The role of cardiovascular autonomic failure in the differential diagnosis of α-synucleinopathies

Leys, Fabian; Wenning, Gregor K.; Fanciulli, Alessandra

doi:10.1007/s10072-021-05746-6

Cited by 7 publications

(3 citation statements)

References 101 publications

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“…Another prioritized recommendation of the Roadmap meeting included the development of clinical, imaging, and other biofluid markers that reliably track disease progression since clinical indices alone are poorly reflective of progression rate [ 24 ]. Ancillary testing includes autonomic function tests [ 25 , 26 ], olfactory testing [ 27 ], 123I-MIBG cardiac scintigraphy [ 28 ], multimodal MRI assessment [ 29 – 31 ] (see also Kim et al [ 32 ]), and positron emission tomography (PET) imaging of the translocator protein (TSPO) [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping

et al. 2022

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Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson’s disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal “n-of-few” clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.

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Section: Introductionmentioning

confidence: 99%

Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping

et al. 2022

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“…Another explanation for the association between RBD and HR was the impact of α-synuclein. Previous studies have confirmed that α-synuclein was detectable within the heart and cardiovascular autonomic failure was a common symptom in α-synucleinopathies [ 47 , 48 ]. The α-synuclein in heart may further contributed to myocardial disorders, including cardiomyopathy, septal fibrosis, and ventricular hypertrophy [ 49 ].…”

Section: Discussionmentioning

confidence: 88%

Genetic associations between Rapid Eye Movement (REM) sleep behavior disorder and cardiovascular diseases

Xu,

Wei,

et al. 2024

PLoS ONE

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Background Previous studies revealed that sleep disorders are potential risk factors for cardiovascular diseases, such as obstructive sleep apnea and rapid eye movement (REM) sleep behavior disorder (RBD). However, the causal associations between RBD and cardiovascular diseases remained unknown. Materials and methods We used the latest and largest summary-level genome-wide association studies of RBD, stroke and its subtypes, coronary artery disease (CAD), myocardial infarction (MI), and heart failure (HF) to select genetic variants as the instrumental variables. Mendelian randomization (MR) analysis was performed to test the causal associations between RBD and the cardiovascular diseases above. Inverse variance weighted method was used as the main analysis. Results After multiple comparisons, genetically predicted RBD was significantly associated with the risk of HF [odds ratio (OR) = 1.033, 95% CI 1.013–1.052, p = 0.001]. Leave-one-out analysis further supported the robustness of the causal association. Furthermore, we identified a suggestive association between genetically predicted MI and RBD (OR = 0.716, 95% CI 0.546–0.940, p = 0.016). However, in our study no associations were identified of RBD with CAD or stroke and its subtypes. Conclusion Our study highlighted the potential associations between RBD and cardiovascular diseases at genetic level, including HF and MI. More studies were required to clarify the biological mechanisms involved the associations.

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“…Cardiac denervation is rare at the early stages of MSA, a close differential diagnosis of PAF. [ 17 ]…”

Section: P Athophysiology [ F ...mentioning

confidence: 99%

Pure Autonomic Failure-A Localized Alpha Synucleinopathy with a Potential for Conversion to More Extensive Alpha Synucleinopathies

Bhattacharjee¹,

Alsukhni²

2022

Annals of Indian Academy of Neurology

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Pure autonomic failure (PAF) is an alpha synucleinopathy with predominant involvement of the autonomic ganglia and peripheral nerves. The hallmark clinical feature is orthostatic hypotension. However, genitourinary, sudomotor, and cardiac involvement is also common. Many patients also develop supine hypertension. Almost a quarter of patients can phenoconvert or evolve into Parkinson's disease, multiple system atrophy, and Lewy body dementia in the future. Early severe bladder involvement, higher supine noradrenaline level, early motor involvement, and dream enactment behavior increase the risk of phenoconversion. The diagnosis is confirmed via autonomic function testing and serum noradrenaline measurement. The treatment is mainly supportive. The non-pharmacological treatment includes adequate fluid, dietary salt, compression stockings, and abdominal binders. The drug therapies to improve blood pressure include midodrine, fludrocortisone, pyridostigmine, and droxidopa. The diagnostic criteria need to be updated to incorporate the recent understandings. The treatment of orthostatic hypotension and supine hypertension is mainly based on case series and anecdotal reports. Randomized control trials are needed to ascertain the best treatment strategies for PAF.

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The role of cardiovascular autonomic failure in the differential diagnosis of α-synucleinopathies

Cited by 7 publications

References 101 publications

Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping

Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping

Genetic associations between Rapid Eye Movement (REM) sleep behavior disorder and cardiovascular diseases

Pure Autonomic Failure-A Localized Alpha Synucleinopathy with a Potential for Conversion to More Extensive Alpha Synucleinopathies

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