パーキンソン病

BACKGROUND: Conventional deep brain stimulation (cDBS) is an established treatment for motor complications in Parkinson's disease, whereas adaptive deep brain stimulation (aDBS) adjusts stimulation in response to physiological or behavioral feedback. This review examines whether aDBS provides clinically meaningful advantages over cDBS for bradykinesia and akinesia, while also considering stimulation delivery, adverse effects, and non-motor outcomes. METHODS: A structured narrative review of relevant literature was conducted using PubMed/MEDLINE, Scopus, Web of Science, citation tracking, and focused searches. Evidence was grouped by comparison paradigm, adaptive control strategy, and outcome. RESULTS: The clinical evidence consists mainly of proof-of-concept investigations, brief crossover studies, feasibility studies, and small cohorts. Selected short-term comparisons generally did not detect a motor-outcome difference from cDBS, but most were underpowered for equivalence or non-inferiority. Several beta-guided paradigms reduced stimulation time or energy delivery, but this was not universal and cannot be assumed to indicate better symptom control, fewer adverse effects, or longer device life. No adequately powered large-scale randomized trial has demonstrated the clinical superiority of aDBS over optimized cDBS. Evidence concerning gait, speech, cognition, mood, and other neuropsychiatric outcomes remains limited. Interpretation is further restricted by differences in patient selection, stimulation targets, biomarkers, adaptive algorithms, medication states, outcome measures, follow-up, and timing after implantation. CONCLUSIONS: Adaptive DBS is technically feasible and offers a promising approach to individualized stimulation, but its comparative clinical value remains uncertain. Larger randomized trials with standardized outcomes and long-term follow-up are needed before superiority over conventional stimulation can be established.

BACKGROUND: Orthostatic hypotension (OH) is an important manifestation of cardiovascular autonomic dysfunction in Parkinson's disease (PD), but biomarkers associated with incident OH have not been well established. Cerebrospinal fluid (CSF) LRRK2 provides a measurable marker of LRRK2-related biology, but its association with incident OH is unknown. OBJECTIVE: To determine whether baseline CSF LRRK2 is associated with incident OH and whether this association differs between sporadic PD and LRRK2-PD. METHODS: We analyzed longitudinal Parkinson's Progression Markers Initiative (PPMI) data from 190 participants with PD, including 159 participants free of OH at baseline with follow-up orthostatic assessments. Cox proportional hazards models evaluated the association between standardized ln-transformed baseline CSF LRRK2 and time to incident OH, including a CSF LRRK2-by-genetic-group interaction and adjustment for age, sex, disease duration, and baseline systolic blood pressure change after standing. RESULTS: During follow-up, 52 of 159 participants developed OH. Higher baseline CSF LRRK2 was associated with a higher hazard of incident OH in sporadic PD (HR 10.50 per 1-SD higher ln-transformed CSF LRRK2, 95% CI 2.95-37.35; p < 0.001), whereas no clear association was observed in LRRK2-PD (HR 1.74, 95% CI 0.63-4.79; p = 0.284). The CSF LRRK2-by-genetic-group interaction was significant (interaction HR 0.166, 95% CI 0.083-0.331; p < 0.001) and remained consistent across sensitivity analyses. CONCLUSIONS: The association between baseline CSF LRRK2 and incident OH differed by genetic background. Baseline CSF LRRK2 was associated with incident OH in sporadic PD, whereas no clear association was observed in LRRK2-PD. Independent replication is required.

