Expert Review of Neurotherapeutics最新文献

Introduction: Restless Legs Syndrome (RLS) is a sensorimotor disorder linked to brain iron deficiency and dopaminergic dysfunction. Increasing evidence suggests that alterations in adenosine signaling may represent the missing link connecting dopaminergic and glutamatergic abnormalities. The 'adenosine hypothesis' proposes that brain iron deficiency induces a hypoadenosinergic state, primarily through adenosine A₁ receptor downregulation, resulting in cortical hyperexcitability, hyperarousal, and periodic limb movements.

Areas covered: This critical perspective examines experimental, neurophysiological, and clinicaldata supporting the adenosine hypothesis of RLS. Findings from animal models demonstrate altered A₁/A_2A receptor balance in cortico-striatal terminals, promoting glutamatergic hyperactivity. In particular, neurophysiological studies further support the adenosine hypothesis, highlighting a pattern of cortical hyperexcitability and impaired inhibitory control in RLS. In this context, preliminary clinical trials with dipyridamole, an equilibrative nucleoside transporter inhibitor that enhances extracellular adenosine, showed symptomatic improvement, supporting adenosinergic enhancement as a therapeutic approach.

Expert opinion: The adenosine hypothesis provides an integrative framework uniting dopaminergic, glutamatergic, and iron-related mechanisms in RLS. Targeting adenosine transmission could complement existing therapies and mitigate augmentation. Future research should prioritize receptor-selective ligands, multimodal biomarkers, and controlled trials to translate this hypothesis into mechanism-based neurotherapeutic strategies.

Introduction: Perry syndrome (PS) is a rare, inherited neurodegenerative disorder caused by mutations in the DCTN1 gene. It is characterized by parkinsonism, neuropsychiatric symptoms, central hypoventilation, and progressive weight loss, typically leading to a rapid disease course and early death. As genetic testing becomes more widespread, PS is increasingly diagnosed, and its clinical spectrum is expanding.

Areas covered: The authors conducted a comprehensive search of public databases through September 2025 to identify original research, conference proceedings, and book chapters related to Perry syndrome. This review summarizes the current understanding of the disease, including its clinical, pathologic, and genetic aspects. The authors also provide practical recommendations for managing symptoms, particularly through optimization of dopaminergic therapy, antidepressive treatment, and noninvasive or invasive ventilation support, which can greatly improve quality of life and extend survival.

Expert opinion: Although there are currently no approved disease-modifying therapies for PS, recent research into the underlying pathology, such as TDP-43 and axonal transport dysfunction, offers promising targets for future treatments. A new staging system for PS is recommended for PS, which will help to standardize the clinical assessment of PS and guide therapeutic decision-making.

Introduction: The ketogenic diet as a potential treatment for Alzheimer's disease (AD) has been investigated in several controlled trials. This topic is significant because of the limited nature of current interventions for AD, and the increasing recognition that lifestyle interventions may be important for reducing the risk of AD. The ketogenic diet is one of the few lifestyle interventions that has the potential to be beneficial after diagnosis.

Areas covered: In this narrative review, the authors discuss the biological plausibility of how a ketogenic diet may improve amyloid burden and reduce neuroinflammation by providing an alternative energy source. They review relevant meta-analyses, systematic reviews, and controlled trials to investigate this diet in people diagnosed with AD. To this end, the authors used PubMed to search for appropriate systematic reviews and human trials, and closely examined the bibliographies of these papers to find trials potentially missed in their initial search.

Expert opinion: More research is needed before a ketogenic diet could be broadly recommended in patients diagnosed with AD. However, to the extent a treatment effect has been demonstrated, it is comparable to some pharmaceutical interventions in AD. Challenges that remain include demonstrating improvement in quality of life, improving adherence, and standardizing ketogenic therapies.

Introduction: Migraine is among the most disabling neurological disorders worldwide and preventive treatment remains a cornerstone for reducing disease burden. Recent advances in mechanism-based therapies have positioned calcitonin gene-related peptide (CGRP) and its main receptor as central targets for migraine prophylaxis.

Areas covered: This updated narrative overview summarizes the pharmacological profile, clinical efficacy, safety and regulatory status of rimegepant, integrating evidence published through 2025 and highlighting emerging real-world and clinical trends. Relevant literature was identified through searches in PubMed/MEDLINE and Scopus (last search: 19 November 2025) using predefined combinations of terms related to rimegepant and migraine. The review also examines emerging concepts such as situational prevention, potential combination approaches with traditional or novel preventives and exploratory use in other CGRP-mediated headache disorders.

Expert opinion: Rimegepant represents a significant addition to migraine prophylaxis by offering a flexible and well-tolerated option that bridges acute and preventive care. Its role may expand through rational combinations and investigation in other headache disorders. Persistence and long-term safety require careful monitoring, and reimbursement frameworks will determine its future clinical adoption.

