emerged as a crucial therapeutic strategy for various neurological and psychiatric disorders. Precise target localization is essential for optimizing therapeutic outcomes, necessitating advanced neuroimaging techniques. Normative atlases provide standardized references for accurate electrode placement, enhancing treatment customization and efficacy. This comprehensive review explores the application of normative atlases in DBS, emphasizing their role in target identification, patient-specific electrode placement, and predicting stimulation outcomes. Challenges, such as variability across atlases and technical complexities, are addressed alongside future directions and innovations, including advancements in neuroimaging technologies and the integration of machine learning (ML) and artificial intelligence (AI). Normative atlases play a pivotal role in enhancing DBS precision and patient outcomes, promising a future of personalized and effective therapies in neurology and psychiatry.

How can MSI enhance our understanding of ASO distribution?

In the dynamic field of drug discovery and development, a comprehensive understanding of drug absorption, distribution, metabolism, excretion, and toxicity is crucial. Mass spectrometry imaging (MSI) has become a key analytical tool in the pharmaceutical industry, allowing evaluation of drug biodistribution and molecular profiles. Antisense oligonucleotides (ASOs) are emerging drug candidates for treating neurologic diseases. This review explores the potential of MSI in investigating ASOs' spatial distribution within neurological disease models. Here, we focus on multimodal molecular imaging to gain insights into ASO distribution, simultaneously with a better understanding of the molecular pathways affected by ASOs. An improved understanding of therapeutic ASOs in tissue will potentially improve neurologic therapies, emphasizing their importance in patient care.

Reflections and Aspirations: Shaping the Future of Neurologic Physical Therapy.

Reflections and Aspirations: Shaping the Future of Neurologic Physical Therapy.

Neurological Monitoring and Management for Adult Extracorporeal Membrane Oxygenation Patients: Extracorporeal Life Support Organization Consensus Guidelines.

Critical care of patients on extracorporeal membrane oxygenation (ECMO) with acute brain injury (ABI) is notable for a lack of high-quality clinical evidence. Here, we offer guidelines for neurological care (neurological monitoring and management) of adults during and after ECMO support. These guidelines are based on clinical practice consensus recommendations and scientific statements. We convened an international multidisciplinary consensus panel including 30 clinician-scientists with expertise in ECMO from all chapters of the Extracorporeal Life Support Organization (ELSO). We used a modified Delphi process with three rounds of voting and asked panelists to assess the recommendation levels. We identified five key clinical areas needing guidance: (1) neurological monitoring, (2) post-cannulation early physiological targets and ABI, (3) neurological therapy including medical and surgical intervention, (4) neurological prognostication, and (5) neurological follow-up and outcomes. The consensus produced 30 statements and recommendations regarding key clinical areas. We identified several knowledge gaps to shape future research efforts. The impact of ABI on morbidity and mortality in ECMO patients is significant. Particularly, early detection and timely intervention are crucial for improving outcomes. These consensus recommendations and scientific statements serve to guide the neurological monitoring and prevention of ABI, and management strategy of ECMO-associated ABI.

Utilization of Neurology and Allied Health Services by People With Parkinson's Disease in Israel: A Retrospective Observational Study.

Sustainable utilization of neurology and allied health professions' services is pivotal for effective management of Parkinson disease (PD) and is correlated with positive health-related outcomes. (1) To describe the utilization of neurology and allied health services by people with PD (PwP); (2) to explore the associations between demographic and structural variables and utilization; and (3) to test associations between utilization and unplanned hospitalizations. A retrospective observational cohort study of 1761 PwP in the years 2014-2019 was conducted. Utilization of neurology and allied health services was mapped. Regression models were examined to test associations between demographic and structural variables, utilization of neurology and physical therapy (PT), and unplanned hospitalizations. Approximately 50% of the study population utilized neurology services. Utilization rate of allied health services ranged between 0% and 19%. The likelihood of utilizing neurology services increased for people with extended health insurance and people with more years since diagnosis and decreased for women and for people living at a great distance from a neurology service. The likelihood of utilizing PT increased for Jews and people with extended health insurance and decreased for people with more years since diagnosis and for people living at a great distance from a PT service. Among patients with fewer years since diagnosis (<5years), those who utilized PT had a higher likelihood of unplanned hospitalization. Neurology and allied health services are underutilized by PwP, particularly by minorities and women. Policymakers should take proactive steps to increase utilization. for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A496).

A retrospective analysis of a clinician-initiated high-intensity locomotor training implementation project in an inpatient rehabilitation facility.

