Neurocirculatory and nigrostriatal abnormalities in Parkinson disease from LRRK2 mutation.
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.


CONCLUSIONS
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.
Goldstein
D S
DS
Clinical Neurocardiology Section, National Institutes on Neurological Disorders and Stroke, National Institute on Aging, NIH, Bethesda, MD 20892-1620, USA. goldsteind@ninds.nih.gov
Imrich
R
R
Peckham
E
E
Holmes
C
C
Lopez
G
G
Crews
C
C
Hardy
J
J
Singleton
A
A
Hallett
M
M
D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D001342:Autonomic Nervous System Diseases / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D017704:Baroreflex / Q000235:genetics; D004252:DNA Mutational Analysis; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006321:Heart / Q000000981:diagnostic imaging / Q000294:innervation / Q000503:physiopathology; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D049268:Positron-Emission Tomography; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012021:Reflex, Abnormal / Q000235:genetics; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D014636:Valsalva Maneuver / Q000235:genetics
C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases