RESUMEN
BACKGROUND: Recent work has shown loss of phosphodiesterase 10A levels in middle-stage and advanced treated patients with PD, which was associated with motor symptom severity. OBJECTIVES: To assess phosphodiesterase 10A levels in early PD and compare with loss of dopamine transporter as markers of disease burden. METHODS: Seventy-eight subjects were included in this study (17 early de novo, 15 early l-dopa-treated, 24 moderate-advanced l-dopa-treated patients with PD, and 22 healthy controls). All participants underwent [11 C]IMA107 PET, [11 C]PE2I PET, and 3-Tesla MRI scan. RESULTS: Early de novo PD patients showed loss of [11 C]IMA107 and of [11 C]PE2I binding in caudate and putamen (P < 0.001); early l-dopa-treated PD patients showed additional loss of [11 C]IMA107 in the caudate (P < 0.001; annual decline 3.6%) and putamen (P < 0.001; annual decline 2.8%), but loss of [11 C]PE2I only in the putamen (P < 0.001; annual decline 6.8%). Lower [11 C]IMA107 correlated with lower [11 C]PE2I in the caudate (rho = 0.51; P < 0.01) and putamen (rho = 0.53; P < 0.01). Longer disease duration correlated with lower [11 C]IMA107 in the caudate (rho = -0.72; P < 0.001) and putamen (rho = -0.48; P < 0.01), and with lower [11 C]PE2I only in the putamen (rho = -0.65; P < 0.001). Higher burden of motor symptoms correlated with lower [11 C]IMA107 in the caudate (rho = -0.42; P < 0.05) and putamen (rho = -0.41; P < 0.05), and with lower [11 C]PE2I only in the putamen (rho = -0.69; P < 0.001). CONCLUSION: Our findings demonstrate loss of phosphodiesterase 10A levels very early in the course of PD and is associated with the gradual and progressive increase of motor symptoms. Phosphodiesterase 10A imaging shows similar potential with dopamine transporter imaging to follow disease progression. © 2019 International Parkinson and Movement Disorder Society.
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/efectos de los fármacos , Compuestos Heterocíclicos con 2 Anillos/farmacología , Nortropanos/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Quinoxalinas/farmacología , Progresión de la Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Humanos , Imagen por Resonancia Magnética/métodos , Enfermedad de Parkinson/diagnóstico , Tomografía de Emisión de Positrones/métodos , Putamen/efectos de los fármacos , Putamen/metabolismoRESUMEN
Little is known about the rate of progression of striatal dysfunction in subjects with parkin-linked parkinsonism. Being a heterozygous parkin gene carrier may confer susceptibility to Parkinson's disease (PD). In a previous (18)F-dopa PET study, we reported that 69% of carriers of a single parkin mutation showed subclinical loss of putamen dopaminergic function. Using serial (18)F-dopa PET, the present longitudinal study addresses rates of progression of nigrostriatal dysfunction in both compound heterozygous (parkin-linked parkinsonism) and single heterozygous parkin gene carriers. Three symptomatic patients who were compound heterozygotes for parkin gene mutations and six asymptomatic heterozygous carriers were clinically assessed and had (18)F-dopa PET at baseline and again after 5 years. The patients with symptomatic parkin showed a mean 0.5% annual reduction in putamen (18)F-dopa uptake over 5 years while caudate (18)F-dopa uptake declined by a mean annual rate of 2 %. The asymptomatic heterozygote gene carriers showed a mean 0.56% annual reduction in putamen and 0.62 % annual reduction in caudate (18)F-dopa uptake. Neurological examination at both baseline and follow-up showed no evidence of parkinsonism. Loss of nigrostriatal dysfunction in parkin-linked parkinsonism occurs at a very slow rate compared to the 9-12% annual loss of putamen (18)F-dopa uptake reported for idiopathic PD. Although subclinical reductions of striatal (18)F-dopa uptake are common in carriers of a single parkin mutation their slow rate of progression suggests that few if any of these will develop clinical parkinsonism.
