Lewy body disease (LBD) and Alzheimer’s disease (AD) are the most common causes of cognitive decline and dementia and are associated with characteristic alterations in resting-state electroencephalographic (rsEEG) activity. This multicenter exploratory study investigated periodic and aperiodic rsEEG features in patients with cognitive decline due to Lewy body disease (LBCD) and Alzheimer’s disease (ADCD), compared with cognitively unimpaired older adults (Nold), and examined the clinical relevance of these markers in LBCD. A total of 140 LBCD, 135 ADCD, and 118 Nold datasets from the PDWAVES archive underwent spectral parameterization to decompose rsEEG power spectra (1–30 Hz) into periodic peaks and aperiodic background activity. Both clinical groups showed a significant slowing of the individual alpha frequency (IAF), more pronounced in LBCD, along with reduced periodic alpha and beta power reflected in a lower vigilance index. The aperiodic exponent was elevated in both groups, and the aperiodic offset was also higher in LBCD, suggesting steeper spectral profiles consistent with increased inhibitory cortical tone. Within the LBCD group, poorer cognition was associated with higher low-frequency alpha power, whereas better cognition was predicted by higher high-frequency alpha power. A reduced vigilance index was associated with the presence of visual hallucinations, while no associations emerged for other symptoms. These findings suggest that combined periodic and aperiodic rsEEG features may provide relevant markers of altered vigilance regulation in LBCD. Future studies should evaluate whether these EEG markers can inform targeted interventions, such as neuromodulatory or audiovisual stimulation, to stabilize quiet-vigilance states and improve clinical outcomes. Panel A shows the spectral parameterization of rsEEG activity into periodic and aperiodic components. Panel B summarizes the main group differences in key rsEEG markers across LBCD, ADCD, and Nold participants. Panel C shows the topographical associations between the vigilance index and cognition and visual hallucinations in LBCD; colors reflect the direction and strength of the associations. For the visual hallucinations map, negative log-odds indicate lower odds of hallucinations for higher vigilance index values, whereas positive log-odds indicate higher odds; values around ± 1.5 correspond approximately to odds ratios of 0.22 and 4.5, respectively. Abbreviations: rsEEG, resting-state electroencephalography; LBCD, cognitive decline due to Lewy body disease; ADCD, cognitive decline due to Alzheimer’s disease; Nold, cognitively unimpaired older adults; IAF, individual alpha frequency; MMSE, Mini-Mental State Examination; p, standardized regression coefficient; log-odds, logistic regression coefficient.

Non-motor symptoms (NMSs) are highly prevalent in Parkinson’s disease (PD) and affect patients’ quality of life. Data on gender differences in NMSs are largely cross-sectional and derived from chronically treated populations. Longitudinal evidence in early, levodopa-naïve PD patients remains limited. This study aims to longitudinally investigate gender differences in a wide range of NMSs in early-stage levodopa-naïve PD patients during the first 2 years following levodopa initiation. This multicenter, prospective study enrolled 216 levodopa-naïve PD patients (139 men, 77 women) from 17 Italian movement disorder centers. Patients were evaluated at baseline and after 24 months (24 M) using validated scales. Baseline gender differences were explored using group comparisons. Gender effects at 24 M were examined using ANCOVA models adjusted for baseline values and levodopa dose at follow-up. At baseline, women showed greater cardiovascular and thermoregulatory autonomic dysfunction, higher anxiety, pain, fatigue, and worse quality of life, whereas men exhibited greater sexual dysfunction, daytime sleepiness, and better attentional performance. At the 24 M, gender differences persisted only for anxiety, pain, mobility, and emotional well-being, while additional significant differences emerged, including hypersexuality, visuo- spatial domain, and orthostatic-hypotension. Women exhibited greater symptom severity than men across all aforementioned variables, with the exception of hypersexuality. Gender significantly influences the expression and early evolution of NMSs in PD, independently of levodopa exposure. Gender-specific NMSs profiles are already evident in the first two years of treatment. These findings highlight the importance of integrating gender considerations into early assessment and personalized management of NMSs in PD.

