Elisa Mantovani

Apathy is one of the most prevalent and disabling non‐motor symptoms in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), collectively referred to as Lewy body disorders (LBDs). It is associated with reduced quality of life, accelerated cognitive decline, increased caregiver burden, and poorer functional outcomes, yet remains underrecognized and undertreated. A Working Group of the International Parkinson and Movement Disorder Society's Non‐Motor Symptoms Study Group conducted a comprehensive review of the literature and developed a position paper through iterative expert discussion and critical appraisal of available data. This review aims to provide a structured, expert‐informed synthesis of the current evidence on the clinical features, neurobiology, assessment, and management of apathy in LBDs and to define priorities for future research and clinical trials. Apathy in LBDs is a multidimensional syndrome encompassing reward insensitivity, negative affect, executive dysfunction, and auto‐activation deficits. Converging evidence implicates dysfunction within distributed frontal‐striatal‐limbic networks and multi‐neurotransmitter systems, including dopaminergic, serotonergic, noradrenergic, and cholinergic pathways. Although several pharmacological and nonpharmacological interventions have been explored, few randomized controlled trials have specifically targeted apathy, and no treatment can currently be considered definitively efficacious. Methodological heterogeneity, inadequate phenotyping, and inconsistent outcome measures have limited therapeutic progress. Apathy should be recognized as a primary clinical and research priority in LBDs. Future adequately powered, mechanistically informed trials using standardized diagnostic criteria and validated outcome measures are urgently needed to advance treatment development. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Staged bilateral Magnetic Resonance–guided Focused Ultrasound (MRgFUS) thalamotomy is an incisionless option for medication‐refractory essential tremor (ET). While the efficacy and safety of unilateral MRgFUS are established, evidence for bilateral treatment remains limited. Objective: To evaluate the efficacy and safety of staged bilateral MRgFUS in a prospective single‐centre observational cohort and to perform a systematic review and meta‐analysis of the literature. Methods: Consecutive ET patients undergoing second‐side MRgFUS were prospectively assessed. The primary efficacy endpoint was the longitudinal change in Clinical Rating Scale for Tremor (CRST) A + B scores for the treated hand after FUS2, while safety was evaluated by collecting and grading adverse events (AEs). A systematic review identified published bilateral MRgFUS series; efficacy data were meta‐analysed, while AEs were reported descriptively. Results: Fifteen patients (60% men; mean age 74.1 ± 8.9 years) underwent FUS2 28.9 ± 22.5 months after first‐side treatment. At the 12‐month evaluation, CRST A + B decreased from 21.0 to 8.8 (−58%), CRST C from 7.3 to 1.9 (−74.2%), and QUEST from 30.5 to 9.5 (−68.7%). Head and voice tremor were reduced by 73.8% and 40.3%, respectively. AEs were predominantly mild (95.2%) and transient (88%). Cognition at 1 year was globally preserved, with a selective decline in verbal episodic memory. Meta‐analysis confirmed significant improvement in tremor severity. Conclusion: Staged bilateral MRgFUS thalamotomy was associated with sustained tremor reduction, including midline tremor, functional improvement and acceptability, with a manageable safety profile. Overall, consistent with literature, these findings support its potential role as a therapeutic option in selected ET patients.

