¶ MDS 2026 — Sleep and Circadian Disorders in Parkinson's Disease
Congress: Movement Disorder Society (MDS) International Congress 2026
Dates: October 4-8, 2026
Location: Seoul, Korea — COEX Convention and Exhibition Center
Theme: Understanding Aging in Movement Disorders
Sleep and circadian disorders represent among the most prevalent and clinically significant non-motor manifestations in Parkinson's disease (PD), affecting up to 90% of patients. These disturbances often precede motor symptoms by years or decades and serve as critical prodromal biomarkers for synucleinopathies. MDS 2026 will highlight advances in understanding the pathophysiology of sleep-circadian dysfunction, biomarkers for phenoconversion prediction, and emerging therapeutic approaches for these often underrecognized symptoms.
The bidirectional relationship between sleep disruption and neurodegeneration creates a self-reinforcing cycle: while alpha-synuclein pathology damages brainstem and hypothalamic circuits governing sleep-wake regulation, impaired sleep accelerates pathological protein accumulation through glymphatic system dysfunction and circadian disruption. This mechanistic interplay positions sleep-circadian disorders as both early diagnostic markers and potential disease-modifying intervention targets.
REM Sleep Behavior Disorder (RBD) is the strongest prodromal marker for alpha-synucleinopathies, with over 80% of individuals with isolated RBD eventually developing Parkinson's disease, Dementia with Lewy Bodies, or Multiple System Atrophy[@iranzo2013][@hogl2018]. The disorder is characterized by loss of normal skeletal muscle atonia during REM sleep, resulting in dream-enactment behaviors ranging from limb movements to violent thrashing, punching, and kicking.
Key epidemiological features:
- Prevalence in PD: 30-50% of patients
- Annual phenoconversion rate: 6-8% per year
- 5-year cumulative rate: ~35-41%
- Lifetime risk: >90%
The neurodegenerative process underlying RBD involves:
- alpha-synuclein deposition in brainstem nuclei controlling REM sleep, including the sublaterodorsal nucleus (SLD), locus coeruleus, and dorsal raphe nucleus
- Neuronal loss in REM-atonia generating regions
- Circuit disruption of glycinergic/GABAergic inhibition of spinal motor neurons
This aligns with the Braak staging model, where alpha-synuclein pathology begins in the lower brainstem (Braak stages 1-2) before ascending to the substantia nigra (stage 3) and cortex (stages 4-6). RBD corresponds to early Braak stages, explaining why it often precedes motor symptoms by years to decades[@galbiati2025].
Recent advances have improved prediction of which iRBD patients will convert to overt synucleinopathy[@miglis2021]:
| Biomarker Category |
Markers |
Predictive Value |
| Clinical |
Quantitative motor testing, olfactory function, autonomic testing |
Moderate |
| Neuroimaging |
DAT imaging, MRI volumetrics, FDG-PET metabolic patterns |
High |
| Fluid |
Alpha-synuclein SAA, neurofilament light chain, glial fibrillary acidic protein |
Very high |
| Electrophysiological |
EEG slowing, event-related potentials |
Moderate |
Alpha-Synuclein Seed Amplification Assays (SAA):
RT-QuIC and PMCA assays detect pathological alpha-synuclein in CSF with >90% sensitivity in iRBD patients, confirming the underlying synucleinopathy nature of the disorder.
Pharmacological:
- Clonazepam: 0.25-2 mg at bedtime; first-line treatment effective in ~80% of patients
- Melatonin: 3-12 mg at bedtime; preferred in patients with contraindications to clonazepam
Non-pharmacological:
- Environmental safety measures (padding floor, removing sharp objects, bed rails)
- Sleep hygiene optimization
¶ Insomnia and Sleep Fragmentation
Insomnia and sleep fragmentation affect the majority of PD patients, resulting from multiple converging mechanisms:
- Motor symptoms (tremor, rigidity, dyskinesias) disrupting sleep
- Nocturia
- Depression and anxiety
- Neurodegeneration of sleep-wake regulatory nuclei
- Dopaminergic medications
- Sleep onset insomnia: Prolonged time to fall asleep
- Sleep maintenance insomnia: Frequent nighttime awakenings
- Early morning awakening: Premature waking with inability to return to sleep
- Sleep hygiene optimization
- Cognitive behavioral therapy for insomnia (CBT-I)
- Melatonin supplementation
- Optimizing dopaminergic medication timing
Circadian dysfunction in PD arises from degeneration of multiple structures:
- Suprachiasmatic nucleus (SCN): The brain's master clock shows degeneration in PD
- Brainstem nuclei: Raphe nuclei, locus coeruleus, pedunculopontine nucleus
- Hypothalamic orexin neurons: Loss contributes to wakefulness instability
- Advanced sleep phase syndrome: Tendency to fall asleep and wake earlier
- Irregular sleep-wake pattern: Lack of consistent sleep schedule