OBJECTIVE:We evaluated the accuracy of standard machine learning (ML) algorithms in predicting 1-year cognitive decline in Alzheimer's disease patients with mild cognitive impairment (ADMCI) using resting-state electroencephalographic (rsEEG) biomarkers enriched with APOE genotype, sex, age, and educational attainment data. METHODS:The study analyzed datasets from 63 ADMCI patients obtained from an international archive. The ML algorithms included Simple Logistic Regression, Model Trees, Logistic Regression, K-nearest neighbor, and Support Vector Machine. Input features comprised lobar rsEEG source activities across delta (<4 Hz) to alpha (≈10-12 Hz) bands, cerebrospinal fluid (CSF Aβ1-42/p-tau), and structural magnetic resonance imaging (sMRI) biomarkers. Cognitive decline was assessed over a 1-year follow-up ("stable" vs. "decliner") based on Mini-Mental State Examination (MMSE) scores. RESULTS:The four independent ML algorithms accurately predicted changes in the MMSE score over a 1-year follow-up, with accuracies of 77-78% in ADMCI participants aged ≥ 70 years and 74-77% in those aged < 70 years. CONCLUSIONS AND SIGNIFICANCE:These findings suggest that rsEEG biomarkers in ADMCI patients may not only reveal underlying pathophysiological mechanisms affecting cortical arousal and vigilance but also hold predictive value for cognitive outcomes.

INTRODUCTION:We evaluated whether the brain glymphatic drainage function estimated by the diffusion tensor imaging along the perivascular space (DTI-ALPS) index relates to white matter (WM) integrity, Alzheimer's disease (AD) neuropathology, resting-state electroencephalogram (rsEEG) alpha rhythms underpinning quiet vigilance, and cognitive decline in mild cognitive impairment (MCI). METHODS:Clinical, neuroimaging, and rsEEG data were analyzed in matched mild cognitive impairment due to AD (ADMCI) and MCI not due to AD (noADMCI) participants. DTI-ALPS index and aperiodic and periodic components of the rsEEG power spectra were calculated following standard pipelines. RESULTS:Lower DTI-ALPS index was associated with higher AD neuropathology and WM lesions, lower periodic rsEEG alpha rhythms, and worse cognition in patients with ADMCI and noADMCI as a whole population, with the ADMCI (over noADMCI) group showing lower DTI-ALPS index, greater AD neuropathology, and lower periodic rsEEG alpha rhythms. CONCLUSIONS:The DTI-ALPS index may capture glymphatic system impairment linked to AD neuropathology, vigilance dysfunction, and cognitive decline in MCI.

Parkinson’s disease (PD) affects approximately 1

BACKGROUND AND OBJECTIVES:Substitution therapy with oral levodopa is the primary treatment of Parkinson's disease (PD). However, long-term levodopa use is associated with fluctuations in response and dyskinesia. These complications severely affect the patient quality of life. Fluctuation management in long-standing PD is poorly documented. The Parkinson's Disease Fluctuations treatment Pathway (PD-FPA) study was an Italian multicenter, observational study designed to describe how fluctuations are treated in patients with advanced disease. PATIENTS AND METHODS:Between July 2018 and December 2020, ten centres enrolled consecutive patients aged ≥18 years who had been diagnosed with PD 10-15 years before enrollment and had been experiencing fluctuations for at least 2 years before enrollment. Data on patient characteristics, PD stage, fluctuations, and treatments were collected at enrollment (T0) and prospectively at 6 months (T1) and 12 months (T2). Data were also collected retrospectively, at 1 and 2 years before T0. RESULTS:At T0, patients (n = 296, 60.1% male, mean age 68 years) had Hoehn and Yahr disease stage 2-3 and 47% had comorbidities (29.8% cardiovascular disease). PD stage and other PD assessment scores were overall stable during the entire 3-year observation period. Over 3 years, the use of dopamine agonists progressively decreased (51% of patients at T2), the use of monoamine oxidase-B inhibitors was stable (63%), while the use of catechol-O-methyltransferase inhibitors progressively increased (42%). Safinamide and opicapone showed the biggest increase in use over the 3-year observation period. Treatment changes were mostly prompted by fluctuations and were reported in about 50% of patients at T0 and 30% at T1 and T2. CONCLUSION:Maintenance of stable disease in patients with long-standing PD and fluctuations is feasible with non-invasive treatments. Accurate treatment adjustments and individualized strategies with new-generation add-on drugs may be of key importance.

