Management of Early-stage Parkinson Disease

Educational Objectives

The goal of this program is to improve the management of early Parkinson disease. After hearing and assimilating this program, the clinician will be better able to:

1. Analyze the relationship between hyposmia, constipation, and the risk for Parkinson disease.
2. Evaluate the role of α-synuclein skin biopsy in the diagnosis of Parkinson disease.

Summary

Early Parkinson disease (PD): progresses through 3 stages, ie, preclinical, prodromal, and clinical; in the preclinical stage, neurodegeneration occurs without noticeable symptoms; the prodromal stage involves subtle, nonmotor symptoms (eg, hyposmia, constipation, rapid eye movement [REM] sleep behavior disorder [RBD]), which are insufficient for diagnosis but may appear 5 to 20 yr before motor symptoms; the clinical stage is marked by classic motor symptoms, eg, tremors, rigidity; a key theory of PD pathophysiology involves aggregation of α-synuclein into Lewy bodies, spreading from peripheral areas to the brainstem and eventually the substantia nigra; early symptoms like hyposmia (present in >80% of early cases) are being studied as potential markers for early diagnosis and recruitment for neuroprotective clinical trials, despite their low specificity in the general elderly population

REM sleep behavior disorder: a notable premotor marker for PD, with high specificity but low sensitivity; ≈50% of PD patients experience RBD, and ≈65% of those with RBD develop PD within 10 yr (develops after motor symptoms begin in ≈50% of patients); autonomic symptoms, particularly constipation, are common in early PD, showing good sensitivity but low specificity because of their prevalence in the general population; objective markers of cardiac autonomic dysfunction, eg, heart rate variability (measured by electrocardiography or Holter monitors) and metaiodobenzylguanidine scans (assess postganglionic sympathetic neuron integrity), show abnormalities in most PD and RBD patients, warranting further exploration

Depression: a potential premotor marker for PD but has low sensitivity (30%-40% of patients) and low specificity because of its prevalence in the general population; visual abnormalities (eg, issues with saccades, retinal imaging, reduced color vision) show some promise as markers but require further research; polysomnography (PSG)-confirmed RBD is highly predictive, increasing PD risk by 130-fold; neurogenic orthostatic hypotension is associated with 18.5-fold increased risk; hyposmia is linked to 6.4-fold increased risk; combining markers significantly raises predictive accuracy, eg, having constipation, RBD, and hyposmia increases risk 160-fold (having >5 markers, >1325-fold increased risk)

Predictive clinical markers for PD: hyposmia — best assessed using the University of Pennsylvania Smell Identification Test, a 40-item test (with a shorter 12-item version) that provides age- and sex-normative values; scores <20th percentile are considered abnormal; constipation — scales assessing nonmotor symptoms include questions about bowel habits, specifically <3 bowel movements (BM) per week and straining frequency; 1 BM every 2 days increases PD risk by 2.62-fold, and 1 every ≤3 days, by 3.93-fold; quantifying BMs is critical, as patients may not recognize chronic constipation because of long-term normalization of their symptoms

Diagnosing RBD: gold standard for diagnosis is PSG, following criteria from International Classification of Sleep Disorders; diagnosis requires repeated episodes of sleep-related vocalizations or complex motor behaviors, confirmed by PSG showing REM sleep without atonia; behaviors must not be better explained by other conditions, eg, sleep apnea, medications (eg, selective serotonin reuptake inhibitors), psychiatric disorders, substance use, or epilepsy

Screening questionnaires for RBD: have moderate sensitivity (70% range) but poor specificity (40%-60%); in a study of 400 patients, only 30 with positive questionnaires were confirmed to have RBD via PSG; Single-Question Screen (RBD1Q; “do you know or suspect that you have movements where you act out your dreams, eg, flailing, kicking, punching, running?”) had best specificity; sleep experts demonstrated high specificity (96.3%) but similar sensitivity (70%); in clinical practice, RBD1Q may be the most reliable initial screening tool

Diagnosis: the best diagnostic tool for early PD is a thorough history and physical examination; a clinical diagnosis can be made based on bradykinesia plus rigidity or resting tremor, supported by features like unilateral onset and the absence of red flags; additional diagnostic tools should serve as secondary adjuncts to clinical findings; dopamine transporter (DAT) scan — uses ioflupane with single photon emission computed tomography to assess presynaptic dopamine transporter integrity in the basal ganglia; useful for distinguishing PD from essential tremor and drug-induced parkinsonism but less helpful in differentiating PD from atypical syndromes, as all typically show abnormal DAT scans; while DAT scans may sometimes show asymmetry in PD compared with the symmetry in atypical syndromes, this is not definitive

α-synuclein skin biopsy: detects phosphorylated α-synuclein in cutaneous nerve fibers and involves 3 punch biopsies to improve sensitivity; while it has good sensitivity and specificity for PD, its clinical utility is still under investigation; it may help differentiate PD from secondary parkinsonism (eg, drug-induced) and synucleinopathies from tauopathies (eg, PSP, corticobasal degeneration); however, its role in distinguishing PD from essential tremor is unclear, as some essential tremor cases also show abnormal biopsies; preliminary findings suggest differences in deposition patterns and nerve fiber density between PD and MSA, but further research is needed; the biopsy should complement clinical evaluation, as abnormal results can occur in patients without PD symptoms, complicating interpretation

