Heart rate variability in leucine‐rich repeat kinase 2‐associated Parkinson's disease

Visanji, Naomi P.; Bhudhikanok, Grace S.; Mestre, Tiago; Ghate, Taneera; Udupa, Kaviraja; AlDakheel, Amaal; Connolly, Barbara S.; Gasca-Salas, Carmen; Kern, Drew S.; Jain, Jennifer; Slow, Elizabeth; Faust-Socher, Achinoam; Kim, S.; Valappil, Ruksana Azhu; Kausar, Farah; Rogaeva, Ekaterina; Langston, J. William; Tanner, Caroline M.; Schüle, Birgitt; Lang, Anthony E.; Goldman, Samuel; Marras, Connie

doi:10.1002/mds.26896

Cited by 22 publications

(15 citation statements)

References 37 publications

(84 reference statements)

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“…Although no significant GWAS hit was found in a large series of pathologically confirmed MSA cases, some interesting findings involving a mixed MSA pathology have been reported. The SNCA p.Gly51Asp mutation was found in families presenting with autosomal‐dominant parkinsonism with autopsy findings typical for both PD and MSA . Similar pathology findings were also observed in a family with the p.Ala53Glu mutation .…”

Section: Autonomic Dysfunction In Familial Pd Vs Msa and Ipdsupporting

confidence: 64%

“…The [ 18 F]fluorodopamine PET scan showed absent myocardial radioactivity, despite approximately normal perfusion on 13 N ‐ammonia scanning consistent with loss of sympathetic nerves in the left ventricle. Similarly, other patients with PD and OH attributed to p.Ala53Thr or SNCA triplications had higher rates of cardiac 6‐[18F]‐dopamine loss when compared to patients with iPD and OH …”

Section: Familial Pd and Autonomic Dysfunctionmentioning

confidence: 87%

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Autonomic dysfunction in genetic forms of synucleinopathies

et al. 2018

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The discovery of genetic links between alpha-synuclein and PD has opened unprecedented opportunities for research into a new group of diseases, now collectively known as synucleinopathies. Autonomic dysfunction, including cardiac sympathetic denervation, has been reported in familial forms of synucleinopathies that have Lewy bodies at the core of their pathogenesis. SNCA mutations and multiplications, LRRK2 disease with Lewy bodies as well as other common, sporadic forms of idiopathic PD, MSA, pure autonomic failure, and dementia with Lewy bodies have all been associated with dysautonomia. By contrast, in familial cases of parkinsonism without Lewy bodies, such as in PARK2, the autonomic profile remains normal throughout the course of the disease. The degeneration of the central and peripheral autonomic systems in genetic as well as sporadic forms of neurodegenerative synucleinopathies correlates with the accumulation of alpha-synuclein immunoreactive-containing inclusions. Given that dysautonomia has a significant impact on the quality of life of sufferers and autonomic symptoms are generally treatable, a prompt diagnostic testing and treatment should be provided. Moreover, new evidence suggests that autonomic dysfunction can be used as an outcome prediction factor in some forms of synucleinopathies or premotor diagnostic markers that could be used in the future to define further research avenues. In this review, we describe the autonomic dysfunction of genetic synucleinopathies in comparison to the dysautonomia of sporadic forms of alpha-synuclein accumulation and provide the reader with an up-to-date overview of the current understanding in this fast-growing field. © 2018 International Parkinson and Movement Disorder Society.

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Section: Autonomic Dysfunction In Familial Pd Vs Msa and Ipdsupporting

confidence: 64%

Section: Familial Pd and Autonomic Dysfunctionmentioning

confidence: 87%

Autonomic dysfunction in genetic forms of synucleinopathies

et al. 2018

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“…Several hub-genes involved directly or indirectly that regulate the nervous system were found among AF-DEGs. Visanji’s group compared resting electrocardiograms of LRRK2 -associated Parkinson’s disease (PD) patients, nonmanifesting carriers, noncarriers, and idiopathic PD patients to investigate heart rate variability in LRRK2 -associated PD [24]. There is evidence that LRRK2 may act as a biofunctional mediator to correlate heart rate variability and PD [24].…”

Section: Discussionmentioning

confidence: 99%

“…Visanji’s group compared resting electrocardiograms of LRRK2 -associated Parkinson’s disease (PD) patients, nonmanifesting carriers, noncarriers, and idiopathic PD patients to investigate heart rate variability in LRRK2 -associated PD [24]. There is evidence that LRRK2 may act as a biofunctional mediator to correlate heart rate variability and PD [24]. In a molecular mechanistic study, the neural protective role for regulating mitochondrial complex I function and oxidative stress in ischemia/reperfusion was identified [25, 26].…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic gene analysis for potential biomarkers and therapeutic targets of atrial fibrillation-related stroke