As of today, levodopa remains the cornerstone of symptomatic management in Parkinson’s disease (PD). As PD progresses, the limitations of immediate-release (IR) levodopa/carbidopa, such as its short half-life and inconsistent absorption, result in unstable fluctuating levodopa plasma concentrations. These fluctuations contribute to motor complications including wearing off, delayed ON responses, and dyskinesias. To maintain symptom control, patients often require frequent dosing or, eventually, transition to device-aided therapies (DATs). Although effective, these therapies are invasive and require intensive clinical monitoring. IPX203, a next-generation modified-release (MR) levodopa/carbidopa formulation, may address these challenges. Approved by the US Food and Drug Administration (FDA) in 2024, IPX203 combines IR granules and extended-release (ER) pellets within a single capsule. IPX203 is designed to improve levodopa delivery and absorption, enhancing therapeutic benefit. It ensures both rapid onset and sustained levodopa plasma concentrations, minimising peak-to-trough fluctuations and reducing dosing frequency. The formulation delivers 100

The autotoxicity of the monoamine oxidase (MAO) reaction product 3,4-dihydroxyphenylacetaldehyde (DOPAL) is central to the “catecholaldehyde hypothesis”, which posits that interactions between DOPAL and the protein α-synuclein contribute to the degeneration of catecholaminergic neurons in Parkinson's disease (PD). Dopamine (DA) can undergo spontaneous or enzymatic oxidation, generating dopamine-quinone (DA-Q) and DOPAL, respectively. While growing evidence highlights the quinonization of numerous proteins in catecholaminergic cells due to the high reactivity of DA-Q, the electrophilic properties of DOPAL and its quinone derivative (DOPAL-quinone, DOPAL-Q) have received less attention, along with potential detoxification pathways.Here, we propose a refinement of the “catecholaldehyde hypothesis” by extending the detoxification machinery described for 3-glutathionyl-4-hydroxynonenal (GS-HNE) to the formation of glutathionylated DOPAL adducts. Conjugation of DOPAL-Q with glutathione (GSH) would generate 5-S-glutathionyl-3,4-dihydroxyphenylacetaldehyde (GS-DOPAL). Analogous to GS-HNE, the aldehyde group of GS-DOPAL could be reduced to 5-S-glutathionyl-3,4-dihydroxyphenylethanol (GS-DOPET) by glutathione-dependent aldehyde reductases such as aldose reductase (AKR1B1) and carbonyl reductase 1 (CBR1). Conversely, oxidation of the phenolic hydroxyl groups by CBR1 to yield 5-S-glutathionyl-3,4-dioxophenylacetaldehyde (GS-DOPAL-Q) may also occur. We suggest that the excretion of such GS-adducts via glutathione-electrophile transporters could open new perspectives for identifying early biomarkers of PD and for evaluating the disease-modifying potential of MAO inhibitors.

Unsupervised serious video games on the SmartMe You home telemonitoring platform may enable the assessment of cognitive fluctuations in older individuals, with or without cognitive deficits. Here, we tested their validity in cognitively unimpaired older adults (Healthy) and patients with mild cognitive impairment and mild to moderate dementia due to Parkinson’s disease (PDCD). Such validity was assessed using Mini-Mental State Examination (MMSE) scores and resting-state eyes-closed electroencephalography (rsEEG) activity. Clinical, demographic, and rsEEG datasets were collected from 34 healthy and 68 PDCD participants. The SmartMe You video games included 7 unsupervised cognitive tasks implemented on a commercial tablet. The rsEEG source activities in the individual delta, theta, and alpha frequency bands were estimated using the eLORETA freeware. As novel findings, we showed that game performance: (1) discriminated between healthy participants and PDCD patients, with overall accuracy exceeding 90

Parkinson's disease (PD) is often associated with depression, which poses an additional burden for patients and their families. However, evidence regarding the optimal treatment for depression in PD remains limited, with insufficient data supporting the efficacy of most antidepressant drugs. The primary objective of this pilot, prospective, open-label, single-arm study was to analyze the safety and tolerability of vortioxetine drops on depressive symptoms in PD patients over 16 weeks of treatment. The secondary objective was to study vortioxetine's effectiveness on depression. Sixteen out of 20 PD patients who completed the study demonstrated that the treatment was safe and well tolerated; no change in PD symptom severity, abnormality of clinical parameters, body weight, or ECG emerged. The most common side effect was nausea. Depressive symptoms rated by the Beck Depression Inventory and the Hamilton Depression Rating Scale score (HAM-D-17) showed a significant improvement at the end of the study period without a worsening of motor functions, as measured by UPDRS part III. The majority of patients also reported an improvement in depressive symptoms measured by the Patient Global Impression of Improvement scale. Vortioxetine is a safe and well-tolerated therapeutic approach for depression in Parkinson's disease. As a secondary objective, an improvement in depressive symptoms was observed. However, the study's open-label design and small sample size limit the generalizability of the findings.