- Reduced circadian amplitude: Weakened distinction between day and night
- Daytime sleepiness: Excessive somnolence not explained by nighttime sleep
Recent research reveals circadian clock gene dysregulation in PD[@chen2025]:
- BMAL1: Reduced expression in peripheral blood mononuclear cells
- PER2: Phase advance in expression pattern
- CRY1: Altered circadian amplitude
- REV-ERBα: Dysregulated as potential therapeutic target
- Light therapy: Morning bright light exposure to strengthen circadian rhythms
- Melatonin supplementation: For circadian alignment
- Chronotherapy: Timing of activities to align circadian rhythms
- Exercise timing: Morning/afternoon activity preferred
¶ Autonomic Dysfunction and Sleep
Autonomic dysfunction compounds sleep disturbances through multiple mechanisms:
- Orthostatic hypotension: Causes nighttime awakenings, sleep fragmentation
- Reduced heart rate variability: Impairs cardiovascular adaptation to sleep stages
- Blunted nocturnal blood pressure dipping: Disrupts normal sleep physiology
- Abnormal core body temperature rhythms
- Reduced nighttime temperature drop (normal nocturnal dip absent)
- Impaired sweating responses affecting sleep comfort
Autonomic testing provides important prognostic information:
- Cardiac sympathetic denervation (reduced 123I-MIBG uptake) predicts faster phenoconversion
- Orthostatic hypotension correlates with disease severity and RBD presence
- Prevalence in PD: 10-20% of patients
- Features: Uncomfortable sensations in legs at rest, worsened in evening, relieved by movement
- Association: Often correlates with disease severity and dopaminergic medication use
- Common comorbidity with RLS
- Can cause significant sleep fragmentation
- Dopaminergic agents (pramipexole, ropinirole, rotigotine)
- Gabapentin, pregabalin for refractory cases
- Prevalence: Up to 50% of PD patients
- Contributing Factors:
- Dopaminergic medications
- Sleep fragmentation
- Neurodegeneration of wakefulness-promoting nuclei
- Obstructive sleep apnea
- Epworth Sleepiness Scale
- Multiple Sleep Latency Test
- Modafinil or methylphenidate (with caution)
- Treatment of underlying sleep apnea
- Sleep hygiene optimization
Recent studies demonstrate actigraphy utility for tracking PD progression through sleep-wake pattern analysis[@suzuki2025]:
| Measure |
Utility |
| Sleep efficiency |
Diagnostic and progression marker |
| Circadian amplitude |
High for disease staging |
| Activity patterns |
Very high for progression tracking |
| Rest-activity rhythms |
Correlates with disease severity |
The recognition of iRBD as a prodromal synucleinopathy has catalyzed neuroprotective intervention development:
- Anti-alpha-synuclein immunotherapy
- GLP-1 receptor agonists (semaglutide, exenatide)
- Exercise interventions
- Iron chelation therapy
Genotype-Phenotype Correlations:
- GBA carriers: Earlier onset, more severe autonomic dysfunction, faster phenoconversion
- LRRK2 carriers: Lower RBD prevalence, distinct progression pattern
Subtype Stratification:
- Motor-predominant (likely PD conversion)
- Cognitive-predominant (likely DLB conversion)
- Autonomic-predominant (likely MSA conversion)
- Alpha-synuclein reduction (antisense oligonucleotides, siRNA, CRISPR)
- Neuroinflammation modulation (TNF-alpha inhibitors, microglial modulators)
- Neurotrophic factor support (BDNF mimetics, GDNF delivery)
- Circadian clock gene targeting (REV-ERBα modulators)
¶ Sessions and Presentations at MDS 2026
- RBD as Prodromal Marker: Update on Biomarkers and Trials
- Circadian Dysfunction in PD: From Mechanisms to Treatment
- Sleep Pharmacology in Movement Disorders
- Autonomic Contributions to Sleep Disruption
- Actigraphy and Wearable Sleep Monitoring
- Phenoconversion Prediction in Isolated RBD
- Novel Therapeutic Approaches for Sleep-Circadian Disorders
- MDS Congress 2026
- Postuma RB, et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain. 2019;142(3):744-759 (2019)
- Iranzo A, et al. Neurodegenerative disease status and post-mortem pathology in idiopathic REM sleep behaviour disorder. Lancet Neurol. 2013;12(5):443-453 (2013)
- Hogl B, et al. Idiopathic REM sleep behaviour disorder and neurodegeneration: an update. Nat Rev Neurol. 2018;14(1):40-55 (2018)
- Galbiati A, et al. REM sleep behavior disorder as a prodromal synucleinopathy. Curr Neurol Neurosci Rep. 2025;25:15 (2025)
- Miglis MG, et al. Biomarkers of conversion to alpha-synucleinopathy in isolated RBD. Lancet Neurol. 2021;20(8):671-684 (2021)
- Chen Y, et al. Circadian clock gene dysregulation in Parkinson's disease. NPJ Parkinson's Disease. 2025 (2025)
- Suzuki K, et al. Actigraphy as progression marker in PD sleep disorders. Mov Disord. 2025 (2025)
- Cesari M, et al. Polysomnographic features associated with clonazepam and melatonin treatment in isolated RBD. Sleep Med. 2024;115:14-21 (2024)