Parkinson's disease (PD) exhibits highly heterogeneous clinical trajectories, yet "advanced PD" (aPD) lacks a standardized definition. Current reliance on clinical milestones (e.g., motor fluctuations, cognitive decline) is limited by non-linear progression and the absence of objective measures. Although biomarkers like aggregated α-synuclein, MRI, and PET are under investigation, their correlation with clinical progression remains modest. Robust, reproducible endpoints are urgently needed to evaluate disease-modifying therapies across diverse phenotypes, accounting for genetic background, age of onset, co-pathologies, and motor/autonomic/cognitive domains. Given this complexity, single-target interventions are likely insufficient. We propose a multi-domain therapeutic framework for aPD that integrates: (A) simultaneous targeting of key pathological cascades, including α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, proteostasis imbalance, neuroinflammation, and the gut-brain axis; (B) biology-driven patient stratification using emerging biomarkers to match subgroups with targeted interventions; and (C) systematic management of comorbidities and lifestyle factors, such as cardiovascular health and exercise, to enhance neuroresilience. Finally, advancing aPD care requires addressing systemic determinants, including global healthcare inequities, and prioritizing caregiver well-being. Mechanistically informed, patient-centered strategies that combine multi-target therapies with precision stratification and holistic support will be essential to modify disease progression and improve long-term outcomes.

Synucleinopathies are a group of neurodegenerative disorders characterized pathologically by the presence of neuronal and/or oligodendrocyte inclusions composed of aggregated alpha-synuclein (αS). These disorders can be divided into two major sub-types: Lewy body disease and multiple system atrophy, which have distinct clinical and pathological profiles. As is seen with other neurodegenerative diseases, recent evidences suggest that the conformation and molecular organization of αS amyloid filaments deposited in brains might dictate the distinct pathological and clinical profiles in synucleinopathies. Resolving the structure of disease-specific αS aggregates becomes, therefore, of clinical interest. Until recently, the specific conformations of these aggregates at molecular resolution have remained elusive. This is now possible due to the advent and development of cryo-electron microscopy (cryo-EM) technology. This review aims to cover the recent advances in the structural biology of αS amyloid filaments implicated in synucleinopathies, raising a number of critical questions that continue to be investigated. What can we learn from these structures? What are the main structural differences between experimental systems and human tissue derived protein aggregates? What factors drive these differences? Do the amplified assemblies represent faithfully the seed structures? How these new findings improve our understanding of the molecular mechanisms behind fibril formation in disease? Can this knowledge be exploited for the design of diagnostic and therapeutical strategies? These aspects and the recent advances in the field will be addressed and discussed in this work.

ObjectiveA mixed methods study was conducted to investigate how clinical neuropsychologists engage with and provide cognitive assessment to persons living with Parkinson's disease (PD). Current practices were examined to identify service gaps and generate recommendations for future research.MethodAustralian neuropsychologists experienced in PD assessment were recruited to complete an online survey (N = 20) and semi-structured interviews (N = 5). Quantitative data was summarised descriptively. Qualitative data underwent coding reliability thematic analysis. Findings were combined through mixed methods integration to identify service gaps.ResultsIntegration revealed four service gaps for neuropsychologists when assessing persons living with PD. These were: (1) varied assessment practices across neuropsychologists; (2) infrequent engagement of neuropsychologists; (3) suboptimal test availability for PD assessment; and (4) limited integration of digital modalities within practice.ConclusionsThe findings provide preliminary observation into service gaps for neuropsychologists in PD assessment to help direct future research.

Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, and ALS remain some of the most challenging disorders to diagnose at an early stage. Conventional approaches rely on costly neuroimaging or invasive cerebrospinal fluid sampling, which limit accessibility and early intervention. Recent advances in 3D printing have enabled rapid prototyping of lab-on-chip (LOC) platforms that integrate microfluidics, biosensors, and biological models to detect disease-specific biomarkers with high sensitivity and throughput. Herein, we explore the synergistic role of 3D printing technologies and biomaterials in fabricating LOC systems for NDs. We highlight key biomarkers, and neuron- and organoid-on-chip platforms, and discuss the challenges and opportunities in clinical translation. By combining technical innovation in additive manufacturing with biological relevance, 3D-printed LOC devices represent a transformative approach toward precision diagnostics in neuro-medicine.

