Koay, Shiwen; (2024) Multimodal biomarkers to improve the diagnosis and treatment of autonomic diseases. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The autonomic nervous system orchestrates the vital but unconscious control of every organ in the body. Autonomic failure can be a primary feature in several autoimmune and neurodegenerative diseases, presenting with severe disabling orthostatic hypotension, genitourinary and pupillary deficits. Overlapping clinical features at initial presentation may lead to diagnostic uncertainty. We explored whether multiple physiological and morphological biomarkers could identify characteristic phenotypes to distinguish between different autonomic diseases and quantify response to treatment. Firstly, we demonstrated ganglionic acetylcholine receptor (gAChR-positive) patients with autoimmune autonomic ganglionopathy (AAG) had a distinct phenotype with severe widespread parasympathetic and sympathetic autonomic failure, with prominent cholinergic deficits, and defined biomarkers to quantify improvements followingimmunotherapy. In contrast, gAChR-negative patients had heterogenous phenotypes, with a subset demonstrating sympathetic predominant autonomic failure, with significantly greater cutaneous adrenergic denervation, suggesting a different pathophysiological process. We then described the largest longitudinal cohort to date of patients with neurodegenerative α-synucleinopathies, including pure autonomic failure (PAF), multiple system atrophy (MSA), and Lewy body diseases (LBD), including Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). Patients with PAF had significantly greater orthostatic hypotension, lower supine noradrenaline, and more frequent sympathetic pupillary deficits, suggesting greater postganglionic adrenergic denervation compared to other patients. Normal pupils, supine noradrenaline, and less severe orthostatic hypotension at initial assessment predicted conversion to a more widespread α-synucleinopathy by final assessment. We applied indirect immunofluorescence techniques to assess for cutaneous neural phosphorylated synuclein (p-syn) deposits in PAF, MSA, and PD, using a semiquantitative score to describe the presence of p-syn on autonomic and other cutaneous nerves. Total p-syn scores were significantly higher in PAF compared to MSA and PD, consistent with a peripherally predominant α-synucleinopathy. Autonomic p-syn subscores correlated with severity of cardiovascular autonomic failure, suggesting p-syn deposition on autonomic nerves may contribute to the pathophysiology of autonomic failure.

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