Asunto(s)
Cuerpo Estriado , Dihidroxifenilalanina , Enfermedad de Parkinson , Sustancia Negra , Ubiquitina-Proteína Ligasas/genética , Anciano , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/patología , Cuerpo Estriado/fisiopatología , Dihidroxifenilalanina/análogos & derivados , Dihidroxifenilalanina/efectos de los fármacos , Femenino , Heterocigoto , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Tomografía de Emisión de Positrones/métodos , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/patología , Sustancia Negra/fisiopatologíaRESUMEN
Autosomal recessive parkin (PARK2) gene-related parkinsonism may be phenotypically and pathophysiologically distinct from idiopathic Parkinson's disease (PD). Furthermore, asymptomatic subjects carrying a single parkin mutation ("parkin carriers") may show striatal dopaminergic dysfunction and increased cortical movement-related activation. Here, we used transcranial magnetic stimulation (TMS) to study corticospinal and intracortical excitability in manifesting parkin patients and asymptomatic carriers. We studied resting and active motor thresholds (RMT/AMT), central motor conduction time (CMCT), active recruitment curves, short-interval intracortical inhibition (SICI) and facilitation (ICF), SICI recruitment curve, and cortical silent period (CSP) in 8 patients "off" medication, 7 carriers, and two groups of age-matched controls (n = 21). Patients had longer CMCTs compared to controls with a significant negative correlation between CMCT duration and onset age (r = -0.83, P = 0.04). Carriers had increased RMT/AMT; the time course of SICI/ICF and the duration of CSP were normal in both patients and carriers; however slight abnormalities in the recruitment of SICI were found in the carriers. Prolonged CMCT and normal cortical inhibitory mechanisms in parkin patients may be of value in the differentiation from idiopathic PD. The subclinical electrophysiological abnormalities found in carriers may represent underlying compensatory mechanisms.
Asunto(s)
Corteza Motora/fisiopatología , Mutación/genética , Enfermedad de Parkinson , Tractos Piramidales/fisiopatología , Ubiquitina-Proteína Ligasas/genética , Adulto , Anciano , Análisis de Varianza , Estudios de Casos y Controles , Estimulación Eléctrica , Electromiografía , Potenciales Evocados Motores/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Conducción Nerviosa/fisiología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Tiempo de Reacción/fisiología , Reclutamiento Neurofisiológico/fisiología , Umbral Sensorial , Estimulación Magnética Transcraneal/métodosRESUMEN
We have established that the frequency of LRRK2 mutations in a series of 118 cases of familial Parkinson's disease is 5.1%. In the largest family with autosomal dominant, late-onset Parkinson's disease where affected subjects share a Y1699C missense mutation we provide a detailed clinical, pathological and imaging report. The phenotype in this large British kindred included asymmetrical, levodopa-responsive parkinsonism where unilateral leg tremor at onset and foot dystonia were prominent features. There was no significant abnormality of cognition but there was prominent behavioural disorder. We observed a lower age of onset in successive generations. Histopathology in one patient showed substantia nigra cell loss and Lewy body formation, with small numbers of cortical Lewy bodies. 18F-dopa positron emission tomography (PET) in another patient showed a pattern of nigrostriatal dysfunction typical of idiopathic Parkinson's disease. 18F-dopa-PET scans in unaffected family members prior to identifying the disease locus did not detect subclinical nigrostriatal dysfunction. Olfaction was assessed in affected subjects and Lewy bodies were identified in the olfactory bulb as well as cortex and brainstem of one deceased patient. In order to assess the role of mutations in this gene in other familial cases we undertook a mutation screen of all 51 exons of LRRK2 in 117 other smaller British kindreds with familial Parkinson's disease. The commonest mutation was G2019S and we also identified two novel mutations, R1941H and T2356I, in the coding sequence. These data suggest that parkinsonism caused by mutations in LRRK2 is likely to represent the commonest locus for autosomal dominant Parkinson's disease with a phenotype, pathology and in vivo imaging similar to idiopathic, late-onset Parkinson's disease.
