RESUMEN
BACKGROUND: The concept of prodromal Parkinson's disease (PD) involves variable combinations of nonmotor features and subtle motor abnormalities as a result of ongoing neurodegeneration in the brain stem including substantia nigra (SN) and abnormal findings upon transcranial sonography and nuclear imaging. Except for nuclear imaging, the predictive value of risk markers for the conversion to overt PD is low. OBJECTIVE: The objective of this study was to determine whether PD risk markers are associated with changes in brain structure and to what extent cognitive changes are risk markers for PD. METHODS: Diffusion-weighted imaging, voxel-based morphometry, and cortical thickness analysis was performed in 29 individuals with hyposmia and/or an increased SN hyperechogenicity (SN+) upon transcranial sonography and 28 controls without these 2 risk markers. Classical parkinsonian signs were an exclusion criterion. All of the participants underwent a neuropsychological test battery addressing executive functions, learning ability, and verbal fluency. RESULTS: In the PD risk group, diffusion-weighted imaging mean diffusivity was increased in 4 left hemisphere clusters (posterior thalamus, inferior longitudinal fasciculus, fornix, corticospinal tract). A negative relationship of mean diffusivity and smell function was present for the posterior thalamus and the corticospinal tract. There was a significant correlation of mean diffusivity values and SN+ in all clusters. Neither voxel-based morphometry nor cortical thickness analysis revealed any group differences. No relevant group differences were observed for cognitive tests included. CONCLUSION: PD-free individuals with PD risk markers show microstructural changes of the white matter, including areas relevant for motor and limbic processes. In addition, our study provides for the first time a neuroanatomical correlate for SN hyperechogenicity. © 2018 International Parkinson and Movement Disorder Society.
Asunto(s)
Encéfalo/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética/métodos , Enfermedad de Parkinson/diagnóstico por imagen , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Lateralidad Funcional , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estadísticas no Paramétricas , Ultrasonografía Doppler TranscranealRESUMEN
Carriers of a single heterozygous PINK1 (PTEN-induced putative kinase 1) gene mutation provide an ideal opportunity to study the development of parkinsonian motor signs from the very beginning. Measuring tools that reliably represent mild motor symptoms could also facilitate the assessment of future neuroprotective therapies and early diagnosis of Parkinson's disease (PD). We investigated nine family members carrying a heterozygous PINK1 mutation in comparison with 25 age-matched healthy controls. Arm kinematics were quantified during treadmill walking at four different speeds using ultrasound-based motion analysis. Heterozygous PINK1 mutation carriers showed a bilateral reduction of arm swing amplitudes (P = 0.003) and arm anteversion (P = 0.001), which was more pronounced on the predominantly affected body side but also was present, albeit to a lesser degree, contralaterally (amplitude P = 0.01, anteversion P = 0.002, repeated measures analysis of covariance [rmANCOVA]). Single post-hoc comparisons revealed similar results for all speeds on both body sides (P < 0.05) except for 2.0 km/h on the less affected side. A single heterozygous mutation in the PINK1 gene is associated with a bilateral dopaminergic dysfunction in this family. Ultrasound-based three-dimensional motion analysis of arm swing during gait is a suitable tool to quantify even subtle hypokinesia in mildly affected PINK1 mutation carriers, which tends to be easily overlooked on the less affected body side during clinical examination. Therefore, this technique is a promising application in early stage PD and in at-risk populations for the disease.