The Academy of Neurologic Physical Therapy's Intensity Matters campaign recommends the implementation of high-intensity locomotor training for all patients with neurologic dysfunction with goals to improve walking. Retrospectively determine the effectiveness of a clinician-initiated implementation project on the adoption, reach, and fidelity of high-intensity locomotor training for patients with stroke during inpatient rehabilitation and, determine whether the project led to changes in patient outcomes. Retrospective analysis of electronic medical records from 1 year before and after the project. Patients admitted with a stroke diagnosis were included. Demographic information, the number of high-intensity sessions, the percentage of time spent in the target heart rate zone, standardized assessment scores for motor function, functional mobility, balance, gait speed and endurance, and discharge destination were extracted for descriptive and linear mixed model analysis. Clinician reach was 75%, and adoption of high-intensity training varied between clinicians from 47.1% and 83.3%. Of eligible patients, 55% received the target intervention at least once, reflecting the patient reach. Implementation fidelity was 18.84%. Linear mixed effects modeling revealed a statistically significant effect of time (p < .001) but not group allocation or group × time interaction. Although statistically significant differences in patient outcomes compared to pre-implementation were not found, results highlight the limitations associated with adopting high-intensity locomotor training for patients post-stroke in this setting .It remains unclear whether the implementation fidelity achieved was sufficient to impact patient outcomes. Further research is needed to establish fidelity targets and identify barriers to successful implementation projects by clinicians.

Codesign of a Neurological Physiotherapy Student-Led Clinic With Students and Patients: An Exploratory Qualitative Study.

This study explores students' and patients' views of a UK physical therapy student-led clinic (SLC) for neurological rehabilitation and, using a codesign approach, it proposes an optimal design of a physical therapy SLC for neurological rehabilitation for patient participation and student learning. There is a paucity of literature examining experiences of neurological rehabilitation SLCs. Although research supports the utilization of codesign methodologies with patients and for curriculum development, there remains a gap regarding its application to SLCs in physical therapy for individuals with neurological conditions. Convenience sampling was used to recruit 4 patient and 4 student participants to take part in the study. This qualitative study employed exploratory codesign based on the participatory action research approach. Three online codesign workshops were facilitated by the research team. Thematic analysis of each workshop informed the outline for the next. Patients perceived that the SLC improved their overall well-being, and they highly valued being able to access rehabilitation. Students reported that they developed a range of clinical skills through participation in the SLC but would have liked a more in-depth orientation. The codesign process identified 5 key elements for the optimal design of the physical therapy neurological SLC: student support, continuity, supervision, peer-assisted learning, and orientation. Findings suggest that the SLC provides both a quality learning experience and a patient service, which is safe, effective, and sustainable. Future research should be undertaken with different stages of students and in different university settings. The codesign approach has been shown to be feasible for students and patients and could be used across other aspects of curriculum design. This novel study using codesign methodology provides initial findings of key elements to optimize SLCs in neurological physical therapy, to enhance student learning and patient experience.

Transforming lives in autism spectrum disorder treatment through acupuncture: A case report

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication, restricted and repetitive behaviors, and narrow interests. Given the high prevalence of ASD and the lack of specific pharmacological treatments, there is a pressing need for alternative therapeutic approaches. Acupuncture has shown promise in improving the clinical symptoms of ASD. This report presents the case of a 6-year-old girl diagnosed with ASD, intellectual developmental disorder, attention deficit hyperactivity disorder, and articulation disorder. She underwent Liu&amp;rsquo;s pediatric neurological rehabilitation acupuncture therapy (PNRAT) for over 2 years. The treatment involved specific scalp acupuncture techniques targeting cognitive and linguistic rehabilitation. After the treatment course, the patient showed significant improvements in cognitive, linguistic, social, and behavioral symptoms, transitioning from limited verbal communication and marked social difficulties to thriving in a mainstream school setting. This case highlights the potential of Liu&amp;rsquo;s PNRAT as an effective intervention for ASD. The observed improvements suggest that acupuncture may offer valuable therapeutic benefits for children with ASD, contributing to the growing interest in its potential as an adjunct therapy. Further research is needed to optimize treatment protocols and explore synergies with conventional therapies.