Background and aimsParkinson’s disease (PD) is a neurodegenerative disorder for which no disease-modifying therapy currently exists, making it crucial to investigate alternative strategies that may slow its progression. The PRIME study will investigate the effects of combined dietary and physical activity interventions- performed in rehabilitative settings with health professional supervision and evaluation, versus single interventions on the gut microbiome in PD. The aim is to identify microbiome profiles – comparing traditional 16s rRNA gene sequencing with the third-generation method – as potential non-invasive, stage specific biomarkers of PD. In addition, the study will assess whether the combined intervention affects disease progression, symptoms, cognitive abilities, and quality of life.MethodsEighty participants with PD will be randomized into four arms: a Mediterranean-diet intervention group; a structured physical-activity group; a combination group receiving both dietary and exercise interventions; a control group receiving standard care only.ConclusionBy integrating microbiome characterization with the evaluation of these interventions, the study aims to explore whether intervention-induced changes in the microbiota are associated with clinical improvement in PD, thus paving the way for the design of future non-pharmacological protocols to slow disease progression, mitigate symptom severity, and promote diagnosis.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT07097103.

BACKGROUND:Citicoline is a promising therapeutic option for improving both motor and non-motor symptoms in Parkinson's disease (PD) beyond levodopa and other standard dopaminergic treatments. OBJECTIVES:The CITIPARK study evaluated the efficacy and safety of citicoline in improving clinical outcomes and quality of life (QOL) in PD patients on dopaminergic therapies. METHODS:The randomized, double-blind, multicenter trial compared citicoline (1000 mg/day intramuscular, two six-week cycles) with placebo for 24 weeks in PD under stable medications. The primary endpoint was change in Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) total score; secondary endpoints included motor and non-motor subscores, QOL, clinical global impression (CGI) and safety. RESULTS:The study enrolled 485 participants, randomizing 474 (citicoline: 303; placebo: 171). Citicoline significantly increased the likelihood of achieving a minimal clinically important difference compared with placebo (OR 2.06, 95% CI 1.06-3.99; P = 0.031) on the MDS-UDPRS total score in the modified intention-to-treat population. Among secondary outcomes, the citicoline group showed greater improvement in motor function (MDS-UPDRS III -2.97 vs -0.13; p = 0.009) and a greater improvement on CGI -II and CGI-III (3.26 vs 3.59; p = 0.021 and 9.30 vs 10.38; p = 0.018, respectively). AEs occurred in 22.1% and 27.1% of the citicoline and placebo groups, respectively. CONCLUSIONS:Citicoline was well tolerated and associated with motor benefits compared with placebo in a highly compliant population. The results suggest a role of citicoline as a safe and possibly effective supportive therapy in PD treated with concomitant dopaminergic agents.

BACKGROUND:Prasinezumab has previously shown potential for reducing the progression of motor signs (Movement Disorder Society-sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III) in patients with early-stage Parkinson's disease who were treatment-naive or receiving monoamine oxidase type B (MAO-B) inhibitors. The aim of the PADOVA trial was to evaluate the efficacy and safety of prasinezumab in a broader population of patients receiving stable symptomatic medication. METHODS:This phase 2b, multicentre, double-blind, parallel-group, placebo-controlled, randomised, superiority trial recruited participants with early-stage Parkinson's disease (age 50-85 years, 3 months to 3 years from diagnosis, Hoehn and Yahr stage 1 or 2) on stable symptomatic medication from 110 centres in nine countries in Europe and North America. Participants were individually randomly assigned (1:1) via permuted blocks (stratified by symptomatic medication [levodopa or MAO-B inhibitor]) to intravenous prasinezumab (1500 mg) or placebo every 4 weeks for at least 76 weeks and until the target number of motor progression events was reached. Participants, investigators, and clinical assessors were masked to group assignment. The primary endpoint was time to a confirmed motor progression event (≥5-point increase in MDS-UPDRS Part III off-medication score), assessed in the full analysis set (all randomly assigned participants according to the treatment to which they were assigned). Safety and tolerability were assessed in all randomly assigned participants who received at least one dose of study drug, with participants grouped according to treatment received. The trial is registered with ClinicalTrials.gov (NCT04777331) and EudraCT (2020-004997-23), and is active, not recruiting. FINDINGS:Between May 5, 2021, and March 22, 2023, 787 individuals were screened. 586 were enrolled and randomly assigned (n=293 per group; mean age 64·2 years [SD 7·3]; 214 [37%] female and 372 [63%] male); 550 completed double-blind treatment (prasinezumab, n=277; placebo, n=273). The primary endpoint was not met; the primary analysis showed a non-significant delay in motor progression with prasinezumab versus placebo (hazard ratio 0·84 [95% CI 0·69-1·01]; p=0·066); median time to confirmed motor progression in the prasinezumab group was 61·1 weeks (95% CI 52·3-71·9), compared with 49·7 weeks (40·1-58·1) in the placebo group. The incidence of one or more serious adverse events was similar between groups (prasinezumab, 34 [12%] of 292; placebo, 34 [12%] of 290) and three recorded deaths were unrelated to the study drug (prasinezumab, n=1 [<1%]; placebo, n=2 [1%]). INTERPRETATION:Although PADOVA did not meet the primary endpoint, prespecified exploratory evidence suggests clinical activity of prasinezumab in early-stage Parkinson's disease, supporting continued investigation in the ongoing phase 3 PARAISO trial (NCT07174310). FUNDING:F Hoffmann-La Roche.