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Mutación Missense , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Edad de Inicio , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Análisis Mutacional de ADN , Inglaterra , Femenino , Genes Dominantes , Ligamiento Genético , Pruebas Genéticas , Haplotipos , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Escala de Lod , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Bulbo Olfatorio/patología , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/patología , Linaje , Tomografía de Emisión de Positrones , RadiofármacosRESUMEN
A 24-year-old Ugandan woman was referred for a neurology opinion after complaining of a year long history of right-sided retro-orbital stabbing pain. Brain imaging revealed a coincidental 3 mm left ophthalmic artery aneurysm. Marfanoid habitus was noted; after further investigations she was diagnosed with mild aortic root dilatation, subtle lens dislocation and Marfan syndrome. Her symptoms were secondary to temporomandibular joint dysfunction, an under-recognised complication of Marfan syndrome. Her ophthalmic artery aneurysm is likely to be a coincidental finding.
Asunto(s)
Aneurisma/etiología , Cefalea/etiología , Síndrome de Marfan/complicaciones , Síndrome de Marfan/diagnóstico , Arteria Oftálmica , Femenino , Humanos , Adulto JovenRESUMEN
PET studies in parkin-linked parkinsonism have generally been performed to assess striatal dopaminergic dysfunction and very little is known about the involvement of other monoaminergic structures in these patients. Measurements of (18)F-dopa uptake into serotonergic and noradrenergic structures provide an indication of the functional integrity of these nerve terminals. We used (18)F-dopa PET to assess changes in brain monoaminergic function associated with parkin mutations. Twelve patients with parkin-linked parkinsonism and 12 asymptomatic parkin heterozygotes were included in the study. Eleven healthy controls, 12 patients with idiopathic Parkinson's disease (IPD), and four patients with PINK1 mutations were also investigated for comparison. parkin patients and IPD patients were matched for striatal dopaminergic dysfunction, as measured by (18)F-dopa uptake. Compared to controls, parkin patients showed significant (18)F-dopa reductions in the caudate, putamen, ventral striatum, locus coeruleus, midbrain raphe, and pallidum. The same structures showed reduced uptake in IPD patients, who additionally had significant reductions in hypothalamus, ventral anterior thalamus, and pineal gland. Direct comparison of parkin with IPD patients showed that hypothalamus was targeted in IPD and midbrain raphe in parkin disease. Patients with PINK1 mutation and several parkin heterozygotes also showed monoaminergic dysfunction. These findings suggest that parkin patients and IPD patients with similar striatal dysfunction have different patterns of monoaminergic involvement, with more widespread dysfunction in IPD.
Asunto(s)
Monoaminas Biogénicas/metabolismo , Encéfalo/diagnóstico por imagen , Mutación/genética , Enfermedad de Parkinson , Tomografía de Emisión de Positrones , Ubiquitina-Proteína Ligasas/genética , Adulto , Anciano , Encéfalo/metabolismo , Encéfalo/patología , Femenino , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Proteínas Quinasas/genética , Estadísticas no ParamétricasRESUMEN
Medicated patients with Parkinsonism and parkin gene mutations have been reported to show a significant decrease in striatal dopamine D2 receptors (D2R) in comparison to medicated idiopathic Parkinson's disease (IPD) patients with similar age and disease severity. The aim of this study was to verify whether the genetic defect per se is responsible for this decrease. We have studied with [11C]raclopride (RAC) positron emission tomography (PET) in a group of 14 sporadic patients with parkin-linked Parkinsonism, 6 of whom had never received levodopa or dopamine agonists. The remaining 8 patients had been treated with levodopa for at least 5 years. Presynaptic striatal [18F]dopa storage was not significantly different between these two groups of patients. In untreated parkin-positive patients, significant putaminal increases in RAC-binding potential (BP) were found in comparison to an age-matched healthy control group by using a classical region of interest approach and statistical parametric mapping. In contrast, levodopa-treated parkin-positive patients showed significant decreases in RAC-BP in the caudate and putamen when compared to an age-matched healthy control group. The RAC PET findings revealed that striatal D2R upregulation occurs in dopaminergic drug-naive parkin-positive patients, in a similar fashion to the upregulation reported in drug-naive IPD. D2R downregulation observed in medicated parkin-positive patients, therefore, is not caused primarily by the genetic defect itself. Parkin-positive patients appear to have a greater susceptibility to the exposure to dopaminergic medication than IPD patients, which in turn might be an indirect effect of their genetic mutation.