Mitochondrial complex I dysfunction, ATP depletion, and impaired autophagy are key features of Parkinson's disease (PD), but their causal relationship remains unclear. Although energy stress induces autophagy, autophagy execution requires ATP. Available evidence suggests a biphasic effect of ATP depletion on autophagy in PD, with mild early energy decline promoting autophagy and more severe ATP loss, below a critical threshold, suppressing its completion. This mechanism may contribute to the accumulation of dysfunctional mitochondria and other undegraded cargo, creating a vicious cycle in which mitochondrial dysfunction, ATP decline, and autophagy failure progressively reinforce one another in PD. Here, we review current evidence linking cellular energy status to autophagic dysfunction in PD and discuss its pathogenic and therapeutic implications.

Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are progressive neurodegenerative disorders characterized by alpha-synuclein pathology. As current therapies largely target symptoms, there is a clear need for disease-modifying treatments. Emerging evidence links these disorders to glucose metabolism dysregulation, suggesting antidiabetic agents may hold therapeutic potential.

Safinamide is a selective, reversible monoamine oxidase type B inhibitor (MAO-B inhibitor) used as an adjunct to oral levodopa in patients with Parkinson's disease (PD) experiencing motor fluctuations. Unlike other MAO-B inhibitors, safinamide possesses a dual mechanism of action, combining dopaminergic enhancement through MAO-B inhibition with modulation of abnormal glutamatergic transmission. In clinical practice, safinamide is primarily recognized for its ability to reduce motor fluctuations. However, its pharmacological profile suggests a broader therapeutic potential beyond dopaminergic modulation alone. Randomized controlled trials have shown that safinamide increases daily ON time without worsening troublesome dyskinesia. Nevertheless, reported effects on dyskinesia have generally been modest and inconsistent across studies. Clinical observations from longer-term follow-up and real-world studies suggest that improvements in dyskinesia and certain non-motor symptoms may emerge more gradually than the early motor benefits. Based on this observed pattern, it can be hypothesized that safinamide may exhibit a dual timeline of clinical effects, with early dopaminergic improvements in motor ON time followed by later modulation of dyskinesia and selected non-motor symptoms potentially mediated through glutamatergic mechanisms. On the basis of these pharmacological characteristics and clinical observations, a phenotype-oriented approach to patient selection for safinamide therapy may be considered. In addition, recognizing the potential for a dual timeline of therapeutic effects may help clinicians guide patients' expectations of treatment and interpret treatment response, as well as optimizing follow-up strategies in routine clinical practice.

Parkinson's disease is a neurodegenerative disorder characterized by degeneration of nigrostriatal dopamine neurons and basal ganglia dysfunction, with sex differences in risk and progression that are not yet fully understood. Here, we investigated how peripubertal loss of gonadal hormones influences nigrostriatal integrity, striatal synaptic architecture, and motor behavior in male mice. Using a castration model, we show that early androgen deprivation recapitulates key neuropathological and behavioral features of Parkinsonian hypodopaminergia, including reduced tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta, impaired motor performance on the vertical pole and rotarod, and disrupted forelimb kinematics. At the circuit level, androgen loss markedly reduced mushroom spine density on both direct- and indirect pathway striatal spiny projection neurons, with a concomitant increase in immature spine classes, consistent with impaired synaptic maturation. These structural and behavioral deficits were accompanied by reduced striatal Tyrosine receptor kinase-B (TrkB) protein, suggesting attenuation of brain derived neurotrophic factor (BDNF)/TrkB trophic signaling. Testosterone replacement preserved nigral dopaminergic neurons, normalized motor behavior, prevented mushroom spine loss across both striatal pathways, and selectively increased long/thin spines on direct-pathway neurons, suggesting enhanced synaptic plasticity. Together, these findings support a hormone-trophic model in which androgen signaling maintains nigrostriatal integrity and striatal synaptic maturation through androgen receptor-dependent BDNF/TrkB mechanisms. Although Parkinson's disease predominantly manifests with aging, these results suggest that early disruption of androgen signaling can produce lasting circuit-level alterations that influence vulnerability to degeneration over time, providing mechanistic insight into sex differences in Parkinson's Disease.