OBJECTIVES:This exploratory study tested the hypothesis that Huntington's disease (HD) is characterized by distinct abnormalities in resting-state electroencephalographic (rsEEG) rhythms compared to Alzheimer's disease (AD). METHODS:Clinical and rsEEG data were collected from 35 patients with HD, 81 patients with AD, and 102 healthy controls (HC). The rsEEG cortical source activations from 30 electrodes were estimated using eLORETA and were harmonized across clinical sites. RESULTS:Compared to the HC group, both the HD and AD groups showed widespread increases in rsEEG delta source activation and decreases in alpha source activation, with the HD patients exhibiting the most pronounced frontal effects. In patients with HD, those abnormal rsEEG source activations were associated with cognitive, motor, and functional deficits. CONCLUSIONS:Patients with HD were characterized by a particular slowing of frontal rsEEG rhythms associated with clinically relevant variables. SIGNIFICANCE:A topographically widespread slowing of cortical oscillatory activity was observed in both HD and AD groups, with a particularly pronounced frontal effect in HD, which may predict a greater impact on the sleep-wake cycle. These observations should be considered exploratory and need validation in future studies with enhanced vigilance monitoring during longer rsEEG recordings.

Primary results from the 24-week EPSILON study (NCT04978597) showed that adding opicapone to levodopa in non-fluctuating Parkinson's patients significantly improved motor impairment without increasing the development of motor complications versus placebo. All participants finishing the double-blind phase became eligible for open-label treatment with opicapone. Symptomatic efficacy of opicapone was maintained with 1-year open-label treatment (adjusted-mean ± SE change in MDS-UPDRS motor score from double-blind baseline to Week 76: −7.4 ± 0.81); participants who switched from placebo to opicapone had a motor improvement of −6.1 ± 0.79. At Week 76, 80.2% of opicapone-opicapone-treated participants remained motor complication-free versus 69.7% in the placebo-opicapone group (p = 0.1).

Dopaminergic drugs represent the cornerstone in the symptomatic management of Parkinson's disease motor manifestations, although their long-term use is associated with the appearance of motor fluctuations and dyskinesias. The correlation between pulsatile plasmatic levels of dopaminergic drugs and motor complications suggested that a central continuous dopaminergic stimulation (CDS) could prevent their development. Therefore, several methods have been implemented to provide more stable plasmatic levels of dopaminergic drugs and obtain a continuous drug delivery (CDD). Nevertheless, CDD does not necessarily mean CDS, since other peripheral pharmacokinetic factors intervene before the striatal dopamine release, along with central pharmacodynamic mechanisms. Here, we provide an overview of the different pharmacological approaches taken over time to reach CDS, with limitations and questions that remain open.

