Lucy Norcliffe-Kaufmann

Central metabolism has a profound impact on the clinical phenotypes and penetrance of neurological diseases such as Alzheimer’s (AD) and Parkinson’s (PD) diseases, Amyotrophic Lateral Sclerosis (ALS) and Autism Spectrum Disorder (ASD). In contrast to the multifactorial origin of these neurological diseases, neurodevelopmental impairment and neurodegeneration in Familial Dysautonomia (FD) results from a single point mutation in the ELP1 gene. FD patients represent a well-defined population who can help us better understand the cellular networks underlying neurodegeneration, and how disease traits are affected by metabolic dysfunction, which in turn may contribute to dysregulation of the gut–brain axis of FD. Here, ¹H NMR spectroscopy was employed to characterize the serum and fecal metabolomes of FD patients, and to assess similarities and differences in the polar metabolite profiles between FD patients and healthy relative controls. Findings from this work revealed noteworthy metabolic alterations reflected in energy (ATP) production, mitochondrial function, amino acid and nucleotide catabolism, neurosignaling molecules, and gut-microbial metabolism. These results provide further evidence for a close interconnection between metabolism, neurodegeneration, and gut microbiome dysbiosis in FD, and create an opportunity to explore whether metabolic interventions targeting the gut–brain–metabolism axis of FD could be used to redress or slow down the progressive neurodegeneration observed in FD patients.

Despite its increasing recognition and extensive research, there is no unifying hypothesis on the pathophysiology of the postural tachycardia syndrome. In this cross-sectional study, we examined the role of fear conditioning and its association with tachycardia and cerebral hypoperfusion on standing in 28 patients with postural tachycardia syndrome (31 ± 12 years old, 25 females) and 21 matched controls. We found that patients had higher somatic vigilance (P = 0.0167) and more anxiety (P < 0.0001). They also had a more pronounced anticipatory tachycardia right before assuming the upright position in a tilt-table test (P = 0.015), a physiological indicator of fear conditioning to orthostasis. While standing, patients had faster heart rate (P < 0.001), higher plasma catecholamine levels (P = 0.020), lower end-tidal CO₂ (P = 0.005) and reduced middle cerebral artery blood flow velocity (P = 0.002). Multi-linear logistic regression modelling showed that both epinephrine secretion and excessive somatic vigilance predicted the magnitude of the tachycardia and the hyperventilation. These findings suggest that the postural tachycardia syndrome is a functional disorder in which standing may acquire a frightful quality, so that even when experienced alone it may elicit a fearful conditioned response. Heightened somatic anxiety is associated with and may predispose to a fear-conditioned hyperadrenergic state when standing. Our results have therapeutic implications.

Objective: The susceptibility to suffer neurally mediated syncope and loss of consciousness varies markedly. In addition to vasodilatation and bradycardia, hyperventilation precedes loss of consciousness. The resultant hypocapnia causes cerebral vasoconstriction and peripheral vasodilatation. We postulate that more pronounced cerebral and peripheral vascular responses to reductions in arterial CO₂ levels underlie greater susceptibility to neurally mediated syncope.Methods: We compared vascular responses to CO₂ among 31 patients with histories of recurrent neurally mediated syncope and low orthostatic tolerance and 14 age‐ and sex‐matched control subjects with no history of syncope and normal orthostatic tolerance. Vascular responses to CO₂ were calculated after all subjects had fully recovered and their blood pressures and heart rates were stable. We measured blood flow velocity in the middle cerebral artery (transcranial Doppler) and in the left brachial artery (brachial Doppler), and end‐tidal CO₂ during voluntary hyperventilation and hypoventilation (end‐tidal CO₂ from 21–45mm Hg), and determined the slopes of the relations.Results: Hypocapnia produced a significantly greater reduction in cerebral blood flow velocity and in forearm vascular resistance in patients with neurally mediated syncope than in control subjects. Opposite changes occurred in response to hypercapnia. In all subjects, the changes in cerebral blood flow velocity and forearm vasodilatation were inversely related with orthostatic tolerance.Interpretation: Susceptibility to neurally mediated syncope can be explained, at least in part, by enhanced cerebral vasoconstriction and peripheral vasodilatation in response to hypocapnia. This may have therapeutic implications. Ann Neurol 2007