多系統萎縮症

BACKGROUND: Involuntary inspiratory sigh (IIS) is a characteristic symptom of multiple system atrophy (MSA) and a supportive non-motor feature in the current diagnostic criteria. However, IIS during wakefulness has not been systematically investigated. OBJECTIVES: This study explored the clinical significance and neural correlates of IIS by comparing clinical characteristics and cerebral blood flow (CBF) single-photon emission computed tomography findings between patients with and without IIS, and evaluated a practical method for IIS assessment. METHODS: We retrospectively investigated 90 patients with clinically established or probable MSA. IIS was assessed via structured interview and direct examination. Patients were classified as IIS-positive if either method yielded positive results. Clinical characteristics were compared between IIS-positive and IIS-negative patients. Agreement between the two detection methods was examined. CBF was also compared between groups. RESULTS: IIS was identified in 21 (23.3%) of 90 patients. The IIS-positive patients showed higher Unified Multiple System Atrophy Rating Scale Part I scores and REM Sleep Behavior Disorder Screening Questionnaire scores, and more frequent severe orthostatic hypotension in exploratory comparisons. Interview- and examination-based IIS assessments showed moderate agreement, and IIS was significantly more likely to be detected during interviews than during examinations. The IIS-positive patients exhibited reduced CBF in the bilateral supplementary motor area. CONCLUSIONS: In MSA, IIS was associated with greater disease burden, more severe autonomic dysfunction, and reduced perfusion in the supplementary motor area. Interview-based assessment may help capture IIS in routine clinical practice. Clinicians should actively inquire about this clinically relevant symptom when evaluating patients with suspected MSA.

BACKGROUND AND OBJECTIVES: Degeneration of the central autonomic network with relative sparing of peripheral autonomic neurons underlies neurogenic orthostatic hypotension in patients with multiple system atrophy (MSA). Ampreloxetine, a novel, selective, norepinephrine (NE) reuptake inhibitor, allows once-daily dosing to precisely target residual peripheral autonomic neurons. Based on the hypothesis that patients with MSA would be most responsive and the substantial unmet need for symptomatic therapy in this population, an MSA subgroup analysis was prespecified. METHODS: We conducted a run-in 4-week, parallel-group, randomized controlled trial (SEQUOIA), followed by a pivotal enriched randomized withdrawal (RW) trial with 16-week open-label treatment and 6 weeks of 1:1 RW (REDWOOD). Inclusion criteria for the MSA subgroup included (1) probable or possible MSA, (2) 3-minute orthostatic blood pressure (BP) fall >20/10 mm Hg, and (3) dizziness or lightheadedness score >4 points. Outcome measures included self-reported symptom burden captured on the 10-item OH Questionnaire (OHQ). Differences were analyzed using logistic regression and mixed-model repeated measures analysis. RESULTS: Seventy-three patients with MSA entered the program (mean age 63 years old [range: 43-80], 52% male). Both SEQUOIA and REDWOOD did not meet their primary endpoints. In REDWOOD, 40 (61%) fulfilled enrichment criteria and were randomized. After 16-week open-label, OHQ symptom assessment (OHSA) composite domain scores improved 2.6 ± (SD = 2.1) points from pretreatment. The proportion of participants with treatment failure at week 6 of RW treatment period was 40% in the placebo arm and 15% in the ampreloxetine arm (p = 0.11). In secondary endpoints, at week 6 of RW, symptoms remained stable in the ampreloxetine group, but worsened on placebo (mean difference OHSA composite: -1.6 points ± 0.5; p = 0.0056, minimal clinically important worsening = 0.7-1.1 points). Standing for a short time favored ampreloxetine (-2.0 points ± 0.8; p = 0.015). Standing BP remained unchanged from open-label in the ampreloxetine group (systolic: 5.6 ± 4.1; diastolic: 3.7 ± 2.9 [SE] mm Hg) but fell after placebo withdrawal (systolic: -10.0 ± 4.5; diastolic: -6.0 ± 3.1 mm Hg). The catecholamine profile was consistent with NE transporter inhibition. There were no observed increases in supine BP. DISCUSSION: In a prespecified subgroup analysis of MSA participants in the REDWOOD trial, patients randomized to placebo worsened, whereas those who were randomized to treatment maintained their open-label level of function. TRIAL REGISTRATION INFORMATION: REDWOOD trial, NCT03829657; first submitted to registry January 10, 2019; first participant enrolled February 22, 2019. SEQUOIA trial, NCT03750552; first submitted to registry November 20, 2018; first participant enrolled January 24, 2019. See ClinicalTrials.gov for full-protocol and statistical analysis plan. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in patients with MSA who had symptomatic benefit on orthostatic hypotension with ampreloxetine, there was no difference in the odds of treatment failures between those maintained on ampreloxetine and those withdrawn to placebo.