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Brazo/fisiopatología , Marcha/fisiología , Hipocinesia , Movimiento (Física) , Mutación/genética , Proteínas Quinasas/genética , Adulto , Análisis de Varianza , Fenómenos Biomecánicos , Estudios de Casos y Controles , Femenino , Lateralidad Funcional , Alemania , Humanos , Hipocinesia/genética , Hipocinesia/patología , Hipocinesia/fisiopatología , Masculino , Persona de Mediana Edad , UltrasonografíaRESUMEN
The prerequisite for an earlier diagnosis of Parkinson's disease (PD) are markers that are both sensitive and specific for clinically definite PD and its prediagnosic phases. Promising candidates include enlarged hyperechogenicity of the substantia nigra (SN+) on transcranial sonography (TCS) and hyposmia. However, despite good sensitivity and specificity, both markers have yet failed to yield reliable predictions. We pursue the possibility of combined use in an ongoing population-based cohort. Subjects were recruited from 10,000 inhabitants of Luebeck/Germany aged 50 to 79 years and additional PD patients from our outpatient clinic. After neurological examination, 715 subjects were grouped into clinically definite PD (n = 106), possible prediagnostic PD (ppPD; n = 73), and a control group subdivided into healthy individuals (n = 283) and controls with diseases other than PD (n = 253). Subjects underwent TCS and smell testing. Sensitivity and specificity of SN+ and hyposmia were good for PD; however, positive predictive values (PPV) of both SN+ (5.2%) and olfaction (2.5%) were low. At least one positive/both positive markers were present in 33%/1% of healthy controls, 33%/2% of diseased controls, 62%/7% of ppPD, and 94%/51% of PD. When combining SN+ and hyposmia, PPV increased to 17.6%, with a sensitivity of 51% and a specificity of 98%. Both SN+ and hyposmia offer good enrichment towards PD and ppPD, are stable against other diseases, and the combination of markers highly increases specificity. However, if the combination of SN+ and hyposmia were used as criterion for PD diagnosis, almost half of clinically definite PD and more than 90% of ppPD would have been missed.
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Trastornos del Olfato/etiología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Sustancia Negra/patología , Edad de Inicio , Anciano , Planificación en Salud Comunitaria , Femenino , Humanos , Masculino , Persona de Mediana Edad , Curva ROC , Análisis de Regresión , Sustancia Negra/diagnóstico por imagen , Ultrasonografía Doppler TranscranealRESUMEN
Mutations in the E3 ubiquitin ligase Parkin and the mitochondrial PTEN-induced putative kinase 1 (PINK1) have been identified to cause autosomal recessive forms of familial Parkinson disease, with PINK1 functioning upstream of Parkin in a pathway important for the maintenance of mitochondrial function and morphology. Upon the loss of the mitochondrial membrane potential, Parkin translocates to mitochondria in a PINK1-dependent manner to ubiquitinate mitochondrial proteins. Parkin-mediated polyubiquitination of outer mitochondrial membrane (OMM) proteins recruits the ubiquitin- and LC3-binding adaptor protein p62 to mitochondria and induces mitophagy. Although previous studies examined mitophagy in established cell lines through overexpression approaches, there is an imperative to study the role of endogenous Parkin and PINK1 in human-derived and biologically relevant cell models. Here, we demonstrate in human primary fibroblasts and induced pluripotent stem-derived neurons from controls and PINK1 mutation carriers that endogenous levels of Parkin are not sufficient to initiate mitophagy upon loss of the mitochondrial membrane potential, caused by its (self-)ubiquitination, followed by degradation via the ubiquitin proteasome system. Next, we showed differential PINK1-dependent, Parkin-mediated ubiquitination of OMM proteins, which is Parkin dose-dependent and affects primarily OMM proteins of higher molecular mass. In contrast to the situation fibroblasts, we did not detect mitophagy in induced pluripotent stem-derived neurons even upon overexpression of Parkin. Taken together, our data demonstrate that mitophagy differs between human non-neuronal and neuronal cells and between "endogenous" and "Parkin-overexpressing" cellular models.
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Fibroblastos/citología , Células Madre Pluripotentes Inducidas/citología , Pulmón/citología , Mitofagia , Neuronas/citología , Proteínas Quinasas/metabolismo , Células Madre/citología , Ubiquitina-Proteína Ligasas/metabolismo , Línea Celular , Relación Dosis-Respuesta a Droga , Homocigoto , Humanos , Microscopía Fluorescente/métodos , Mitocondrias/metabolismo , Modelos Biológicos , Mutación , Mutación Missense , Neuronas/metabolismo , Enfermedad de Parkinson/metabolismo , Ubiquitina/química , Ubiquitina/metabolismoRESUMEN
OBJECTIVE: A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family. METHODS: Genome-wide linkage analysis was carried out in 14 family members followed by genome sequencing in 2 individuals. The index patient underwent a detailed neurological follow-up examination, including electrophysiological studies and magnetic resonance imaging scanning. Biopsies of the skin and olfactory mucosa were obtained, and expression levels of TUBB4 mRNA were determined by quantitative real-time polymerase chain reaction in 3 different cell types. All exons of TUBB4 were screened for mutations in 394 unrelated dystonia patients. RESULTS: The disease-causing gene was mapped to a 23cM region on chromosome 19p13.3-p13.2 with a maximum multipoint LOD score of 5.338 at markers D9S427 and D9S1034. Genome sequencing revealed a missense variant in the TUBB4 (tubulin beta-4; Arg2Gly) gene as the likely cause of disease. Sequencing of TUBB4 in 394 unrelated dystonia patients revealed another missense variant (Ala271Thr) in a familial case of segmental dystonia with spasmodic dysphonia. mRNA expression studies demonstrated significantly reduced levels of mutant TUBB4 mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls. INTERPRETATION: A mutation in TUBB4 causes DYT4 dystonia in this Australian family with so-called whispering dysphonia, and other mutations in TUBB4 may contribute to spasmodic dysphonia. Given that TUBB4 is a neuronally expressed tubulin, our results imply abnormal microtubule function as a novel mechanism in the pathophysiology of dystonia.