Asunto(s)
Enfermedad de Parkinson/genética , Receptores de Dopamina D2/genética , Ubiquitina-Proteína Ligasas/genética , Adulto , Edad de Inicio , Cuerpo Estriado/fisiopatología , Antagonistas de Dopamina/farmacocinética , Amplificación de Genes , Regulación de la Expresión Génica , Humanos , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/fisiopatología , Reacción en Cadena de la Polimerasa , Tomografía de Emisión de Positrones , Racloprida/farmacocinética , Radiografía , Valores de ReferenciaRESUMEN
We have used MR segmented inversion recovery ratio imaging (SIRRIM) of the substantia nigra pars compacta to detect and correlate nigral signal change in idiopathic Parkinson's disease (PD) and parkin patients with striatal (18)F-dopa uptake. Nine PD patients, nine parkin patients, and eight control subjects were studied with a combination of MR inversion recovery sequences sensitive to nigral cell loss. Blinded independent observer rating and quantified nigral signal analysis were performed on all subjects. Striatal regions of interest were defined on T(1)-weighted MRI co-registered to (18)F-dopa positron emission tomography. On blinded observer rating of the SIRRIM dorsal and ventral nigral images, 25% (2/8) of control subjects, 44% (4/9) of PD patients, and 67% (6/9) of parkin patients were classified as abnormal. Quantified total nigral signal intensities were reduced to a greater extent in the parkin compared to PD patients. There was a greater predilection for signal reduction in the ventral nigral slice of the PD compared to the parkin patient group, who showed a more uniform involvement. All PD and parkin patients were discriminated from controls on the basis of caudate and putamen (18)F-dopa Ki reductions. Our results suggest that MR segmented inversion recovery ratio imaging shows poor sensitivity for discriminating parkin and idiopathic PD patients from normal controls. Where nigral signal abnormalities were seen, parkin patients manifested generalized nigral cell loss with widespread striatal dopamine terminal dysfunction compared with the lateral nigral targeting seen in PD and selective loss of putamen (18)F-dopa uptake.
Asunto(s)
Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Dopamina/metabolismo , Degeneración Nerviosa/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Sustancia Negra/patología , Ubiquitina-Proteína Ligasas/genética , Adulto , Núcleo Caudado/metabolismo , Núcleo Caudado/patología , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Degeneración Nerviosa/metabolismo , Enfermedad de Parkinson/diagnóstico por imagen , Mutación Puntual/genética , Tomografía de Emisión de Positrones , Putamen/metabolismo , Putamen/patología , Radiofármacos/farmacocinética , Sustancia Negra/metabolismoRESUMEN
SCA6 is a slowly progressive, late-onset cerebellar ataxia due to a trinucleotide expansion in the CACNA1A gene. We describe two unrelated cases that presented with Parkinsonism and cerebellar ataxia. One case was L-dopa-responsive with a pattern of (18)F-dopa uptake similar to Parkinson's disease, and the second case was not L-dopa-responsive and had an atypical pattern of nigrostriatal dysfunction. We suggest that SCA6, in common with SCA2 and SCA3, may be associated with Parkinsonism attributable to nigral loss and dopaminergic dysfunction. Moreover, isolated cases may be confused with multiple system atrophy.
Asunto(s)
Canales de Calcio/genética , Cuerpo Estriado/fisiopatología , Trastornos Parkinsonianos/etiología , Trastornos Parkinsonianos/fisiopatología , Ataxias Espinocerebelosas/complicaciones , Ataxias Espinocerebelosas/genética , Sustancia Negra/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Cuerpo Estriado/metabolismo , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Trastornos Parkinsonianos/diagnóstico , Linaje , Fenotipo , Mutación Puntual/genética , Tomografía de Emisión de Positrones , Ataxias Espinocerebelosas/diagnóstico , Sustancia Negra/metabolismo , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
We report on a large Brazilian kindred with young-onset parkinsonism due to either a homozygous or heterozygous mutation in parkin. A total of 6 members were affected: 5 were homozygous and 1 heterozygous for a deletion in exon 4. Two other heterozygotes also had extrapyramidal signs. All affected subjects showed characteristic features of parkin disease with foot dystonia and an excellent response to levodopa complicated by motor fluctuations and dyskinesia within 3 years of therapy. Careful clinical follow-up over 10 years showed the phenotype was similar in all the homozygotes with asymmetrical limb bradykinesia and early walking difficulties. Some acceleration of disability was observed in some of the cases as they entered the third decade of illness, but dementia was absent.
