Raúl Martínez-Fernández

Background: In Parkinson's disease, motor dysfunction largely reflects dopamine‐dependent pathophysiological alterations and compensatory mechanisms that progress over time and are partially reversible with dopaminergic treatment. Our recent cross‐sectional observations suggest that disinhibition of the primary motor cortex—assessed with short‐interval intracortical inhibition (SICI) using transcranial magnetic stimulation—does not correlate with clinical motor features, does not progress across disease stages, and instead correlates with olfactory dysfunction, a common prodromal and dopamine‐independent feature. Objective: We aimed to provide longitudinal evidence for or against the hypothesis that motor cortex disinhibition is dissociated from clinical motor features in Parkinson's disease. Methods: We compared SICI across three cohorts (total n = 95 patients): (1) baseline and 2‐year follow‐up (n = 43), with concurrent motor assessment and ¹⁸ F‐DOPA positron emission tomography (PET) imaging (n = 24); (2) before and after levodopa administration (n = 30); and (3) before and after focused ultrasound subthalamotomy (n = 22). We also included a pooled healthy control group (n = 75) from two previously published studies. Bayesian statistics was applied to formally assess evidence for the presence or the absence of an effect. Results: SICI was expectedly reduced, with very strong to extreme Bayesian evidence, in patients compared with control subjects. We found evidence that cortical disinhibition did not worsen with clinically evident disease progression confirmed with ¹⁸ F‐DOPA PET and did not improve following a clinically effective dose of levodopa or subthalamotomy. Moreover, changes in SICI did not correlate with changes in motor features across cohorts. Conclusions: These findings provide longitudinal evidence that motor cortex disinhibition is largely dissociated from clinical motor features in Parkinson's disease. © 2026 International Parkinson and Movement Disorder Society.

Background: The Huntington's Disease Integrated Staging System (HD‐ISS) provides a framework for staging HD but does not incorporate fluid biomarkers. Objective: The aim of this study was to examine neurofilament light chain (NfL) and mutant huntingtin (mHTT) and total tau across HD‐ISS stages and their associations with genetic burden, neuroimaging, and clinical measures. Methods: We performed cross‐sectional analysis of the Barcelona‐Huntington's Disease (BCN‐HD) cohort with external replication in the multicenter HDClarity study. HD gene expansion carriers were classified as HD‐ISS stages 0 to 3. NfL (cerebrospinal fluid [CSF] and plasma), CSF mHTT, total tau, striatal volumes, and Unified Huntington's Disease Rating Scale measures were quantified. Group differences and associations were analyzed using adjusted models. Results: The BCN‐HD cohort included 78 participants (50 HD gene expansion carriers [HDGECs], 28 controls) and HDClarity included 218 participants (166 HDGECs, 52 controls). CSF NfL increased across HD‐ISS stages and discriminated premanifest from manifest individuals, as well as HD‐ISS stage 0 from stage 1. Plasma NfL showed parallel increases and strongly correlated with CSF NfL ( ρ = 0.88, P < 0.001). More than half of HD‐ISS 0 individuals had NfL levels above the age‐adjusted 95th percentile (P95) and shorter predicted time to onset (13 years for CSF and 10 years for plasma). From HD‐ISS 1 onward, NfL levels exceeded P95 in most individuals. Higher NfL concentrations were associated with genetic burden, striatal atrophy, and clinical measures (all P < 0.001). CSF mHTT was detectable from HD‐ISS 0 but showed weaker associations, whereas CSF total tau increased only from HD‐ISS 3. Conclusions: NfL identifies biological activity across the HD‐ISS continuum and shows neuroaxonal injury in a subset of individuals classified as stage 0. These findings suggest that fluid biomarkers may complement current HD‐ISS criteria and support biological stratification in observational studies and clinical trials. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: In patients with fluctuating Parkinson's disease (PD), treatment decisions predominantly focus on motor complications, whereas neuropsychiatric symptoms are often regarded as static. Neuropsychiatric fluctuations (NPF), however, are frequent, can rival or exceed motor symptoms in their impact on quality of life, and may predispose patients to persistent neuropsychiatric complications if left unrecognized. Objective: To propose a structured approach to the definition, mechanistic underpinnings, assessment, and management of NPF. Methods: Narrative review of clinical and mechanistic studies on NPF in patients with fluctuating PD, complemented by the authors’ clinical and research experience in the recognition and management of these phenomena. Findings were synthesized to provide a structured overview of their clinical characteristics, underlying mechanisms, assessment, and management, and to inform the proposed framework. Results: NPF are characterized by intradiurnal changes in mood, motivation, anxiety, and cognition that closely track the short‐term pharmacodynamics of dopaminergic therapy, reflecting transitions between relative dopaminergic deficiency during OFF periods and excessive dopaminergic stimulation during peak dose states. Converging clinical and mechanistic evidence supports dynamic fluctuations in dopaminergic tone within limbic and associative circuits as a key driver of NPF, whereas other neurotransmitter systems may also modulate their clinical expression. Recognition of NPF remains difficult because, unlike motor complications, they are less amenable to objective observation and quantification, patient self‐report is often limited by impaired insight, and commonly used PD rating scales fail to capture these phenomena. Consequently, effective management requires early identification and therapeutic strategies aimed at stabilizing dopaminergic tone within mesolimbic and mesocortical circuits. Timely detection and proactive treatment adjustments may help limit the progression and severity of neuropsychiatric complications over time. Conclusions: To move beyond a motor‐centric paradigm, the field requires consensus definitions, improved understanding of underlying mechanisms, validated assessment instruments, and clinical trials that prioritize NPF as primary outcomes.