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Distonía Muscular Deformante/genética , Predisposición Genética a la Enfermedad , Mutación/genética , Tubulina (Proteína)/genética , Trastornos de la Voz/congénito , Cromosomas Humanos Par 19/genética , Análisis Mutacional de ADN , Distonía Muscular Deformante/fisiopatología , Salud de la Familia , Femenino , Estudios de Seguimiento , Ligamiento Genético , Humanos , Imagenología Tridimensional , Imagen por Resonancia Magnética , Masculino , Índice de Severidad de la Enfermedad , Trastornos de la Voz/genética , Trastornos de la Voz/fisiopatologíaRESUMEN
Musician's dystonia (MD) affects 1% to 2% of professional musicians and frequently terminates performance careers. It is characterized by loss of voluntary motor control when playing the instrument. Little is known about genetic risk factors, although MD or writer's dystonia (WD) occurs in relatives of 20% of MD patients. We conducted a 2-stage genome-wide association study in whites. Genotypes at 557,620 single-nucleotide polymorphisms (SNPs) passed stringent quality control for 127 patients and 984 controls. Ten SNPs revealed P < 10(-5) and entered the replication phase including 116 MD patients and 125 healthy musicians. A genome-wide significant SNP (P < 5 × 10(-8) ) was also genotyped in 208 German or Dutch WD patients, 1,969 Caucasian, Spanish, and Japanese patients with other forms of focal or segmental dystonia as well as in 2,233 ethnically matched controls. Genome-wide significance with MD was observed for an intronic variant in the arylsulfatase G (ARSG) gene (rs11655081; P = 3.95 × 10(-9) ; odds ratio [OR], 4.33; 95% confidence interval [CI], 2.66-7.05). rs11655081 was also associated with WD (P = 2.78 × 10(-2) ) but not with any other focal or segmental dystonia. The allele frequency of rs11655081 varies substantially between different populations. The population stratification in our sample was modest (λ = 1.07), but the effect size may be overestimated. Using a small but homogenous patient sample, we provide data for a possible association of ARSG with MD. The variant may also contribute to the risk of WD, a form of dystonia that is often found in relatives of MD patients.
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Arilsulfatasas/genética , Trastornos Distónicos/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Desempeño Psicomotor/fisiología , Sitios Genéticos , Pruebas Genéticas/métodos , Humanos , Riesgo , Factores de RiesgoRESUMEN
BACKGROUND: Recently, an exonic GGC repeat expansion (RE) was identified by long-read genome sequencing in the ZFHX3 gen, causing spinocerebellar ataxia type 4 (SCA4), a dominant form of ataxia with sensory neuropathy. However, the analysis of larger cohorts of patients remained demanding, resulting in a challenge to diagnose patients and leaving the question of anticipation in SCA4 unanswered. OBJECTIVES: We aimed to develop a GGC repeat test for clinical SCA4 screening and to apply this test to screen two large German SCA pedigrees and samples of unrelated patients collected over the last 25 years. METHODS: We modulated a commercial GGC-RE kit (Bio-Techne AmplideX® Asuragen® PCR/CE FMR1 Reagents) with ZFHX3-specific primers and adapted PCR conditions. The test was applied to patients and 50 healthy controls to determine the exact repeat number. Clinical data were revised and correlated with the expanded allele sizes and an exploratory analysis of structural MRI was performed. RESULTS: Repeat size, determined by our protocol for (GGC)n RE analysis shows a strong inverse correlation between repeat length and age at onset and anticipation in subsequent generations. The phenotype also appears to be more strongly expressed in carriers of longer RE. Clinical red flags were slowed saccades, sensory neuropathy and autonomic dysfunction. CONCLUSION: Our protocol enables cost-effective and robust screening for the causative SCA4 RE within ZFHX3. Furthermore, detailed clinical data of our patients gives a more precise view on SCA4, which seems to be more common among patients with ataxia than expected.