Zou¹,

Zhang²,

Lv³

et al. 2019

J Transl Med

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Background Atrial fibrillation (AF) is one of the most prevalent sustained arrhythmias, however, epidemiological data may understate its actual prevalence. Meanwhile, AF is considered to be a major cause of ischemic strokes due to irregular heart-rhythm, coexisting chronic vascular inflammation, and renal insufficiency, and blood stasis. We studied co-expressed genes to understand relationships between atrial fibrillation (AF) and stroke and reveal potential biomarkers and therapeutic targets of AF-related stroke. Methods AF-and stroke-related differentially expressed genes (DEGs) were identified via bioinformatic analysis Gene Expression Omnibus (GEO) datasets GSE79768 and GSE58294, respectively. Subsequently, extensive target prediction and network analyses methods were used to assess protein–protein interaction (PPI) networks, Gene Ontology (GO) terms and pathway enrichment for DEGs, and co-expressed DEGs coupled with corresponding predicted miRNAs involved in AF and stroke were assessed as well. Results We identified 489, 265, 518, and 592 DEGs in left atrial specimens and cardioembolic stroke blood samples at < 3, 5, and 24 h, respectively. LRRK2 , CALM1 , CXCR4 , TLR4 , CTNNB1 , and CXCR2 may be implicated in AF and the hub-genes of CD19 , FGF9 , SOX9 , GNGT1 , and NOG may be associated with stroke. Finally, co-expressed DEGs of ZNF566 , PDZK1IP1 , ZFHX3 , and PITX2 coupled with corresponding predicted miRNAs, especially miR-27a-3p, miR-27b-3p, and miR-494-3p may be significantly associated with AF-related stroke. Conclusion AF and stroke are related and ZNF566 , PDZK1IP1 , ZFHX3 , and PITX2 genes are significantly associated with novel biomarkers involved in AF-related stroke. Electronic supplementary material The online version of this article (10.1186/s12967-019-1790-x) contains supplementary material, which is available to authorized users.

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“…Non-motor features and early predictors of PD also include reduced heart-rate variability (HRV) and cardiac sympathetic neurodegeneration [71,72]. In a study using classic HRV parameters, there was no difference between LRRK2-PD and healthy controls [73]. However, a follow-up study of the same cohort analyzed novel HRV parameters and showed that there is more vagal involvement in LRRK2-PD and even in a subset of LRRK2 nonmanifesting carriers suggesting a pre-clinical endophenotype of impairment of cardiac innervation [74].…”

Section: Motor and Non-motor Features In Lrrk2-pdmentioning

confidence: 99%

Genetic and Environmental Factors Influence Pleomorphy of lRRK2 Parkinsonism

Chittoor-Vinod¹,

Nichols²,

Schüle³

2020

Preprint

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Missense mutations in the LRRK2 gene were first identified as a pathogenic cause of Parkinson’s disease (PD) in 2004. Soon thereafter, a founder mutation in LRRK2, p.Gly2019Ser (rs34637584), was described, and it is now estimated that there are approximately 100,000 people worldwide that carry this risk variant. While the clinical presentation of LRRK2 parkinsonism has been largely indistinguishable from sporadic PD, disease penetrance and age at onset can be quite variable. In addition, its neuropathological features span a wide range from nigrostriatal loss with Lewy body pathology, lack thereof, or atypical neuropathology including a large proportion of cases with concomitant Alzheimer’s pathology, hailing LRRK2 parkinsonism as the "Rosetta stone" of parkinsonian disorders. These differences may result from interactions between LRRK2 mutant protein and other proteins or environmental factors that modify LRRK2 function, and thereby influence pathobiology. This review explores how potential genetic and biochemical modifiers of LRRK2 function may contribute to the onset and clinical presentation of LRRK2 parkinsonism. We review, which genetic modifiers of LRRK2 influence clinical symptoms, age at onset, and penetrance, what LRRK2 mutations are associated with pleomorphic LRRK2 neuropathology, and which environmental modifiers can augment LRRK2 mutant pathophysiology. Understanding how LRRK2 function is influenced and modulated by other interactors and environmental factors –either increasing toxicity or providing resilience- will inform targeted therapeutic development in the years to come. This will allow developing disease-modifying therapies for PD and LRRK2-related neurodegeneration.

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Heart rate variability in leucine‐rich repeat kinase 2‐associated Parkinson's disease

Abstract: Heart rate variability may remain intact in LRRK2-associated PD, adding to a growing literature supporting clinical-pathologic differences between LRRK2-associated and idiopathic PD. © 2017 International Parkinson and Movement Disorder Society.

Cited by 22 publications

References 37 publications

Autonomic dysfunction in genetic forms of synucleinopathies

Autonomic dysfunction in genetic forms of synucleinopathies

Bioinformatic gene analysis for potential biomarkers and therapeutic targets of atrial fibrillation-related stroke

Genetic and Environmental Factors Influence Pleomorphy of lRRK2 Parkinsonism

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