Cognitive and neuropsychiatric non-motor symptoms (NMS) are common in Parkinson’s disease (PD) and atypical parkinsonism (AP), yet their management is difficult. Non-invasive brain stimulation (NIBS) may offer a therapeutic option. To provide a joint and comprehensive overview of studies on NIBS to treat cognitive and neuropsychiatric NMS in PD and AP. We searched for randomized, sham-controlled trials on repeated NIBS sessions for treating cognitive and neuropsychiatric NMS in PD and AP. Studies were categorised by NIBS technique/protocol, NMS, and stimulation target. We found 27 studies on repetitive transcranial stimulation (rTMS; N = 1309 patients, range 18–106) and 7 studies on transcranial direct current stimulation (tDCS; N = 221, 10–77). Cognition was assessed in 17 rTMS and 6 tDCS studies, depression by 24 rTMS and 4 tDCS studies, anxiety by 11 rTMS and 1 tDCS studies, apathy by 4 rTMS and 1 tDCS studies, psychosis by 1 tDCS study. Variability in NIBS targets and parameters, outcome measures, treatment duration and follow-up raised some concerns (N = 26) or high risk of bias (N = 8). The meta-analysis on PD suggested that, despite high heterogeneity and low-to-moderate certainty of evidence, excitatory rTMS of the left dorsolateral prefrontal cortex (DLPFC) and the primary motor cortex, and inhibitory rTMS of the right DLPFC may be effective for depression and anxiety. Methodological heterogeneity impeded robust conclusions on the efficacy of NIBS for cognitive and neuropsychiatric NMS in PD and AP. We propose a roadmap for the design of future studies.

Rationale Impulsive‐compulsive behaviors (ICBs) in Parkinson’s disease are associated with psychiatric comorbidities, reduced quality of life, caregiver burden and serious psychosocial consequences. These behaviors greatly impact patients and their families, and pose a challenge for clinicians. Objectives To assess and compare the effects of pharmacological and non‐pharmacological treatments for ICBs in people with Parkinson’s disease, and to assess whether the effects differ according to ICB subtype. Search methods We searched the Cochrane Movement Disorders Group Specialized Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PEDro, and major trials registries, along with handsearching of abstracts, to 13 June 2025. Eligibility criteria We included parallel‐group and cross‐over randomized controlled trials (RCTs) in people with Parkinson’s disease with ICBs comparing pharmacological or non‐pharmacological treatment with placebo or no treatment. Outcomes Our critical outcomes were change in the frequency and severity of ICBs from baseline, and adverse effects or events. Our important outcomes were change in: quality of life, neuropsychiatric symptoms (depression, anxiety, apathy, anhedonia), impulsivity, cognition, motor and non‐motor symptoms associated with ICBs in Parkinson's disease. Risk of bias We used the revised Cochrane risk of bias tool for randomized trials (RoB 2) for outcomes reported in the summary of findings tables. Synthesis methods We included four studies, each evaluating a different intervention. Due to this heterogeneity, we could not conduct a meta‐analysis and instead provided a narrative summary of the studies and their findings. For continuous outcomes, we calculated mean differences (MDs), while for binary outcomes, we calculated risk ratios (RRs), both with 95% confidence intervals (CIs). We used the GRADE approach to assess the certainty of evidence for each outcome. Included studies We included four RCTs: three parallel‐group and one cross‐over design, with a total of 151 participants. Sample sizes ranged from 17 to 50 per study; participants' mean