RELEVANCE OF COMPETENCE DEVELOPMENTAND ADVANCED TRAINING PROGRAMMES FOR PHYSICAL THERAPISTS WORKING IN PAEDIATRICS

Physical therapists in Ukraine complete six years of study (4 years of first (bachelor's) degree and 2 years of second (master's) degree) to obtain a speciality and diploma of physical therapist, which involves the acquisition of a number of professional competencies described in the relevant educational standards and curricula. These educational standards and the vast majority of educational programmes contain a minimum amount of paediatric physical therapy component. Therefore, additional training based on the competency-based approach in paediatrics is needed to enable physical therapists to provide effective, qualified services to children. The aim of the study is to substantiate the need to develop a list of competencies to improve the training of physical therapists in Ukraine who will specialise in paediatrics. Materials and methods. The study was conducted by questionnaire survey of physical therapists working in paediatrics from 1 to 14 September 2023. The questionnaire was developed to assess the need for advanced training programmes for physical therapists working in paediatrics, as well as to assess the areas of clinical activity and the level of competencies of specialists. Results. The survey involved 82 physical therapists working in paediatrics. Of the 82 physical therapists, 59 (71.9%) were representatives of public institutions, 13 - private, and 10 respondents did not indicate the type of institution. In 80.4% of physical therapists, the total length of service is equal to the length of service in paediatrics. Only 10.97% of the surveyed physical therapists agree with the statement that university education in Ukraine is sufficient to start an effective practice in paediatrics. 6.10% believe that there are sufficient opportunities for advanced training in paediatric physical therapy in Ukraine, while 21.95% disagree with this statement. The majority of respondents provide services on an outpatient basis, only 25.60% - in acute rehabilitation. Among the proposed areas of physical therapy in paediatrics, most physical therapists work with patients with musculoskeletal disorders (79.26%). The next area in terms of the number of physical therapists working in it is physical therapy in neurology (70.73%). Almost not covered areas in physical therapy for children were assistance in neonatal intensive care (only 8.53% of respondents work in this area) and assistance in intensive care units (only 12.19% gave an affirmative answer to the question about this area). Only 4.87% of respondents work with burns, 7.32% - with amputations, 24.4% - with cardiovascular and respiratory disorders. Few specialists are engaged in physical therapy for such complex conditions as Spina bifida (24.4%), spinal cord injury (21.95%) and traumatic brain injury (24.9%). In addition, 14.63% of the surveyed physical therapists indicated other areas of clinical activity. The total number of educational components in paediatric physical therapy is very low compared to the total number of all disciplines in educational and professional programmes. Conclusions. Practicing physical therapists believe that university education in Ukraine does not sufficiently develop professional competencies for work in paediatrics. It is advisable to form the competencies of a physical therapist in paediatrics, which would be the basis for improving university curricula, educational components and the development of postgraduate training programmes.

Mechanical thrombectomy practices in Europe: Insights from a survey of European neuroradiologists from the ESMINT.

Mechanical thrombectomy (MT) has revolutionized the prognosis of acute ischemic stroke. Indications for MT are constantly expanding across countries, presenting healthcare professionals, and institutions with the challenge of offering MT to the entire population despite geographic constraints, while also training enough interventional neuroradiologists (INR) for this highly technical-level procedure. We aimed to provide an overview of current European MT practices and organizations in 2021. Members of the European Society of Minimally Invasive Neurological Therapy (ESMINT) were invited to complete two different online surveys from March to November 2021 to collect data on MT practice. A total of 240 individual responses from INR (from 33 European countries) were received. These included information from 56 thrombectomy-capable stroke centers (TCSC) data (across 26 European countries). The mean number of INR per center was 3.8 ± 1.43, median 4 (IQR, 3-4.5). Half of the centers (28/56, 50.00%) performed less than 150 MT per year. Most INR used a balloon guide catheter in less than 50% of cases (160/240, 66.67%), and limited the number of recanalization attempts to six passes to restore flow (209/240, 87.08%). Additionally, 37.92% of the respondents (91/240, 37.92%) indicated that they already performed MT for distal occlusions (M3, M4) as part of their routine practice. Other details of the MT procedure, anesthetic management, and patient selection are also presented and discussed. This European survey emphasizes the differences between TCSC and INR in modern thrombectomy practices. Even if most centers remain understaffed to meet current and future MT needs, most European TCSCs are actively training young INR.

Neurological conditions and community-based physical activity: physical therapists' belief and actions.

Physical therapists (PTs) are key actors in physical activity (PA) promotion. However, it remains unclear whether PTs in community settings promote community-based PA such as adapted physical activity (APA) and adaptive sports (AS) to their patients with neurological conditions (NCs). The main purposes were to evaluate the beliefs PTs have of APA and AS, and to explore actions they undertake to promote it to their patients with NCs. An online survey was created specifically for the study. PT associations and institutions were contacted and licensed PTs working in community-based settings, treating at least one patient with a NC, were invited to participate. Questionnaires were analyzed only if all mandatory questions had been answered. A total of 165 questionnaires were analyzed. PTs reported prioritizing active treatment. They viewed APA and AS as beneficial for their patients with NCs; however, its promotion remained largely infrequent due to a number of barriers. The PTs' own level of PA seemed to significantly influence their beliefs of the benefits of APA and AS (p = 0.001), while being specialized in neurologic physical therapy enabled the PTs to increase frequency of promotion (p = 0.003). Though community-based PTs are aware of the importance of PA for individuals with NCs, they face difficulties in promoting it to their patients. However, these difficulties are reduced among PTs who are specialized in neurologic physical therapy. Efforts should be made toward educating PTs to neurological pathologies and their specificities when it comes to PA.

Lipid-siRNA conjugate accesses perivascular transport and achieves durable knockdown throughout the central nervous system.

Short-interfering RNA (siRNA) has gained significant interest for treatment of neurological diseases by providing the capacity to achieve sustained inhibition of nearly any gene target. Yet, efficacious drug delivery throughout deep brain structures of the CNS remains a considerable hurdle for intrathecally administered therapeutics. We herein describe an albumin-binding lipid-siRNA conjugate that transports along meningeal and perivascular CSF pathways, leading to broad dispersion throughout the CNS parenchyma. We provide a detailed examination of the temporal kinetics of gene silencing, highlighting potent knockdown for up to five months from a single injection without detectable toxicity. Single-cell RNA sequencing further demonstrates gene silencing activity across diverse cell populations in the parenchyma and at brain borders, which may provide new avenues for neurological disease-modifying therapies.