Early sympathetic hyperactivity in Huntington's disease

Kobal, Jan; Meglič, Bernard; Mesec, Anton; Peterlin, Borut

doi:10.1111/j.1468-1331.2004.00894.x

Cited by 65 publications

(84 citation statements)

References 30 publications

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“…We, therefore, hypothesized that the changes in the cardiovascular ANS functioning could be detected as early as in the presymptomatic phase of the disease due to the successive involvement of the higher order parts of CAN. The common cardiovascular tests like the Valsalva manoeuvre, deep breathing and orthostatic test did not confirm the differences between PHD and EHD subjects [5,20]. In the present study we introduced new tests that could show more subtle differences in ANS function in PHD and EHD subjects.…”

Section: Introductionmentioning

confidence: 59%

“…Nevertheless, only a few studies on ANS function in presymptomatic and early symptomatic HD patients have been performed. Sympathetic predominance was found in presymptomatic and mildly and moderately affected HD patients [20], but another study [5] found no difference in LF and HF values between control, PHD and EHD group. Reasons for the discrepancies might be subtle ANS changes, different clinical methods of evaluation, differences in sample size and individual differences in disease onset and progression.…”

Section: Discussionmentioning

confidence: 95%

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

et al. 2011

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Altered autonomic nervous system (ANS) functioning in early stages of Huntington's disease (HD) has been suggested, presumably due to distorted high-order autonomic control. ANS functioning in the early stages of HD was further investigated. Laser-Doppler (LD) flux in the skin of the fingertips, heart rate (HR), HR variability, systolic and diastolic blood pressure were measured during rest and during a 6 min cooling of one hand at 15°C. Data of 15 presymptomatic gene mutation carriers (PHD), 15 early symptomatic HD patients (EHD), and two groups of 15 age- and sex-matched controls were compared. The area under the low frequency (LF) and high frequency (HF) bands of the HR variability spectrum were calculated. An augmented reduction of cutaneous LD flux was found in response to the direct cooling in the PHD group (37.5 ± 8.5% of resting value) compared to the PHD controls (67.27 ± 8.4%) (p < 0.05). In addition, the PHD group had higher (LF/(LF + HF) index of primary sympathetic modulation of the HR at rest (53.6 ± 3.3) compared to the EHD patients (39.7 ± 4.2) (p < 0.05). In the EHD group, a significantly smaller change of HR during cooling (100.26 ± 1.2%) was found compared to the EHD controls (95.9 ± 1.0%) (p < 0.05). The results are in line with the hypothesis that ANS dysfunction occurs even in PHD subjects. Further, they support the hypothesis that dysfunction of the high-order autonomic centres are involved in HD.

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Section: Introductionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 95%

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

et al. 2011

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“…HF is among the leading causes of death in Huntington disease 114 , and the prevalence of HF in patients with Huntington disease is markedly increased com pared with age matched controls 115 [118][119][120] have demonstrated that whole body expression of polyQ proteins precipitates cardiomyopathy. Although this observation supports a direct involvement of the mutant huntingtin in development of cardiac disease, Huntington disease also features marked imbalance in the autonomic nervous system, leading to enhanced sympathetic tonus 121 , which might (partly) contribute to HF in Huntington disease. Data on the other ~30 proteopathies are even more inconclusive.…”

Section: Derailment Owing To Genetic Mutationsmentioning

confidence: 79%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

144

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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“…L-phenylalanine is a precursor of tyrosine, therefore making L-phenylalanine also precursor of these catecholamine neurotransmitters. Hyperactivity of the sympathetic nervous system has been reported in HD sufferers 40 , and it could be speculated that increased neurotransmitter biosynthesis leads to depletion of tyrosine and L-phenylalanine precursors in both the frontal lobe and striatum.…”

Section: Resultsmentioning

confidence: 99%

“…The unaffected range is (CAG)6-35 repeats, alleles of (CAG)>40 are considered fully penetrant and these individuals carry a 100 % lifetime risk of developing HD and CAG repeat size with alleles of (CAG)>60 causes juvenile onset. Although HD can present itself at any age, the age of onset is typically [40][41][42][43][44][45] years with death typically occurring 15-20 years after the initial manifestation 3,9-11 . Currently there is no neuroprotective therapy 3 or ultimate "cure" for this debilitating neurodegenerative disease 5,8 .…”

Section: Introductionmentioning

confidence: 99%

Metabolic signatures of Huntington's disease (HD): 1 H NMR analysis of the polar metabolome in post-mortem human brain

Graham

Kumar

Bjorndahl

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Abbreviations:1 H NMR-Proton nuclear magnetic resonance; AD -Alzheimer's disease; AUC -area under the curve; AUROC -area under the receiver operating curve; BBB -blood brain barrier; BCAA -branched-chain amino acid; CNS -central nervous system; CSF -cerebral spinal fluid; DSS -Sodium 2,2-dimethyl-2-silapentane-5-sulfonate; FDR -false discovery rate; fMRI -functional magnetic resonance imaging; GC-Tof-MS -gas chromatography time of flight mass spectrometry; HD -Huntington's disease; IGF-1 -insulin like growth factor; MRImagnetic resonance imaging; MAS-NMR -magic angle spinning NMR; MRS -magnetic resonance spectroscopy; ROC -Receiver operating characteristic.

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Early sympathetic hyperactivity in Huntington's disease

Cited by 65 publications

References 30 publications

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

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

Proteostasis in cardiac health and disease

Metabolic signatures of Huntington's disease (HD): 1 H NMR analysis of the polar metabolome in post-mortem human brain

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