RESUMEN
The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.
Asunto(s)
Catecol O-Metiltransferasa/genética , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple/genética , Edad de Inicio , Anciano , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factores SexualesAsunto(s)
Salud de la Familia , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Mutación/genética , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/genética , Sustancia Negra/diagnóstico por imagen , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ultrasonografía Doppler TranscranealRESUMEN
BACKGROUND: The UPDRS is the most widely used rating scale for Parkinson's disease (PD). However, subtle features of early disease stages may be missed. METHODS: We studied 25 early PD patients using a newly compiled battery of motor tests focusing on subtle motor features. Focal dystonia patients (n = 31) and healthy individuals (n = 26) served as controls. Specifically, asymmetric shoulder null position and delayed shoulder shrugs, reduced arm swing, subtle tremor, and timed finger taps were assessed. Spiral drawings and writing were also studied. RESULTS: With a total mean of 9.8 ± 4.9 (possible range: 0-94), PD patients scored significantly higher than dystonia patients (2.9 ± 2.0) and healthy controls (1.9 ± 2.0) (P < 0.001). Reduced arm swing and tremor of individual fingers best distinguished PD from the other groups. CONCLUSIONS: The battery was sensitive to detect subtle motor features missed by the UPDRS. For future revisions of an international motor score, further assessment of these items may be worthwhile.
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Trastornos Distónicos/fisiopatología , Actividad Motora/fisiología , Desempeño Psicomotor/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Dedos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Temblor/etiología , EscrituraRESUMEN
BACKGROUND: Restless legs syndrome (RLS) has a high familial aggregation. To date, several loci and genetic risk factors have been identified, but no causative gene mutation has been found. METHODS: We evaluated a German family with autosomal dominantly inherited RLS in 7 definitely and 2 possibly affected members by genome-wide linkage analysis and exome sequencing. RESULTS: We identified three novel missense and one splice site variant in the PCDHA3, WWC2, ATRN, and FAT2 genes that segregated with RLS in the family. All four exons of the PCDHA3 gene, the most plausible candidate, were sequenced in 64 unrelated RLS cases and 250 controls. This revealed three additional rare missense variants (frequency <1%) of unknown pathogenicity in 2 patients and 1 control. CONCLUSIONS: We present the first next-generation sequencing study on RLS and suggest PCDHA3 as a candidate gene for RLS.
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Cadherinas/genética , Salud de la Familia , Síndrome de las Piernas Inquietas/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Análisis Mutacional de ADN , Exoma , Femenino , Estudios de Asociación Genética , Ligamiento Genético , Alemania , Humanos , Masculino , Proteínas de la Membrana/genética , Factores de Riesgo , TransactivadoresRESUMEN
Quality of life (QoL) is decreased in PD and is linked with depression and anxiety. However, little is known about QoL in monogenic PD. Subjects with mutations in PD genes were recruited from ongoing family and genetic studies (manifesting carriers, n = 23; nonmanifesting carriers, n = 19). For comparison purposes, we included patients with idiopathic PD (IPD; n = 128; early onset, n = 38; late onset, n = 90), healthy controls (n = 127), and data on depressive symptoms of 144 patients with major depression (treated controls). Depression affected 31% of early-onset PD cases, 21% of late-onset cases, and 44% of manifesting carriers of mutations in PD genes, but was rare in the nonmanifesting carriers (7%) and healthy controls (5%). Subjects with Parkinson-associated depression reported fewer feelings of guilt or self-doubt than treated controls, but the occurrence of suicidal ideation was associated with severity of depression only. Social phobia (P = 0.018) and agoraphobia (P = 0.059) were more common in manifesting carriers than in any other group. QoL was decreased in the Parkinson groups, particularly in the early-onset cases (P < 0.001), and QoL correlated with depression in all analyses. In our study, monogenic and IPD cases were comparable in QoL and depression characteristics. The QoL and, possibly, overall prognosis of all PD patients can be improved by appropriate attention and treatment for depression, sleep impairments, and anxiety, even if the treatment of the motor problems cannot be further optimized.