age ranged from 57.6 to 61.2 years. Women comprised 23.5% to 32% of participants. Three studies compared pharmacological interventions – amantadine, naltrexone, and clonidine (one study each) – to placebo. One study compared a non‐pharmacological intervention (cognitive behavioral therapy, CBT) to a wait‐list control. Non‐profit organizations supported three studies; one did not report funding information. The studies were conducted in Europe and North America and were published between 2010 and 2023. Follow‐up durations ranged from one to six months. All studies evaluated critical outcome measures of interest. Only one study assessed any of the review's important outcomes of interest. Synthesis of results Amantadine versus placebo The evidence is very uncertain about the effect of amantadine versus placebo on adverse events (RR 4.50, 95% CI 0.25 to 81.76; 17 participants). The one study exploring this comparison did not assess any other review outcomes. Naltrexone versus placebo Compared to placebo, naltrexone may result in little to no difference in change in severity of ICBs (Figure 3; low‐certainty evidence). The evidence is very uncertain about the effect of naltrexone on adverse events, including dizziness (RR 4.00, 95% CI 0.48 to 33.22; 48 participants), nausea (RR 15.00, 95% CI 0.90 to 248.78; 48 participants), headache (RR 1.25, 95% CI 0.38 to 4.10; 48 participants), and blood pressure changes (RR 1.67, 95% CI 0.72 to 3.86; 48 participants). Open in figure viewer Figure 3 Comparison 2: naltrexone versus placebo, Outcome 1: change in severity of ICBS Clonidine versus placebo The evidence from one study (with 39 participants assessed for all outcomes) is very uncertain about the effect of clonidine on change in frequency of ICBs (RR 0.89, 95% CI 0.54 to 1.47), change in severity of ICBs (Figure 9), and adverse events, including sleepiness (RR 0.53, 95% CI 0.05 to 5.34), falls (RR 3.15, 95% CI 0.14 to 72.88), nausea (RR 3.15, 95% CI 0.14 to 72.88), orthostatic hypotension (RR 1.58, 95% CI 0.30 to 8.43), restless legs syndrome (RR 3.15, 95% CI 0.14 to 72.88), fatigue (RR 0.70, 95% CI 0.13 to 3.75) and asymptomatic bradycardia (RR 3.15, 95% CI 0.14 to 72.88). The evidence is also very uncertain about the effect of clonidine versus placebo on any changes in participants' quality of life (Figure 17), depression (Figure 18) and anxiety (Figure 19). Open in figure viewer Figure 9 Comparison 3: clonidine versus placebo, Outcome 2: change in severity of ICBs Open in figure viewer Figure 17 Comparison 3: clonidine versus placebo, Outcome 3: change in quality of life Open in figure viewer Figure 18 Comparison 3: clonidine versus placebo, Outcome 4: change in neuropsychiatric symptoms ‐ depression Open in figure viewer Figure 19 Comparison 3: clonidine versus placebo, Outcome 5: change in neuropsychiatric symptoms ‐ anxiety CBT versus wait‐list control The evidence suggests that, compared to wait‐list control, CBT may result in little to no difference in change in frequency (RR 0.79, 95% CI 0.50 to 1.26; 42 participants; low‐certainty evidence) and severity of ICBs (Figure 21; 31 participants; low‐certainty evidence). Open in figure viewer Figure 21 Comparison 4: CBT versus waiting‐list, Outcome 2: change in severity of ICBs The variety of interventions and the small sample sizes precluded data synthesis, including meta‐analysis, as well as subgroup and sensitivity analyses. We judged all four studies to have 'some concerns' or a high risk of bias overall. Authors' conclusions The RCTs reviewed here provide only uncertain evidence regarding the effectiveness of both pharmacological and non‐pharmacological treatments for...