Polyamine homeostasis is tightly regulated by interconversion and catabolic pathways and has been increasingly implicated in neurodegenerative disorders, including Parkinson's disease (PD), where accumulation of α-synuclein (α-Syn) perturbs neuronal homeostasis. Spermidine/spermine N¹-acetyltransferase 1 (SAT1) occupies a central position in polyamine interconversion, and alterations in SAT1 activity have been linked to α-Syn toxicity and PD-related neuropathology. To investigate how SAT1 activity influences α-Syn-associated neurodegeneration, we employed a Drosophila model of neuronal α-Syn expression. SAT1 overexpression reduced α-Syn protein levels, altered its subcellular distribution within the brain, and mitigated α-Syn-induced lifespan shortening. Transcriptomic analyses showed that SAT1 modulates stress-associated gene expression in the α-Syn background, including attenuation of chaperone and ubiquitin-related responses and coordinated changes in pathways linked to mitochondrial function and amino acid metabolism. SAT1 co-expression partially restored α-Syn-associated alterations in genes involved in mitochondrial quality control, including USP30, Uch-L5R, RNF185, and the mitochondrial ornithine carrier SLC25A15. At the protein level, SAT1 increased mitochondrial-associated signal, enhanced LC3 association with mitochondrial compartments, restored LC3-II/LC3-I ratios in mitochondrial fractions, and reduced mitochondrial accumulation of α-Syn. Functional analyses further showed that SAT1 increased steady-state ATP levels and attenuated the ATP depletion induced by α-Syn expression. These findings indicate that SAT1 activity is associated with reduced α-Syn toxicity and preservation of mitochondrial homeostasis during α-Syn-associated stress.

Astrocytes are increasingly recognized as active drivers of neurodegeneration rather than passive responders. Single-cell and spatial transcriptomic analyses reveal that astrocytes occupy heterogeneous, regionally patterned states that align closely with selective neuronal vulnerability. Across Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, and rare primary astrocytopathies, astrocytes consistently converge on dysfunction across four mechanistic axes: breakdown of glutamate homeostasis, impaired ion and water buffering, lysosomal, and autophagic insufficiency, as well as maladaptive inflammatory-stress signaling. Spatial multi-omics demonstrates that these disruptions are not uniformly distributed but instead map to discrete niches, including plaque-adjacent astrocytes in Alzheimer's disease, CD44-high fibrotic-like astrocytes in the substantia nigra in Parkinson's disease, and EAAT2-low ventral horn astrocytes in ALS, consistent with patterns of selective neuronal vulnerability. Primary astrocytopathies including Alexander disease, vanishing white matter disease, and megalencephalic leukoencephalopathy illuminate the causal power of perturbing individual astrocytic modules, revealing how isolated disruptions in proteostasis, translation control, or ion-water coupling can initiate widespread neurodegeneration. By integrating neuropathological, imaging, and transcriptomic evidence across studies, we derive a consensus-based regional framework of astrocytic vulnerability across neurodegenerative diseases. Together, these findings define a unifying framework in which astrocytes transition from homeostatic regulators to pathological amplifiers, highlighting astrocyte states as tractable, region-specific therapeutic targets and illustrating how integration of spatial atlases with mechanistic insights might help develop a framework for targeted astrocyte therapies.

Parkinson's disease is strongly associated with mitochondrial dysfunction and impaired mitochondrial quality control, including defective mitophagy. Aerobic exercise is increasingly recognized as a safe and accessible intervention that can improve motor and non-motor outcomes in Parkinson's disease and may also engage mechanisms relevant to disease modification. In this review, we propose a context-dependent framework in which aerobic exercise reshapes nitric oxide signaling toward a more adaptive profile, characterized by relatively moderate, transient, and spatially restricted nitric oxide bioactivity, and we discuss how this shift may influence mitochondrial biogenesis, mitophagy initiation, and autophagic flux regulation. Rather than treating nitric oxide as uniformly protective or deleterious, we argue that its biological effects in Parkinson's disease depend on source, concentration, duration, subcellular localization, cellular target, and surrounding redox milieu. However, direct evidence that exercise-derived nitric oxide activates these pathways in Parkinson's disease-relevant neural tissue is still limited. We further highlight major translational gaps, including cell-type and brain-region heterogeneity, incomplete definition of exercise dose-response relationships, and the lack of validated in vivo biomarkers of neuronal mitophagy and nitric oxide dynamics in patients with Parkinson's disease. Overall, aerobic exercise is a plausible modulator of mitophagy-related pathways in Parkinson's disease, and nitric oxide is a credible contributor to this effect; however, the current evidence supports a multi-node, context-dependent model rather than a simple linear mechanism.