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Depresión/psicología , Trastorno Depresivo/psicología , Enfermedad de Parkinson/psicología , Calidad de Vida/psicología , Adulto , Anciano , Depresión/complicaciones , Depresión/genética , Trastorno Depresivo/complicaciones , Trastorno Depresivo/genética , Femenino , Estado de Salud , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/genética , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
BACKGROUND: Transcranial sonography (TCS) area of hyperechogenicity in the substantia nigra (aSN) is increased in idiopathic and genetic Parkinson's disease (PD). METHODS: We performed TCS in 34 LRRK2 G2019S mutation carriers manifesting PD, 24 non-manifesting mutation carriers, and 28 idiopathic PD patients and compared them with 40 healthy controls (total, n = 126). RESULTS: Compared with the controls (mean 0.15 cm(2) ), the aSN values in all other groups were increased. The mean aSN was 0.23 cm(2) in nonmanifesting mutation carriers (P = .015), 0.34 cm(2) in idiopathic PD patients (P < .0001), 0.32 cm(2) in LRRK2-associated PD patients (P < .0001), and 0.33 cm(2) in the overall PD group (P < .0001). LRRK2-associated PD patients had a higher aSN than did nonmanifesting carriers (P = .011), but there was no significant difference in aSN between patients with idiopathic and LRRK2-associated PD (P = .439). CONCLUSIONS: Our results suggest that SN pathoanatomical alterations may not be substantially different between idiopathic and LRRK2-associated PD. The findings in the nonmanifesting mutation carriers suggest the presence of intermediate nigrostriatal pathology consistent with the age-dependent reduced penetrance of this mutation.
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Predisposición Genética a la Enfermedad/genética , Mutación/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Proteínas Serina-Treonina Quinasas/genética , Sustancia Negra/patología , Adulto , Factores de Edad , Anciano , Femenino , Glicina/genética , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Serina/genética , Sustancia Negra/diagnóstico por imagen , Ultrasonografía Doppler Transcraneal/métodosRESUMEN
BACKGROUND: Musician's dystonia (MD) is traditionally considered a sporadic and task-specific movement disorder. METHODS: The phenotypic spectrum of the disorder was studied in 116 patients suffering from MD including videotaping. RESULTS: Based on the movement disorders observed, we categorized our patients into two different groups: (i) 65 patients with isolated MD, that is only present when playing the instrument and (ii) 51 patients with MD and one or more additional features of primary dystonia independent of MD (complex MD). Patients with a positive family history of movement disorders had an increased risk to develop complex MD [odds ratio = 4.80; 95% confidence interval: 1.94-11.92; P = 0.001]. DISCUSSION: In previous studies, we recently identified 22 relatives with different types of movement disorders in the families of 28 MD patients. Taken together, our results further support a genetic contribution to MD with a broad individual and familial phenotypic spectrum consisting of MD, other dystonias and even other, non-dystonic movement disorders.
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Trastornos Distónicos/fisiopatología , Música , Fenotipo , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Transcranial ultrasound of the substantia nigra (SN) shows a distinct hyperechogenicity in the majority of patients with Parkinson's disease. Recent studies indicate a larger area of hyperechogenicity in elderly healthy adult subjects. The present study aimed to determine the size of the SN hyperechogenicity and of the mesencephalic brainstem in children and adults without evidence of movement disorders. The areas of echogenicity in the substantia nigra (aSN) and the area of the ipsilateral midbrain (aMid) were assessed in 121 healthy infants and children as well as in 64 healthy adults. Furthermore, the ratio of aSN and aMid was calculated (S/M ratio). We found a positive correlation between age and aSN and between age and the S/M ratio. The values for aSN and S/M ratio were smaller in infants and children compared to healthy adults (aSNmax 0.06+/-0.05 cm2 vs. 0.13+/-0.08 cm2). The aSN and S/M ratio grew with increasing age in an almost linear progression. The increase of SN hyperechogenicity over time suggests that the biological process underlying this ultrasound finding may be more dynamic and possibly progressive than previously thought.