Background: Myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) has emerged as an acquired immune‐mediated demyelinating disorder of the central nervous system distinct from multiple sclerosis (MS). Cognitive dysfunction and related symptoms (anxiety, depression, fatigue) and their impact on quality of life (QoL) have been in‐depth characterized in MS, but data in adult MOGAD patients are very preliminary.Methods: This study aims to characterize cognitive changes through an extensive cognitive battery, as well as anxiety, depression, fatigue, and QoL, in adult MOGAD compared to MS patients.Results: Cognitive outcomes (number of patients with abnormal scores, score severity) depression, anxiety, fatigue, and QoL were largely comparable between MOGAD and MS patients. Most cognitive outcomes were not significantly correlated with neuropsychiatric symptoms, fatigue, and QOL in MOGAD.Conclusions: Our study underscores the importance of cognitive and related outcomes in MOGAD patients and the need for future studies exploring their pathophysiological and cortical morphometric underpinnings and potential therapeutic approaches.

Background Drug-resistant epilepsy (DRE) secondary to hypothalamic hamartoma (HH) often requires surgical resection or stereotactic radiosurgery, which frequently fail to provide satisfactory outcomes and are associated with severe side effects. Magnetic resonance-guided focused ultrasound (MRgFUS) may represent a minimally invasive surgical approach to HH by offering precise thermal ablation of sub-millimetric brain targets while sparing surrounding structures. Methods We present the case of a 19-year-old man with HH-associated DRE, who was successfully treated with MRgFUS. The procedure resulted in effective ablation of the hypothalamic interface of the HH, disconnecting the epileptogenic lesion from the surrounding brain tissue. We also reviewed the literature on MRgFUS for DRE. Results The patient experienced a complete resolution of seizures and significant improvements in social and occupational functioning over an 18-month follow-up period. No neurological, cognitive, or endocrinological adverse effects were observed. Conclusion Our case report and literature review suggest that MRgFUS may achieve adequate seizure control in DRE associated with HH without adverse effects. While MRgFUS shows promise for other forms of DRE, data remain preliminary, and some safety concerns persist. Further studies with long-term follow-up are warranted to better support the use of MRgFUS in DRE.

Clonus is characterized by involuntary, rhythmic, oscillatory muscle contractions, typically triggered by rapid muscle stretching and is frequently associated with spastic equinovarus foot (SEVF), where it may increase risk of falls and cause discomfort, pain, and sleep disorders. We hypothesize that selective diagnostic nerve block (DNB) of the tibial nerve motor branches can help identify which muscle is primarily responsible for clonus in patients with SEVF and provide useful information for botulinum neurotoxin type A (BoNT-A) treatment. This retrospective study explored which calf muscles contributed to clonus in 91 patients with SEFV after stroke (n = 31), multiple sclerosis (n = 21), and cerebral palsy (n = 39), using selective DNB. We found that SEVF-associated clonus was most commonly driven by the soleus muscle, followed by the gastrocnemius lateralis and medialis, tibialis posterior, and flexor digitorum longus, and that frequency differed according to SEVF etiology. Our data suggest that identifying the muscles involved in SEVF-associated clonus may aid clinicians in personalizing BoNT-A treatment to single patients. Also, the findings of this study suggest that applying a ‘stroke model’ to treating spasticity secondary to other etiologies may not always be appropriate.

Cognitive impairment (CI) is common in α-synucleinopathies, i.e., Parkinson’s disease, Lewy bodies dementia, and multiple system atrophy. We summarize data from systematic reviews/meta-analyses on neuroimaging, neurophysiology, biofluid and genetic diagnostic/prognostic biomarkers of CI in α-synucleinopathies. Diagnostic biomarkers include atrophy/functional neuroimaging brain changes, abnormal cortical amyloid and tau deposition, and cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers, cortical rhythm slowing, reduced cortical cholinergic and glutamatergic and increased cortical GABAergic activity, delayed P300 latency, increased plasma homocysteine and cystatin C and decreased vitamin B12 and folate, increased CSF/serum albumin quotient, and serum neurofilament light chain. Prognostic biomarkers include brain regional atrophy, cortical rhythm slowing, CSF amyloid biomarkers, Val66Met polymorphism, and apolipoprotein-E ε2 and ε4 alleles. Some AD/amyloid/tau biomarkers may diagnose/predict CI in α-synucleinopathies, but single, validated diagnostic/prognostic biomarkers lack. Future studies should include large consortia, biobanks, multi-omics approach, artificial intelligence, and machine learning to better reflect the complexity of CI in α-synucleinopathies.

One of the aims of diagnostic nerve blocks is to identify the overactive muscles that lead to a specific spasticity pattern. However, to date, there is no evidence on how nerve blocks may affect botulinum neurotoxin-A (BoNT-A) dose in patients with spasticity. This case-control study aims to assess the role of diagnostic nerve block in defining BoNT-A starting dose at first treatment. Patients with upper and lower limb spasticity treated for the first time with BoNT-A were retrospectively divided into two groups: Group 1 (n = 43) was evaluated with clinical assessment and diagnostic nerve block; Group 2 (n = 56) underwent clinical assessment only. Group 1 was injected with higher BoNT-A doses in some muscles (i.e., flexor digitorum profundus, soleus), and received a higher BoNT-A cumulative dose with a larger number of injected muscles for some spasticity patterns (i.e., “clenched fist”, “flexed fingers”, “adducted thigh”). Diagnostic nerve block may help the clinician to optimize and personalize the BoNT-A dose since the first BoNT-A treatment.