The North American Prodromal Synucleinopathy study: protocol for a multi-site, longitudinal, observational study of idiopathic/isolated rapid eye movement sleep behavior disorder

Abstract

Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a usually prodromal manifestation of neurodegenerative disorders with α-synuclein pathology: Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Clinical trials in the iRBD population face substantial barriers: limited access to well-characterized cohorts, inconsistent assessment protocols across centers, and the absence of validated biomarkers of disease burden. The North American Prodromal Synucleinopathy (NAPS) Consortium was established to address these challenges and facilitate clinical trials for neuroprotective therapies targeting synucleinopathy at the earliest known stages. In this multi-site, longitudinal, observational study, nine academic centers across North America will enroll and follow over 500 individuals with iRBD from existing sleep centers. Sixty control participants, matched for age, sex, and race will also be recruited. A harmonized protocol-including a standardized clinical battery assessing motor, cognitive, autonomic, psychiatric, sensory, and sleep function; structured diagnostic adjudication; biospecimen collection; and centralized analysis of both polysomnography and neuroimaging data-is outlined herein and reflects NAPS Stage 2. Each participants completes these assessments annually, and are replaced in the event of phenoconversion. By unifying assessments and expanding geographic reach, NAPS lays the groundwork for efficient, well-powered clinical trials designed to delay or prevent progression of iRBD to overt PD, DLB, or MSA-ultimately enabling earlier, more effective therapeutic intervention for neurodegenerative disease. Registered at clinicaltrials.gov (NCT05826457).

Keywords: Lewy body disease; Parkinson disease; REM sleep behavior disorder; clinical trial protocol; neurodegenerative diseases; prodromal symptoms; synucleinopathies.

Figure 1

The NAPS Consortium. The 9 sites comprising the NAPS Consortium across North America (only NAPS2 study sites listed).

Figure 2

Flowchart outlining study activities. Each participant with iRBD presents for screening evaluation where a PSG is reviewed to confirm REM sleep without atonia and concomitant dream enactment behavior consistent with iRBD. Those with uncertainty around the diagnosis but are from underrepresented groups in medicine obtain a PSG within NAPS2. A complete battery of questionnaires and objective assessments is performed. All eligible participants undergo blood draws, lumbar punctures, neuroimaging assessments and a PSG (if not already completed as part of NAPS2 at enrollment). All procedures are repeated on an annual basis except the imaging and PSG components which are completed once more at a 2-year interval. Those who phenoconvert will continue to be followed in the same manner. All iRBD participants are offered autopsy in the event of death. The protocol for control participants is the same except no imaging procedures are performed. ^*Lumbar punctures are considered optional and NAPS investigators anticipate approximately 25% consent. DaTScan, Dopamine Transporter Scan.

Figure 3

Flowchart for achieving consensus cognitive diagnosis. Any participant lacking cognitive complaints can be categorized as having normal cognition or quantitative cognitive impairment based on neuropsychological testing. Anyone with a cognitive complaint will be classified as “subjective cognitive impairment” in the absence of abnormal testing or MCI or dementia in the presence of abnormal testing. MCI can be further subtyped based on the domains affected. Dementia can be further subtyped into a specific degenerative cause or a non-degenerative cause (as can be seen with certain affective disorders). CDR, clinical dementia rating scale; NOS, not otherwise specified.

Figure 4

Flowchart for achieving consensus motor diagnosis. Any participant lacking subjective motor complaints or abnormalities on the motor exam are classified as having normal motor function or quantitative motor impairment based on their performance on quantitative testing. Quantitative tests include timed up-and-go, Purdue Pegboard, and the alternate tap test. If an alternate etiology is considered unlikely, then a diagnosis of Parkinson’s disease or related disorder is rendered. In the absence of Parkinsonism and cerebellar findings, then a diagnosis of mild motor impairment or subjective motor impairment can be rendered. NOS, not otherwise specified.

Figure 5

Flowchart for achieving consensus autonomic diagnosis. Any participant lacking substantial autonomic complaints and without evidence of orthostatic hypotension after 3 minutes standing is categorized as having normal autonomic function. The most recent diagnostic criteria for the synucleinopathies are used for rendering the diagnoses of PD, DLB, MSA, and pure autonomic failure. Any isolated finding not meeting criteria for a neurodegenerative (or alternative) diagnosis, is labeled as having “abnormal autonomic function”.