Background: Unilateral focused ultrasound subthalamotomy (STN‐FUS) improves motor features of Parkinson's disease (PD) for up to 3 years. Objectives: To assess the efficacy of unilateral STN‐FUS in PD 5 years post‐procedure. Methods: Prospective, open‐label study including PD patients treated with STN‐FUS. Primary outcome: change from baseline in the Movement Disorder Society‐Unified Parkinson's Disease Rating Scale‐Part III (MDS‐UPDRS‐III) off‐medication for the treated side. Secondary outcomes: global motor state, motor complications, functional disability, quality of life, medication, and safety. Results: Forty‐five patients were included; 32 completed 5 years of follow‐up. While off‐medication, the MDS‐UPDRS‐III on the treated side showed 54% improvement from baseline (19.0 [95% CI 17.9–20.1] to 8.8 [7.5–10.1], P < 0.001). The total MDS‐UPDRS‐III was reduced by 27% (37.1 [34.9–39.3] to 27.1 [24.3–29.9], P < 0.001). At 5 years, motor complications, quality of life, and functional disability were equivalent to baseline. Levodopa equivalent daily dose (LEDD) increased from 739.2 (650.1–828.4) to 1053.3 (946.3–1160.3) milligrams ( P < 0.001). Mild‐to‐moderate levodopa‐induced dyskinesias (n = 7) were reported. No late adverse events occurred. Conclusion: Unilateral STN‐FUS for PD may provide sustained motor benefits after 5 years. © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND AND IMPORTANCE: Magnetic resonance–guided focused ultrasound (MRgFUS) ablation is a new therapeutic tool for movement disorders. Side effects after treatment are mild to moderate, and treatment-related severe complications are rare. Technical intraprocedural hurdles such as inertial cavitation can be associated with adverse events. We describe 2 patients who developed symptomatic brain bleeding during MRgFUS ablation associated with the presence of cavitation. This complication has not been reported thus far. CLINICAL PRESENTATION: Two female patients aged 74 and 68 years were treated with MRgFUS ablation for medically refractory essential tremor and Parkinson disease, respectively. The treatment progressed uneventfully, and clinical improvement was seen; however, cavitation occurred before we achieved satisfactory benefit. To mitigate cavitation, sonication power was decreased in both patients, but cavitation activity persisted. After the last sonication, both patients showed contralateral motor weakness, and the treatment was terminated. Post-treatment brain computed tomography scans in both patients showed a brain hematoma in the targeted area. One patient improved progressively within a few months, but the second remained disabled. CONCLUSION: These two cases represent 0.4% of our over 500 patients treated with MRgFUS ablation, and, thus, brain bleeding should be considered a rare complication of the therapy. However, it cannot be ruled out, particularly if uncontrollable cavitation occurs. A conservative approach should be taken in such cases to avoid it.

Iron deposition in the nigrostriatal system plays a pivotal role in Parkinson’s disease (PD) onset and progression. This study explored the time course of nigrostriatal iron accumulation in 54 PD patients at early to moderately advanced stages and 20 age-matched healthy controls. Using multi-echo T2*-MRI and R2* relaxometry, iron content was assessed in the substantia nigra pars compacta (SNpc) and striatum. In vivo findings were contrasted with histological analyses in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism model involving six non-human primates (NHPs) and two controls using Perls’ Prussian blue staining. Complementarily, dopaminergic degeneration was quantified by 6-[¹⁸F]-fluoro-L-dopa PET in humans and TH immunohistochemistry in NHPs. Results showed progressive iron accumulation in the SNpc correlating with striatal dopaminergic denervation and neuronal loss. Striatal iron followed a V-shaped progression, decreasing initially and increasing later. Iron in the SNpc may serve as a marker of neurodegeneration in PD, while decreased striatal iron may indicate pathological susceptibility to dopaminergic loss.

Background: Motor cortex disinhibition, as measured by impaired short‐interval intracortical inhibition (SICI) using transcranial magnetic stimulation (TMS), is a well‐established feature of Parkinson's disease (PD). However, its substantial variability among patients remains unexplained, prompting questions about its origin, clinical relevance, and connection to disease heterogeneity.Objective: Based on biological links between olfaction and motor function, we aimed to investigate the possible relationship between motor cortex disinhibition and olfactory dysfunction in PD.Methods: We assessed motor cortex disinhibition, as measured by SICI, and olfactory dysfunction, as measured by the Sniffin’ Stick Test 12 items (SST‐12), in a new cohort of early‐to‐mid‐stage PD patients (n = 45) and age‐matched and gender‐matched healthy controls (n = 35).Results: We obtained moderate‐to‐extreme Bayesian evidence that patients had the expected decrease of cortical inhibition and decrease of olfactory function, with neither feature correlating with the clinical motor severity. Cortical disinhibition and olfactory dysfunction were correlated, with strong‐to‐extreme evidence, both considering all subjects (n = 80), only healthy controls (n = 35), only patients (n = 45), or only levodopa‐naïve patients (n = 20). We tested and excluded age as a possible confounding factor. The evidence from causal inference analysis supported a mediation role of PD that aligned more with an internal pathogenic mechanism than with an external one.Conclusion: These findings suggest that motor cortex disinhibition and olfactory dysfunction might be linked by a common early pathogenic process in PD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.