Asunto(s)
Heterocigoto , Trastornos Parkinsonianos/etnología , Trastornos Parkinsonianos/genética , Ubiquitina-Proteína Ligasas/genética , Adulto , Antiparkinsonianos/efectos adversos , Brasil , Análisis Mutacional de ADN , Discinesia Inducida por Medicamentos/etiología , Discinesia Inducida por Medicamentos/fisiopatología , Exones/genética , Femenino , Estudios de Seguimiento , Pie/fisiopatología , Genotipo , Humanos , Levodopa/efectos adversos , Masculino , Trastornos Parkinsonianos/tratamiento farmacológico , Linaje , Mutación Puntual/genéticaRESUMEN
The authors report the clinical characteristics of a Sephardic Jewish kindred with autosomal recessive DYT2-like primary torsion dystonia. Three siblings had childhood onset of limb dystonia, and slow progression to generalized dystonia with predominant cranio-cervical involvement. There were no other abnormal signs, apart from dystonia and jerky tremor over a 12-year follow-up. All investigations for other causes of primary and secondary dystonia had normal results.
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Distonía Muscular Deformante/diagnóstico , Distonía Muscular Deformante/genética , Chaperonas Moleculares , Adulto , Proteínas Portadoras/genética , Niño , Preescolar , Consanguinidad , Progresión de la Enfermedad , Distonía Muscular Deformante/clasificación , Familia , Femenino , Genes Recesivos , Humanos , Lactante , Irán/etnología , Judíos/etnología , Judíos/genética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , LinajeRESUMEN
Mutations in the parkin gene, PARK2, are a common cause of parkinsonism in familial as well as isolated cases with an age of onset <40 years and should be considered in the diagnostic work up of young-onset parkinsonism. We report a detailed clinical evaluation of a personal series of 24 patients with mutations in the parkin gene. The clinical presentation of most cases was broadly comparable to that of previous descriptions of autosomal recessive early-onset or juvenile parkinsonism and young-onset Parkinson's disease and also had similarities with phenotypes of dopa-responsive dystonia. However, our only case with consanguineous parents had an age of onset of 54 years. We report three new phenotypes at presentation: cervical dystonia; autonomic dysfunction and peripheral neuropathy; and pure exercise-induced dystonia. We emphasize a number of clinical features that can be seen in parkin disease: focal dystonia; early instability; freezing; festination or retropulsion; concurrent autonomic failure; dramatic response to anticholinergics; early or atypical L-dopa-induced dyskinesias; exquisite sensitivity to small doses of L-dopa; and recurrent psychosis, even taking L-dopa alone. We also report behavioural disorder prior to the onset of parkinsonism. Some relatives carrying a single parkin mutation without extrapyramidal symptoms or signs also had psychiatric symptoms that might be related to their carrier status.
Asunto(s)
Ligasas/genética , Mutación , Trastornos Parkinsonianos/genética , Ubiquitina-Proteína Ligasas , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedades del Sistema Nervioso Autónomo/genética , Distonía/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Levodopa/uso terapéutico , Masculino , Trastornos Mentales/etiología , Trastornos Mentales/genética , Persona de Mediana Edad , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/psicología , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa/métodosRESUMEN
Molecular and clinical characterization of parkin-associated parkinsonism is well described; however, there are no data available on progression of dopamine terminal dysfunction in parkin-associated disease. We have used [(18)F]dopa PET serially to study members of a family with young-onset parkinsonism who are compound heterozygous for mutations in the parkin gene, having an exonic deletion and a novel intronic splice site mutation. Four patients have been studied twice, 10 years apart, to assess disease progression. Additionally, we have studied five asymptomatic family members, four of whom carry a single parkin mutation and one individual who has a normal genotype. Two of the carriers and the individual with the normal genotype had repeat [(18)F]dopa PET. The group of parkin patients showed a significantly slower loss of putamen [(18)F]dopa uptake (P = 0.0008) compared with a group of idiopathic Parkinson's disease (IPD) patients who had baseline putamen [(18)F]dopa uptake and disease severity similar to the parkin group. These results indicate that disease progression in patients with parkin mutations is slower than that of IPD patients. The group of asymptomatic parkin carriers also showed significant striatal dopaminergic dysfunction, and three of them developed subtle extrapyramidal signs. However, the two carriers scanned twice showed no progression over a 7-year period. The slower rate of disease progression in parkin patients may explain the near normal longevity of these patients with young onset parkinsonism.
