Microcirculation response to local cooling in patients with Huntington’s disease

Melik, Ž.; Kobal, Jan; Cankar, Ksenija; Štrucl, Martin

doi:10.1007/s00415-011-6279-3

Cited by 20 publications

(27 citation statements)

References 56 publications

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“…Cardiovascular and lung phenotypes suggest altered ANS function, being most consistent with increased sympathetic activity at young ages. There is considerable evidence for ANS dysfunction in both manifest and premanifest HD individuals [ 41 , 100 - 105 ]. In HD individuals cardiovascular autonomic tests including blood pressure response to sustained hand-grip, orthostatic blood pressure test, heart rate and heart rate variability at rest and in response to maneuvers or stressors revealed deficits in both the sympathetic and parasympathetic branches of the ANS [ 41 , 100 - 105 ].…”

Section: Discussionmentioning

confidence: 99%

A Broad Phenotypic Screen Identifies Novel Phenotypes Driven by a Single Mutant Allele in Huntington’s Disease CAG Knock-In Mice

et al. 2013

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Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing.

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Section: Discussionmentioning

confidence: 99%

A Broad Phenotypic Screen Identifies Novel Phenotypes Driven by a Single Mutant Allele in Huntington’s Disease CAG Knock-In Mice

et al. 2013

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“…In the scientific setting, LDF has been used to study familial dysautonomia and has helped to understand the relationship between receptors and innervation in autonomic dysfunction [28]. Furthermore, research using LDF in patients with Huntington's disease displaying vasomotor impairment was able to lend evidence to the hypothesized involvement of the autonomic nervous system in the disease's pathophysiology [29].…”

Section: Perspectivementioning

confidence: 99%

Assessment of cutaneous axon-reflex responses to evaluate functional integrity of autonomic small nerve fibers

et al. 2020

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Cutaneous autonomic small nerve fibers encompass unmyelinated C-fibers and thinly myelinated Aδ-fibers, which innervate dermal vessels (vasomotor fibers), sweat glands (sudomotor fibers), and hair follicles (pilomotor fibers). Analysis of their integrity can capture early pathology in autonomic neuropathies such as diabetic autonomic neuropathy or peripheral nerve inflammation due to infectious and autoimmune diseases. Furthermore, intraneural deposition of alpha-synuclein in synucleinopathies such as Parkinson's disease can lead to small fiber damage. Research indicated that detection and quantitative analysis of small fiber pathology might facilitate early diagnosis and initiation of treatment. While autonomic neuropathies show substantial etiopathogenetic heterogeneity, they have in common impaired functional integrity of small nerve fibers. This impairment can be evaluated by quantitative analysis of axonal responses to iontophoretic application of adrenergic or cholinergic agonists to the skin. The axon-reflex can be elicited in cholinergic sudomotor fibers to induce sweating and in cholinergic vasomotor fibers to induce vasodilation. Currently, only few techniques are available to quantify axon-reflex responses, the majority of which is limited by technical demands or lack of validated analysis protocols. Function of vasomotor small fibers can be analyzed using laser Doppler flowmetry, laser Doppler imaging, and laser speckle contrast imaging. Sudomotor function can be assessed using quantitative sudomotor axon-reflex test, silicone imprints, and quantitative direct and indirect testing of sudomotor function. More recent advancements include analysis of piloerection (goose bumps) following stimulation of adrenergic small fibers using pilomotor axon-reflex test. We provide a review of the current literature on axon-reflex tests in cutaneous autonomic small fibers.

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“…However, multiple epidemiological studies have shown that heart disease is the second cause of death in patients with HD and the following frequencies have been reported: 12.2% [11], 19% [12] and 24.4% [13]. Moreover, clinical studies have revealed that HD patients have enhanced cardiovagal activity [14], reduced cortical and subcortical blood flow [15] and a reduced heart rate [16]. A further study showed a significant decrease in the parasympathetic heart rate variability values during ‘head-up tilt’ indicating a decreased vagal modulation of heart rate in HD patients.…”

Section: Introductionmentioning

confidence: 99%

Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease

et al. 2014

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Cardiac remodelling and contractile dysfunction occur during both acute and chronic disease processes including the accumulation of insoluble aggregates of misfolded amyloid proteins that are typical features of Alzheimer's, Parkinson's and Huntington's disease (HD). While HD has been described mainly as a neurological disease, multiple epidemiological studies have shown that HD patients exhibit a high incidence of cardiovascular events leading to heart failure, and that this is the second highest cause of death. Given that huntingtin is ubiquitously expressed, cardiomyocytes may be at risk of an HD-related dysfunction. In mice, the forced expression of an expanded polyQ repeat under the control of a cardiac specific promoter led to severe heart failure followed by reduced lifespan. However the mechanism leading to cardiac dysfunction in the clinical and pre-clinical HD settings remains unknown. To unravel this mechanism, we employed the R6/2 transgenic and HdhQ150 knock-in mouse models of HD. We found that pre-symptomatic animals developed connexin-43 relocation and a significant deregulation of hypertrophic markers and Bdnf transcripts. In the symptomatic animals, pronounced functional changes were visualised by cardiac MRI revealing a contractile dysfunction, which might be a part of dilatated cardiomyopathy (DCM). This was accompanied by the re-expression of foetal genes, apoptotic cardiomyocyte loss and a moderate degree of interstitial fibrosis. To our surprise, we could identify neither mutant HTT aggregates in cardiac tissue nor a HD-specific transcriptional dysregulation, even at the end stage of disease. We postulate that the HD-related cardiomyopathy is caused by altered central autonomic pathways although the pathogenic effects of mutant HTT acting intrinsically in the heart may also be a contributing factor.

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Microcirculation response to local cooling in patients with Huntington’s disease

Cited by 20 publications

References 56 publications

A Broad Phenotypic Screen Identifies Novel Phenotypes Driven by a Single Mutant Allele in Huntington’s Disease CAG Knock-In Mice

A Broad Phenotypic Screen Identifies Novel Phenotypes Driven by a Single Mutant Allele in Huntington’s Disease CAG Knock-In Mice

Assessment of cutaneous axon-reflex responses to evaluate functional integrity of autonomic small nerve fibers

Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease

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