Sedentary behavior is a recognized and modifiable risk factor for cognitive decline and dementia across neurodegenerative conditions. This study used a smartwatch-based telemonitoring procedure combined with ecological cognitive assessment to examine whether step counts can capture sedentary behavior and its association with cognitive functioning in patients with mild cognitive impairment (ADMCI) and dementia (ADD) due to Alzheimer’s disease. Then, 19 ADD, 28 ADMCI, and 23 cognitively unimpaired older adults (Nold) were consecutively recruited. Participants underwent clinical assessment, resting-state electroencephalography (rsEEG), and neuropsychological testing. They were then monitored at home for approximately one week using Samsung Galaxy Watch 4–6 devices recording step counts (total, purposeful, and incidental) and activity intensity (peak 30-min cadence), together with the unsupervised SmartMe You-TELEMAIA serious videogame battery administered on a commercial tablet for cognitive assessment. The ADD group showed reduced step counts and lower peak cadence than both ADMCI and Nold participants, whereas rsEEG markers and cognitive measures discriminated the three groups with a graded pattern. Within the AD sample, smartwatch-derived activity metrics were associated with cognitive functioning as assessed by conventional neuropsychological testing and ecological serious videogame performance, but showed limited associations with rsEEG rhythms. EEG delta and alpha rhythms were also more abnormal in the ADD group than in the ADMCI group. Home-based daytime activity monitoring with commercial smartwatches indicated that step volume and intensity are associated with cognitive status in patients with ADMCI and ADD. These findings suggest that smartwatch-derived activity metrics may provide feasible and cost-effective markers of everyday functioning in Alzheimer’s disease. a Schematic overview of the study design, including resting-state EEG, one-week smartwatch-based activity monitoring, and unsupervised ecological cognitive assessment with the SmartMe You-TELEMAIA Platform. b Group differences in daily activity metrics across participants with Alzheimer’s disease with dementia (ADD; N = 19), Alzheimer’s disease with mild cognitive impairment (ADMCI; N = 28), and cognitively unimpaired older adults (Nold; N = 23), indicating reduced daily step volume and peak cadence mainly in ADD. c Representative significant associations within the AD clinical sample (ADD + ADMCI; up to N = 47), showing that step metrics were more closely related to cognition (MMSE) and depressive symptom severity (BDI-II) than to resting-state EEG activity, for which only limited associations emerged.

Alzheimer's disease (AD) dementia is associated with marked disruptions in resting-state eyes-closed electroencephalographic (rsEEG) rhythms, particularly in the periodic alpha band (8-12 Hz), suggesting impaired vigilance regulation. In contrast, the aperiodic rsEEG component, reflecting global cortical arousal, has been reported to remain unchanged. This exploratory study examined periodic and aperiodic EEG activity in patients with mild cognitive impairment due to AD (ADMCI) during transitions from quiet wakefulness to light sleep. EEG datasets (∼30 min) from 19 ADMCI patients and 18 matched cognitively unimpaired older adults (control) were analyzed. Vigilance stages were scored using a reduced version of Hori's system, distinguishing the alpha-dominant wakefulness stage and the theta-dominant light sleep (ripples) stage. EEG spectra were parameterized using the specparam algorithm. ADMCI participants showed reduced reactivity of individual alpha power between the wakefulness and ripples stages compared to the control group. Conversely, both groups exhibited comparable increases in fronto-central theta power and steepening of the aperiodic slope and offset. No group differences emerged in aperiodic exponent and offset, although statistical power was limited by modest sample size. Overall, EEG alpha rhythms reflecting vigilance regulation are disrupted in prodromal AD, while periodic and aperiodic signatures of sleep onset are relatively preserved, suggesting selective vulnerability of attentional thalamocortical systems.

Parkinson's disease (PD) is now recognized as a multisystem, heterogeneous neurodegenerative disease with fluctuating trajectories and complex symptom profiles. Despite therapeutic advances, many patients (particularly women and those in late stages) and their caregivers face substantial unmet needs across physical, psychological, social, and spiritual domains, which highlight the need for a more integrative care model. Palliative care, defined as holistic, person-centered care for individuals with life-limiting illnesses, is increasingly recognized as particularly relevant in PD, from early to terminal stages. However, its implementation in neurology remains limited, notably due to persistent misconceptions, and delayed or absent referrals. This narrative review therefore aims to equip PD care teams with a clearer understanding of palliative care principles and their applicability to PD, by synthesizing emerging evidence in neuropalliative care, and providing practical recommendations for integration into routine neurological practice. Building on the specificities of quality of care for chronic conditions, optimal neuropalliative care in PD involves regular (re)assessment of symptoms and priorities, effective management of the chronic-palliative interface, good communication, continuity of care (including neurological care until the end of life), and a multidisciplinary network of professionals working both in the community and in specialized clinics, while leaving room for the involvement of caregivers. Far from being "the end of the road", neuropalliative care is a strategic and compassionate response to the evolving complexity of PD, which ultimately enhances quality of life, supports families, and reinforces the neurologist's pivotal role in longitudinal, person-centered care.