Asunto(s)
Cuerpo Estriado/metabolismo , Dihidroxifenilalanina/metabolismo , Ligasas/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Sustancia Negra/metabolismo , Ubiquitina-Proteína Ligasas , Adulto , Anciano , Cuerpo Estriado/diagnóstico por imagen , Progresión de la Enfermedad , Femenino , Radioisótopos de Flúor , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Linaje , Estadísticas no Paramétricas , Sustancia Negra/diagnóstico por imagen , Tomografía Computarizada de Emisión/estadística & datos numéricosRESUMEN
PARK6, a locus for early-onset recessive parkinsonism, has been causally implicated in nine unrelated families from four different countries. The gene is still unidentified and hence the importance of PARK6 as a cause of Parkinson's disease is unknown. To date, no pathology or functional imaging studies are available on PARK6-linked parkinsonism. We have used (18)F-dopa positron emission tomography to study four patients who are homozygous and three asymptomatic relatives who are heterozygous for PARK6. The clinically affected PARK6 subjects had a similar 85% reduction in posterior dorsal putamen (18)F-dopa uptake to a group of idiopathic Parkinson's disease patients matched for clinical disease severity and duration but showed significantly greater involvement of head of caudate and anterior putamen. The group of asymptomatic PARK6 carriers showed a significant mean 20 to 30% reduction in caudate and putamen (18)F-dopa uptake in comparison with controls, individual values falling toward the bottom of the normal range. Our results indicate that PARK6 pathology results in a more uniform loss of striatal dopamine terminal function than Parkinson's disease. The subclinical loss of striatal dopamine storage capacity found in the PARK6 carriers implies that the unidentified gene on the short arm of chromosome 1 exhibits either haploinsufficency or a dominant negative effect.
Asunto(s)
Dopamina/fisiología , Ligamiento Genético , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/genética , Tomografía Computarizada de Emisión/métodos , Adulto , Anciano , Dopamina/genética , Femenino , Radioisótopos de Flúor , Tamización de Portadores Genéticos , Marcadores Genéticos/genética , Humanos , Masculino , Persona de Mediana Edad , Trastornos Parkinsonianos/metabolismo , Linaje , Estadísticas no ParamétricasRESUMEN
To investigate striatal and cortical pre- and postsynaptic dopaminergic function in parkin-linked parkinsonism, 13 unrelated patients homozygous or compound heterozygous for parkin mutations were studied with [(18)F]dopa and [(11)C]raclopride (RAC) PET. Data were compared with a young-onset Parkinson's disease (YOPD) cohort, matched for age, disease severity and duration, but negative for parkin mutations. Significant changes in [(18)F]dopa uptake and RAC binding potential (BP) were localized in striatum using regions of interest (ROIs) and throughout the entire brain volume with statistical parametric mapping (SPM). As expected, both YOPD and parkin patients showed significant decreases in striatal [(18)F]dopa uptake; however, in parkin patients, additional reductions in caudate and midbrain were localized with SPM. The RAC-BP was significantly decreased in striatal, thalamic and cortical areas (temporal, orbito-frontal and parietal cortex) in parkin compared with YOPD patients. Our [(18)F]dopa PET findings suggest that, compared with YOPD, parkin disease is associated with more severe and widespread presynaptic dopaminergic deficits. The global decreases in D2 binding found in parkin compared with YOPD patients could be a direct consequence of the parkin genetic defect itself or a greater susceptibility to receptor downregulation following long-term dopaminergic agent exposure. Cortical reductions in D2 binding may contribute to the behavioural problems reported in parkin patients.