Introduction: In spinal muscular atrophy (SMA), irreversible loss of spinal motor neurons and progressive skeletal muscle atrophy cause continuous weakness and loss of motor function. Treatments that increase levels of survival motor neuron (SMN) protein in motor neurons have greatly improved prognoses for patients, but significant unmet needs remain. Myostatin is a protein secreted by skeletal muscle that acts as a negative regulator of muscle growth. Inhibition of the myostatin signaling pathway may improve motor function in SMA and other neuromuscular diseases.

Areas covered: This article reviews the role of muscle in SMA and the potential for treatments that inhibit the myostatin signaling pathway in neuromuscular diseases. Preclinical and clinical trial data are discussed for these muscle-targeted treatments in development for SMA.

Expert opinion: SMN-targeted disease-modifying treatments focus on motor neuron survival rather than muscle. Treated individuals nonetheless experience a range of persistent muscle weakness. Treatments that inhibit myostatin signaling represent a potential complementary pathway for direct muscle enhancement. In the evolving SMA treatment landscape, understanding how muscle-targeted treatment can be incorporated into clinical practice will facilitate individualized treatment decisions and identify outcomes that best encapsulate maintenance or improvement of motor function across the phenotypic spectrum of SMA.

Introduction: Multiple system atrophy is a sporadic α-synucleinopathy, characterized by parkinsonism, cerebellar and pyramidal signs combined in different ways, in association with autonomic failure. In absence of disease-modifying therapies, management is directed toward symptomatic treatment and maintenance of function.

Areas covered: This review critically appraises current evidence, highlights novel therapeutic strategies, and provides guidance for clinical practice and future research directions. A literature search without date restrictions was conducted using PubMed to identify published studies relevant to this review. Motor symptom interventions are primarily levodopa-based, yielding partial and transient responses, especially in MSA-P, whereas dopaminergic agonists, MAO-B inhibitors, amantadine, and device-aided therapies provide a limited or short-lived benefit. Physiotherapy, occupational therapy, and multidisciplinary rehabilitation are integral to motor symptoms management. Non-motor symptoms management target autonomic failure (neurogenic orthostatic hypotension, urinary/sexual dysfunction, etc.), gastrointestinal dysmotility and sleep disorders (REM sleep Behavior Disorder, stridor, etc.), using a stepwise combination of lifestyle measures, pharmacological agents and device-aided interventions.

Expert opinion: Management of MSA remains largely symptomatic. Multimodal treatment and integration of rehabilitative and non-pharmacological strategies are critical, while ongoing trials in neuroprotection and neuromodulation represent key avenues to improve long-term outcomes.

Background: This study compared the efficacy and safety/tolerability of atogepant versus rimegepant as preventive migraine treatments in Japanese patients using anchored matching-adjusted indirect comparisons (MAICs).

Methods: Three placebo-controlled trials were included: RELEASE and PROGRESS (atogepant), and BHV3000-309 (rimegepant). Efficacy outcomes included change from baseline in mean monthly migraine days (MMDs) and mean monthly acute medication use days (MUDs). Quality-of-life endpoints included Migraine-Specific Quality-of-Life Questionnaire (MSQ) v2.1 Role Function-Restrictive (RFR) domain score, Migraine Disability Assessment (MIDAS) total score, and EQ visual analog scale (EQ-VAS) score. Safety/tolerability outcomes included treatment-emergent adverse events (AEs) and AEs leading to treatment discontinuation.

Results: Atogepant demonstrated a statistically significant greater reduction from baseline in mean MMDs (mean difference [MD]: 1.33; 95% confidence interval [CI]: -2.48, -0.18) and monthly acute MUDs (MD: ‑1.97; 95% CI: -3.06, -0.87) versus rimegepant across 12 weeks; and a statistically significant greater improvement from baseline in MSQ v2.1 RFR domain score at Week 12 (MD: 4.80; 95% CI: 0.15, 9.45). No significant differences were identified for other endpoints.

Conclusions: In these MAICs, atogepant was associated with statistically significant greater reductions in MMDs and monthly acute MUDs, and greater improvements in MSQ v2.1 RFR domain scores versus rimegepant in Japanese patients with migraine.

Introduction: Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph Disease (MJD) is the commonest autosomal dominant ataxia worldwide. It is a progressive neurodegenerative disorder with a complex and heterogeneous phenotype that extends far beyond ataxia. Motor and non-motor manifestations lead to a negative impact on quality of life. Despite this, many of these manifestations are amenable to pharmacological interventions.

Areas covered: The current review addresses both disease-modifying and symptomatic therapies for SCA3/MJD. We discuss data on pharmacological and non-pharmacological treatment options for motor and non-motor symptoms of the disease. This narrative review is based on identified literature related to SCA3/MJD and is available on PubMed, Scopus and LILACS.

Expert opinion: There is no currently approved disease-modifying therapy for SCA3/MJD, albeit some recent clinical trials have disclosed encouraging results. The mainstay of clinical care currently relies upon management of symptoms, either using pharmacological or non-pharmacological strategies. Symptomatic treatments for some SCA3/MJD-related manifestations, such as dystonia and cramps, have been tested in controlled studies. For other manifestations, pharmacotherapy is chosen based on empirical evidence and/or experts' opinion. Therefore, better understanding of the natural history of the disease should pave the way for therapeutic discoveries.