99mTc-HMPAO SPECT Perfusion Signatures Associated With Clinical Progression in Patients With Isolated REM Sleep Behavior Disorder

Abstract

Background and objectives: Idiopathic/isolated REM sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies and Parkinson disease. Despite evidence of abnormal cerebral perfusion in iRBD, there is currently no pattern that can predict whether an individual will develop dementia with Lewy bodies or Parkinson disease. The objective was to identify a perfusion signature associated with conversion to dementia with Lewy bodies in iRBD.

Methods: Patients with iRBD underwent video-polysomnography, neurologic and neuropsychological assessments, and baseline ^99mTc-HMPAO SPECT to assess relative cerebral blood flow. Partial least squares correlation was used to identify latent variables that maximized covariance between 27 clinical features and relative gray matter perfusion. Patient-specific scores on the latent variables were used to test the association with conversion to dementia with Lewy bodies compared with that with Parkinson disease. The signature's expression was also assessed in 24 patients with iRBD who underwent a second perfusion scan, 22 healthy controls, and 19 individuals with Parkinson disease.

Results: Of the 137 participants, 93 underwent SPECT processing, namely 52 patients with iRBD (67.9 years, 73% men), 19 patients with Parkinson disease (67.3 years, 37% men), and 22 controls (67.0 years, 73% men). Of the 47 patients with iRBD followed up longitudinally (4.5 years), 12 (26%) developed a manifest synucleinopathy (4 dementia with Lewy bodies and 8 Parkinson disease). Analysis revealed 2 latent variables between relative blood flow and clinical features: the first was associated with a broad set of features that included motor, cognitive, and perceptual variables, age, and sex; the second was mostly associated with cognitive features and RBD duration. When brought back into the patient's space, the expression of the first variable was associated with conversion to a manifest synucleinopathy, whereas the second was associated with conversion to dementia with Lewy bodies. The expression of the patterns changed over time and was associated with worse motor features.

Discussion: This study identified a brain perfusion signature associated with cognitive impairment in iRBD and transition to dementia with Lewy bodies. This signature, which can be derived from individual scans, has the potential to be developed into a biomarker that predicts dementia with Lewy bodies in at-risk individuals.

Figure 1. Study Protocol and Percentage of Covariance of Latent Variables

(A) Analytical protocol of PLS correlation. An imaging matrix of relative perfusion and a clinical matrix of 27 features were correlated, and SVD was applied to derive latent variables maximizing covariance between clinical and relative blood flow in iRBD. Every patient's imaging and clinical data were projected back onto each latent variable's clinical and brain patterns to yield patient-specific clinical and brain scores. (C) The first and third latent variables were significant after permutation testing; the dashed line represents the statistical threshold of p < 0.05, explaining 39.5% and 9.6% of the covariance between brain and clinical data, respectively. iRBD = idiopathic/isolated REM sleep behavior disorder; LV = latent variable; PLS = partial least squares; SVD = singular value decomposition.

Figure 2. Clinical and Brain Patterns Associated With LV1 in iRBD

Thirteen variables contributed to LV1 (A). The correlations represent the association between clinical performance (using the test's original scale) and the brain score. (B) Axial and sagittal slices showing the brain pattern of LV1, with red/yellow representing regions with positive weights and blue representing regions with negative weights. A lower (more negative) brain score (i.e., lower relative perfusion in regions with positive weights and higher relative perfusion in regions with negative weights) associated with worse clinical performance and being men. (C) This is exemplified by the association between higher relative perfusion in the putamen and more severe bradykinesia (blue area, negative weight) and the association between lower relative perfusion in the superior parietal cortex and more severe bradykinesia (red area, positive weight). BDI = Beck Depression Inventory; BP = blood pressure; FM-100 = Farnsworth-Munsell 100 Hue Test; iRBD = isolated/idiopathic REM sleep behavior disorder; LV = latent variable; MCI = mild cognitive impairment; MoCA = Montreal Cognitive Assessment; UPDRS = Unified Parkinson's Disease Rating Scale; UPSIT = University of Pennsylvania Smell Identification Test.

Figure 3. Clinical and Brain Patterns Associated With LV3 in iRBD

Five variables contributed to LV3 (A). The correlations represent the association between clinical performance (using the test's original scale) and the brain score. (B) Axial and sagittal slices showing the brain pattern of LV3, with red/yellow representing regions with positive weights. A higher (more positive) brain score (i.e., higher relative perfusion in regions with positive weights) associated with worse clinical performance. (C) This is exemplified by the positive association between higher relative perfusion in the right insula and basal forebrain and higher percentage of expected score (worse performance) on the FM-100. BDI = Beck Depression Inventory; BP = blood pressure; FM-100 = Farnsworth-Munsell 100 Hue Test; iRBD = isolated/idiopathic REM sleep behavior disorder; LV = latent variable; MCI = mild cognitive impairment; MoCA = Montreal Cognitive Assessment; UPDRS = Unified Parkinson's Disease Rating Scale; UPSIT = University of Pennsylvania Smell Identification Test.

Figure 4. Changes in Brain Scores Over Time Associate With Clinical Features in iRBD

A positive change (less negative brain score at scan 2) in the brain scores of LV1 was associated with worse clinical performance at baseline in patients with iRBD (A), whereas a negative change (less positive brain score at scan 2) in the brain scores of LV3 was associated with worse clinical performance at baseline in iRBD, particularly on motor measures (B). The asterisk indicates correlations surviving the Bonferroni-corrected significance threshold. iRBD = idiopathic/isolated REM sleep behavior disorder; LV = latent variable; MoCA = Montreal Cognitive Assessment; SPECT = single-photon emission CT; UPDRS = Unified Parkinson's Disease Rating Scale.