BACKGROUND: Progressive supranuclear palsy (PSP) is both an underdiagnosed and a frequently misdiagnosed disorder. To remedy these diagnostic limitations, MRI has been used to investigate brain morphology to differentiate PSP from Parkinson's disease (PD) and multiple system atrophy (MSA). However, while nigrostriatal degeneration and tau aggregation are prominent in PSP, and result in iron accumulation and atrophy in the region, substantia nigra (SN) atrophy remains an underexplored diagnostic marker. PURPOSE: To investigate the diagnostic utility of QSM-derived SN parameters for PSP. STUDY TYPE: Retrospective. POPULATION: 123 (59 Males/64 Females) PD patients, 48 (26 M/22 F) MSA patients, and 22 (11 M/11 F) PSP patients were included in the main dataset. MSA patients include 20 parkinsonian type (MSA-P) (11 M/9 F) and 18 cerebellar type (MSA-C) (9 M/9 F) of MSA with 10 undetermined subtype. The external validation set included 12 (6 M/6 F) healthy controls, 13 PD (7 M/6 F), and 10 PSP (6 M/4 F) patients. FIELD STRENGTH AND SEQUENCE: 3 T, MPRAGE T1-weighted imaging and multi-echo gradient echo imaging (mGRE) for QSM. ASSESSMENT: Group level differences of SN volume, magnetic susceptibility, and susceptibility-to-volume ratio (SVR) among PSP, PD, and MSA groups, and these metrics' differentiating power are measured. Bivariate logistic regression with T1-based morphological markers alongside SN metrics is performed. STATISTICAL TESTS: Mann-Whitney U test for group comparisons. Receiver operating characteristic analysis with bootstrapping. p < 0.05 after Bonferroni correction is defined as statistically significant result. RESULTS: The SN SVR was significantly higher in the PSP group compared to the MSA group and the MSA-P group. Moreover, using pons measurements with SN SVR in a bivariate model resulted in the highest differentiation between the PSP and MSA groups (AUC = 0.88, 95% CI: [0.78-0.95]), particularly driven by the increased differentiation between the PSP and MSA-P groups (AUC = 0.88, 95% CI: [0.75-0.98]). External validation supported the generalizability of SN SVR, yielding 100% sensitivity and 80% specificity for differentiating PSP from HC and PD. DATA CONCLUSION: QSM-based SN morphometry can complement T1-weighted imaging for Parkinsonism assessment. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.

BACKGROUND: Behavioral variant of frontotemporal dementia (bvFTD) often presents with parkinsonism. Our study aimed to characterize the dopaminergic deficit pattern in bvFTD-parkinsonism (bvFTD-P) using dopamine transporter (DAT) positron emission tomography (PET) and to assess its potential value in differentiating bvFTD-P from progressive supranuclear palsy (PSP), multiple system atrophy-parkinsonism (MSA-P), and Parkinson disease (PD). METHODS: A total of 30 bvFTD-P patients underwent 11C-CFT or 18F-FP-CIT PET and were compared with 71 patients with PSP, 41 with MSA-P, 61 with PD, and 43 healthy controls (HC). DAT binding values in the caudate, anterior putamen, and posterior putamen, as well as caudate/anterior putamen (C/AP) and caudate/posterior putamen (C/PP) ratios, were analyzed with generalized linear models. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic accuracy of DAT binding values and ratios. RESULTS: BvFTD-P patients exhibited significantly reduced DAT binding in the caudate, anterior putamen, and posterior putamen compared with HC (all P<0.01), with a caudate-predominant deficit pattern (lower C/AP and C/PP ratios), contrasting with the putamen-predominant loss observed in PSP, MSA-P, and PD. This caudate-predominant pattern was replicated in the independent 18F-FP-CIT cohort. ROC analysis demonstrated that the C/PP ratio provided superior discriminatory performance between bvFTD-P and HC or other parkinsonian syndromes than absolute binding values. Furthermore, lateralization of striatal DAT reduction corresponded to the side of predominant motor symptoms. CONCLUSIONS: The caudate-predominant pattern of striatal dopaminergic deficit in bvFTD-P may serve as a useful imaging biomarker for differentiating it from PSP, MSA-P, and PD.