REM sleep atonia loss distinguishes synucleinopathy in older adults with cognitive impairment

Abstract

ObjectiveTo determine whether quantitative polysomnographic REM sleep without atonia (RSWA) distinguishes between cognitive impairment phenotypes.BackgroundNeurodegenerative cognitive impairment in older adults predominantly correlates with tauopathy or synucleinopathy. Accurate antemortem phenotypic diagnosis has important prognostic and treatment implications; additional clinical tools might distinguish between dementia syndromes.MethodsWe quantitatively analyzed RSWA in 61 older adults who underwent polysomnography including 46 with cognitive impairment (20 probable synucleinopathy), 26 probable non-synucleinopathy (15 probable Alzheimer disease, 11 frontotemporal lobar dementia), and 15 age- and sex-matched controls. Submentalis and anterior tibialis RSWA metrics and automated REM atonia index were calculated. Group statistical comparisons and regression were performed, and receiver operating characteristic curves determined diagnostic RSWA thresholds that best distinguished synucleinopathy phenotype.ResultsSubmentalis—but not anterior tibialis RSWA—was greater in synucleinopathy than nonsynucleinopathy; several RSWA diagnostic thresholds distinguished synucleinopathy with excellent specificity including submentalis tonic, 5.6% (area under the curve [AUC] 0.791); submentalis any, 15.0% (AUC 0.871); submentalis phasic, 10.8% (AUC 0.863); and anterior tibialis phasic, 31.4% (AUC 0.694). In the subset of patients without dream enactment behaviors, submentalis RSWA was also greater in patients with synucleinopathy than in those without synucleinopathy. RSWA was detected more frequently by quantitative than qualitative methods (p = 0.0001).ConclusionElevated submentalis RSWA distinguishes probable synucleinopathy from probable nonsynucleinopathy in cognitively impaired older adults, even in the absence of clinical dream enactment symptoms.Classification of evidenceThis study provides Class III evidence that quantitative RSWA analysis is useful for distinguishing cognitive impairment phenotypes. Further studies with pathologic confirmation of dementia diagnoses are needed to confirm the diagnostic utility of RSWA in dementia.

Submentalis Rapid Eye Movement Sleep Muscle Activity: A Potential Biomarker for Synucleinopathy

“…Moreover, submentalis RSWA cutoffs distinguishing synucleinopathy in parkinsonism were highly similar to our cognitive impairment subtype cutoffs for distinction of dementia with Lewy bodies (DLB) from Alzheimer disease and frontotemporal dementia (submentalis “any,” 15.0%; phasic, 10.8%; phasic burst duration, 0.65 seconds) . Similarly, anterior tibialis RSWA was also a poor discriminator for probable synucleinopathy in this and previous studies …”

“…Quantitative RSWA detected significantly more cases of RSWA than qualitative RSWA determination by polysomnographer visual interpretation alone had identified, highlighting the importance of systematic quantification of REM sleep muscle activity. 13 Submentalis duration cutoffs determined in the current parkinsonism study (0.64 seconds) were also highly consistent with those in idiopathic RBD, PD-RBD, and DLB (0.65-0.66 seconds), 5,12,13 suggesting that submentalis phasic burst duration is a biomarker that may be diagnostically useful for RBD and suspected synucleinopathy. 4 Further pathologic validation studies in large prospective cohorts involving unknown parkinsonism and/or cognitive impairment etiologies are necessary to confirm submentalis RSWA as a synucleinopathy biomarker.…”

“…Submentalis RSWA may be a specific marker for synucleinopathy given highly similar cutoff values between patients with parkinsonism and with cognitive impairment having a presumed synuclein etiology. 13 PSG in parkinsonism of unclear etiology may aid diagnosis through RSWA quantification, and enable evaluation and treatment of comorbid sleep disorders such as detection of sleep-related stridor in MSA. Elevated submentalis RSWA signifies likely PD or MSA diagnosis, with significant tonic RSWA suggesting MSA and/or widespread brainstem dysfunction in Lewy body diseases.…”

“…We also compared the frequency of quantitative RSWA muscle activity percentages meeting defined RBD diagnostic thresholds against qualitative visual RSWA determination alone, and comparatively analyzed the diagnostic yield and agreement between these methods for RSWA determination by previous methods. 13…”

“…Area under the curve (AUC) was calculated, and cutoff diagnostic threshold values were chosen that yielded optimal specificity with reasonable sensitivity to distinguish probable synucleinopathy from tauopathy etiology. We also compared the frequency of quantitative RSWA muscle activity percentages meeting defined RBD diagnostic thresholds against qualitative visual RSWA determination alone, and comparatively analyzed the diagnostic yield and agreement between these methods for RSWA determination by previous methods …”