American Academy of Neurology 2021 guidelines: reviewed high-quality evidence on PD treatments; compared the efficacy of levodopa (LEV), dopamine agonists (DAs), and monoamine oxidase type B (MAO-B) inhibitors for motor symptoms, focusing on randomized controlled trials; LEV was more effective than DAs in improving the Unified PD Rating Scale Part 3 motor score over 5 yr; however, many patients randomized to DAs also received supplemental LEV, which may have minimized the observed differences between the 2 groups; adverse effects — LEV was associated with a slightly higher risk for dyskinesia, while DAs had a greater risk for hallucinations over 5 yr; however, this difference may have been minimized since the study focused on patients with early PD, who likely had no significant cognitive impairment; DAs were also linked to a higher likelihood of treatment discontinuation due to adverse effects

LEV vs MAO-B inhibitors: showed inadequate data to assess their effect on motor symptoms; there was a trend toward a higher risk for dyskinesia with both treatments; regarding treatment discontinuation due to adverse effects, the evidence was also limited; when comparing different formulations of LEV (immediate-release vs controlled release or combined with entacapone) and DAs (immediate- vs extended-release), there was insufficient evidence to suggest significant differences between them

Dopamine agonists: more likely to cause impulse control disorders at 2 yr (moderate confidence); LEV may be more likely than ropinirole to cause disabling dyskinesias after 5 yr (low confidence); a study comparing patients in Italy and Ghana showed that delayed treatment with LEV (due to poor access to care in Ghana) led to earlier motor fluctuations (MF), concluding that MFs and dyskinesias are more strongly associated with longer disease duration and higher LEV daily doses; a recent follow-up study from the LEAP trial found no difference in disease progression or prevalence of MFs between early vs delayed start with LEV; however, a separate study showed that higher LEV doses (>600 mg) were associated with a greater proportion of patients experiencing dyskinesia and “wearing off” effects; delaying LEV treatment may negatively impact quality of life; LEV-sparing therapies result in worse outcomes in mobility, daily activities, stigma, cognition, communication, and bodily discomfort (Gray et al, 2022)

Readings

Ahmad MH, Rizvi MA, Ali M, et al. Neurobiology of depression in Parkinson’s disease: Insights into epidemiology, molecular mechanisms and treatment strategies. Ageing Res Rev. 2023;85:101840. doi:10.1016/j.arr.2022.101840; Bidesi NSR, Vang Andersen I, Windhorst AD, et al. The role of neuroimaging in Parkinson’s disease. J Neurochem. 2021;159(4):660-689. doi:10.1111/jnc.15516; Bloem BR, Okun MS, Klein C. Parkinson’s disease. Lancet. 2021;397(10291):2284-2303. doi:10.1016/S0140-6736(21)00218-X; Cabreira V, Massano J. Doença de Parkinson: Revisão Clínica e Atualização [Parkinson’s Disease: Clinical Review and Update]. Acta Med Port. 2019;32(10):661-670. doi:10.20344/amp.11978; Chen R, Gu X, Wang X. α-Synuclein in Parkinson’s disease and advances in detection. Clin Chim Acta. 2022;529:76-86. doi:10.1016/j.cca.2022.02.006; Gray R, Patel S, Ives N, et al; PD MED Collaborative Group. Long-term effectiveness of adjuvant treatment with catechol-o-methyltransferase or monoamine oxidase b inhibitors compared with dopamine agonists among patients with Parkinson disease uncontrolled by levodopa therapy: The PD MED randomized clinical trial. JAMA Neurol. 2022 Feb 1;79(2):131-140. doi: 10.1001/jamaneurol.2021.4736. PMID: 34962574; PMCID: PMC8715387; Jankovic J, Tan EK. Parkinson’s disease: Etiopathogenesis and treatment. J Neurol Neurosurg Psychiatry. 2020;91(8):795-808. doi:10.1136/jnnp-2019-322338; Maggi G, Vitale C, Cerciello F, et al. Sleep and wakefulness disturbances in Parkinson’s disease: A meta-analysis on prevalence and clinical aspects of REM sleep behavior disorder, excessive daytime sleepiness and insomnia. Sleep Med Rev. 2023;68:101759. doi:10.1016/j.smrv.2023.101759; Munhoz RP, Tumas V, Pedroso JL, et al. The clinical diagnosis of Parkinson’s disease. O diagnóstico clínico da doença de Parkinson. Arq Neuropsiquiatr. 2024;82(6):1-10. doi:10.1055/s-0043-1777775; Rajan S, Kaas B. Parkinson’s disease: Risk factor modification and prevention. Semin Neurol. 2022;42(5):626-638. doi:10.1055/s-0042-1758780; Regensburger M, Ip CW, Kohl Z, et al. Clinical benefit of MAO-B and COMT inhibition in Parkinson’s disease: Practical considerations. J Neural Transm (Vienna). 2023;130(6):847-861. doi:10.1007/s00702-023-02623-8; Tolosa E, Garrido A, Scholz SW, et al. Challenges in the diagnosis of Parkinson’s disease. Lancet Neurol. 2021;20(5):385-397. doi:10.1016/S1474-4422(21)00030-2; Woitalla D, Buhmann C, Hilker-Roggendorf R, et al. Role of dopamine agonists in Parkinson’s disease therapy [published correction appears in J Neural Transm (Vienna). 2024 Sep;131(9):1145. doi: 10.1007/s00702-023-02695-6]. J Neural Transm (Vienna). 2023;130(6):863-873. doi:10.1007/s00702-023-02647-0.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Malatt was recorded at The X Cedars-Sinai Parkinson’s Disease and Movement Disorders Annual Symposium, held November 2, 2024, in Culver City, CA, and presented by Cedars-Sinai Medical Center. For information about upcoming CME activities from this presenter, please visit Cedars.cloud-cme.com. Audio Digest thanks the speakers and Cedars-Sinai Medical Center for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

NE160302

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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