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Envejecimiento/fisiología , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/fisiología , Ultrasonografía Doppler Transcraneal/métodos , Adolescente , Adulto , Anciano , Niño , Desarrollo Infantil/fisiología , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Modelos Lineales , Masculino , Mesencéfalo/diagnóstico por imagen , Mesencéfalo/fisiología , Persona de Mediana Edad , Adulto JovenRESUMEN
Several genes associated with monogenic forms of Parkinson's disease (PD) have been discovered, opening up new avenues for the investigation of presymptomatic stages of PD. Using voxel-based morphometry in 30 asymptomatic mutation carriers (MC) with mutations in four different genes for PD and 100 healthy controls, we identified an increase in gray matter volume (GMV) in the striatum in asymptomatic Parkin, PINK1, ATP13A2 and, to a much lesser extent, in LRRK2 MC. Moreover, an increase in GMV was found in the parieto-temporo-occipital association cortex in asymptomatic Parkin and ATP13A2 MC. The observed striatal GMV increase might be the common structural correlate of compensatory mechanisms due to the latent dopaminergic deficit, reflecting the different, but probably interrelated pathogenic pathways resulting in nigral cell death. Asymptomatic PINK1 and LRRK2 MC also revealed smaller GMV in the hippocampal region, which might play a role in the observed psychiatric disorders.
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Encéfalo/patología , Fibras Nerviosas Amielínicas/patología , Trastornos Parkinsonianos/patología , Adulto , Humanos , Procesamiento de Imagen Asistido por Computador , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Imagen por Resonancia Magnética , Persona de Mediana Edad , Trastornos Parkinsonianos/genética , Selección de Paciente , Proteínas Quinasas/genética , Proteínas Serina-Treonina Quinasas/genética , ATPasas de Translocación de Protón/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
OBJECTIVE: Transcranial sonography (TCS) shows characteristic hyperechogenicity of the substantia nigra (SN) in patients with Parkinson's disease (PD). Although this feature is well established, sufficient observer reliability and diagnostic accuracy are prerequisites for advancements of this method. METHODS: The authors investigated both aspects in a cross-sectional study with four blinded TCS raters in 22 PD patients and 10 healthy controls. RESULTS: As expected, the authors found significant bilateral SN hyperechogenicity in PD patients. Quantitative computerised SN planimetry had a substantial intra- (intraclass correlation coefficient (ICC) 0.97 and 0.93 respectively for both hemispheres) and inter-rater reliability (ICC 0.84 and 0.89), while visual semiquantitative echogenicity grading of the SN revealed a moderate intrarater (weighted kappa 0.80 ipsilateral and 0.74 contralateral) and slight (0.33) to fair (0.51) inter-rater reliability only. Diagnostic accuracy measured as the area under the curve of receiver-operating characteristics plots was highest in TCS of the SN opposite the clinically most affected body side (planimetry 0.821, echogenicity grading 0.792) with a hyperechogenic area of 0.24 cm(2) as the optimum cut-off value for the differentiation between PD and controls (sensitivity 79%, specificity 81%). CONCLUSIONS: The data demonstrate that the observer variability of SN planimetry is low in the hands of experienced investigators. This approach also offers adequate diagnostic accuracy. The authors conclude that reliable SN TCS data on PD can be achieved in clinical routine and multicentre trials when standardised analysis protocols and certain quality criteria of brain parenchyma sonography are met.
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Enfermedad de Parkinson/diagnóstico , Sustancia Negra/diagnóstico por imagen , Ultrasonografía Doppler Transcraneal/métodos , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/patología , Valor Predictivo de las Pruebas , Curva ROC , Reproducibilidad de los Resultados , Sustancia Negra/patologíaRESUMEN
We report a 67-year-old patient with idiopathic basal ganglia calcification (IBGC). He presented with progressive cognitive impairment, frontal lobe dysfunction, mild leg spasticity, and levodopa (L-dopa)-responsive parkinsonism. Transcranial sonography (TCS) revealed marked hyperechogenicity of the basal ganglia and periventricular spaces bilaterally. The detected signal alterations showed a fairly symmetric distribution and corresponded to the hyperintense calcifications depicted on the computer tomography brain scan. The combination of symmetric hyperechogenic areas adjacent to the lateral ventricles and of the basal ganglia may serve as an imaging marker characteristic of IBGC. Hyperechogenicity due to extended basal ganglia calcification as presented here is distinct from the pattern of hyperechogenicity caused by heavy metal accumulation, which is described to be less striking. In addition to atypical parkinsonian syndromes such as progressive supranuclear palsy and multiple system atrophy, IBGC is thus another differential diagnosis of parkinsonism with basal ganglia hyperechogenicity.