Journal ArticleDOI
Neurocirculatory and nigrostriatal abnormalities in Parkinson disease from LRRK2 mutation
David S. Goldstein,Richard Imrich,Elizabeth Peckham,Clive Holmes,Grisel Lopez,C. Crews,John Hardy,Amanda Singleton,Mark Hallett +8 more
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TLDR
The results fit with the concept that in LRRK2 PD, parkinsonism, cardiac sympathetic denervation, baroreflex-sympathoneural and barore Flex-cardiovagal failure can result from a common pathogenetic process.Abstract:
BACKGROUND: Patients with Parkinson disease (PD) often have cardiac sympathetic denervation and failure of neurocirculatory regulation by baroreflexes. Familial PD caused by mutation of the gene encoding alpha-synuclein or by alpha-synuclein gene triplication also features cardiac sympathetic denervation and baroreflex failure. METHODS: Here we report results of cardiac sympathetic neuroimaging by 6-[(18)F]fluorodopamine PET, baroreflex testing based on beat-to-beat hemodynamic responses to the Valsalva maneuver, and nigrostriatal neuroimaging using 6-[(18)F] fluorodopa PET in a proband with mutation of the gene encoding leucine-rich repeat kinase 2 (LRRK2), the most common genetic abnormality identified so far in familial PD. RESULTS: The patient had no detectable 6-[(18)F] fluorodopamine-derived radioactivity in the left ventricular myocardium, a progressive fall in blood pressure during the Valsalva maneuver and no pressure overshoot after release of the maneuver, and decreased 6-[(18)F] fluorodopa-derived radioactivity bilaterally in the putamen and substantia nigra. CONCLUSION: This patient with Parkinson disease (PD) caused by LRRK2 mutation had evidence of cardiac sympathetic denervation, baroreflex-sympathoneural and baroreflex-cardiovagal failure, and nigrostriatal dopamine deficiency, a pattern resembling that in the sporadic disease. The results fit with the concept that in LRRK2 PD, parkinsonism, cardiac sympathetic denervation, and baroreflex failure can result from a common pathogenetic process.read more
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Journal ArticleDOI
LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice
Martin C. Herzig,Carine Kolly,Elke Persohn,Diethilde Theil,Tatjana Schweizer,Thomas Hafner,Christine Stemmelen,Troxler Thomas J,Peter Schmid,Simone Danner,Christian Schnell,Matthias Mueller,Bernd Kinzel,Armelle Grevot,Federico Bolognani,Martina Stirn,Rainer Kuhn,Klemens Kaupmann,P. Herman van der Putten,Giorgio Rovelli,Derya R. Shimshek +20 more
TL;DR: A role for LRRK2 in kidney and lung physiology is demonstrated and it is shown that LRRk2 kinase function affects L RRK2 protein steady-state levels thereby altering putative scaffold/GTPase activity.
Journal ArticleDOI
Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study.
Owen A. Ross,Alexandra I. Soto-Ortolaza,Michael G. Heckman,Jan O. Aasly,Nadine Abahuni,Grazia Annesi,Justin A. Bacon,Soraya Bardien,Maria Bozi,Alexis Brice,Laura Brighina,Christine Van Broeckhoven,Christine Van Broeckhoven,Jonathan Carr,Marie-Christine Chartier-Harlin,Marie-Christine Chartier-Harlin,Efthimios Dardiotis,Efthimios Dardiotis,Dennis W. Dickson,Nancy N. Diehl,Alexis Elbaz,Alexis Elbaz,Carlo Ferrarese,Alessandro Ferraris,Brian K. Fiske,J. Mark Gibson,Rachel A. Gibson,Georgios M. Hadjigeorgiou,Georgios M. Hadjigeorgiou,Nobutaka Hattori,John P. A. Ioannidis,John P. A. Ioannidis,Barbara Jasinska-Myga,Beom S. Jeon,Yun Joong Kim,Christine Klein,Rejko Krüger,Elli Kyratzi,Suzanne Lesage,Suzanne Lesage,Suzanne Lesage,Chin-Hsien Lin,Timothy Lynch,Demetrius M. Maraganore,George D. Mellick,Eugénie Mutez,Eugénie Mutez,Christer Nilsson,Grzegorz Opala,Sung Sup Park,Andreas Puschmann,Aldo Quattrone,Manu Sharma,Peter A. Silburn,Young H. Sohn,Leonidas Stefanis,Vera Tadic,Jessie Theuns,Jessie Theuns,Hiroyuki Tomiyama,Ryan J. Uitti,Enza Maria Valente,Simone Van De Loo,Demetrios K. Vassilatis,Carles Vilariño-Güell,Linda R. White,Karin Wirdefeldt,Zbigniew K. Wszolek,Ruey-Meei Wu,Matthew J. Farrer,Matthew J. Farrer +70 more
TL;DR: The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk, and are important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed.
Journal ArticleDOI
Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple system atrophy
David S. Goldstein,Courtney Holmes,Oladi Bentho,Takuya Sato,Jeffrey P. Moak,Yehonatan Sharabi,Richard Imrich,Shielah Conant,Basil A. Eldadah +8 more
TL;DR: PD and MSA feature low PUT:OCC ratios of 6-[18F]fluorodopamine-derived radioactivity and low CSF DOPAC and DOPA concentrations, cross-validating the neuroimaging and neurochemical approaches but not distinguishing the diseases.
Journal ArticleDOI
Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders.
TL;DR: The concept developed here is that DOPAL and alpha-synuclein are nodes in a complex nexus of interacting homeostatic systems that lead to conversion from the stability afforded by negative feedback regulation to the instability, degeneration, and system failure caused by induction of positive feedback loops.
Journal ArticleDOI
Familial Parkinsonism: Study of Original Sagamihara PARK8 (I2020T) Kindred With Variable Clinicopathologic Outcomes
Kazuko Hasegawa,A. Jon Stoessl,Teruo Yokoyama,Hisayuki Kowa,Zbigniew K. Wszolek,Saburo Yagishita +5 more
TL;DR: The study of PARK8-linked parkinsonism affecting several members of the same pedigree shows that the same gene mutation can induce diverse neuropathologies, even if the clinical picture and PET findings are virtually identical.
References
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Journal ArticleDOI
Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen.
TL;DR: The here hypothesized mechanism offers one possible explanation for the sequential and apparently uninterrupted manner in which vulnerable brain regions, subcortical grays and cortical areas become involved in idiopathic Parkinson's disease.
Journal ArticleDOI
A common LRRK2 mutation in idiopathic Parkinson's disease
William P. Gilks,Patrick M. Abou-Sleiman,Sonia Gandhi,Shushant Jain,Andrew B. Singleton,Andrew J. Lees,Karen Shaw,Kailash P. Bhatia,Vincenzo Bonifati,Niall Quinn,John B. Lynch,Daniel G. Healy,Janice L. Holton,Tamas Revesz,Nicholas W. Wood +14 more
TL;DR: It is shown that a common single Mendelian mutation, 2877510 g-->A, which produces a glycine to serine aminoacid substitution at codon 2019 (Gly2019 ser), in idiopathic Parkinson's disease, and suggested that testing for this mutation will be important in the management and genetic counselling of patients with Parkinson's Disease.
Journal ArticleDOI
Pathoanatomy of Parkinson's disease
Heiko Braak,Eva Braak +1 more
TL;DR: The selective vulnerability of nerve cells induces a distinctive distribution pattern of lesions which remains remarkably consistent across cases, and components of the limbic system and the motor system have been shown to be particularly vulnerable to severe destruction.
Journal ArticleDOI
Sources and Significance of Plasma Levels of Catechols and Their Metabolites in Humans
TL;DR: Human plasma contains several catechols, including the catecholamines norepinephrine, epinephrine, and dopamine, their precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), and their deaminated metabolites, dihydroxyphensylglycol, the main neuronal metabolite of nore Pinephrine,
Journal ArticleDOI
Cardiac Sympathetic Denervation in Parkinson Disease
David S. Goldstein,Courtney Holmes,Sheng-Ting Li,Simon R. Bruce,Leo Verhagen Metman,Richard O. Cannon +5 more
TL;DR: S sympathetic neurocirculatory failure is defined as chronic, reproducible orthostatic hypotension associated with abnormal blood pressure responses in both phase II-L and phase IV of the Valsalva maneuver and neurochemical findings indicating decreased norepinephrine release, neuronal uptake, turnover, and synthesis in the heart could provide confirmation.
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