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BACKGROUND: Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. OBJECTIVE: We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. METHODS: We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. RESULTS: We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). CONCLUSIONS: We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
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Neoplasias Pulmonares , Melanoma , Neoplasias Ováricas , Enfermedad de Parkinson , Neoplasias de la Próstata , Humanos , Masculino , Femenino , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/genética , Estudio de Asociación del Genoma Completo , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Melanoma/epidemiología , Melanoma/genética , Factores de RiesgoRESUMEN
BACKGROUND: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. OBJECTIVE: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). METHODS: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). RESULTS: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029). CONCLUSIONS: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society.
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Enfermedad de Parkinson , Productos Lácteos/efectos adversos , Femenino , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Análisis de la Aleatorización Mendeliana , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple/genética , Factores de RiesgoRESUMEN
BACKGROUND: Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions. OBJECTIVE: To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction. METHODS: We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1. RESULTS: At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59-0.93, PInteraction = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of α-synuclein on binding affinity showed findings consistent with this interaction pattern. CONCLUSIONS: Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Enfermedad de Parkinson , Predisposición Genética a la Enfermedad , Cadenas HLA-DRB1/genética , Humanos , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple/genética , Fumar/genéticaRESUMEN
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.
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Predisposición Genética a la Enfermedad , Inflamación/genética , Esclerosis Múltiple/genética , Transcriptoma/genética , Adulto , Codón sin Sentido , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/patología , Exoma/genética , Femenino , Humanos , Inflamación/metabolismo , Inflamación/patología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Vaina de Mielina/genética , Vaina de Mielina/patología , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Neuronas/metabolismo , Neuronas/patología , Linaje , Secuenciación del Exoma , Adulto JovenRESUMEN
INTRODUCTION: In the current edition, Fujioka and colleagues report on four Japanese patients with Parkinson disease (PD) and severe postural abnormalities treated with istradefylline (adenosine A2A receptor antagonist); further, dopamine agonists were with- drawn. Three patients experienced significant improvements of postural abnormalities. CLINICAL REFLECTIONS: Postural abnormalities in PD include camptocormia, antecollis, lateral trunk flexion, and scoliosis. They may be very pronounced and significantly reduce quality of life. The therapy of postural deformities in PD is currently disappointing. CLINICAL IMPLICATIONS: Effective therapeutic strategies for postural deformities in PD are an unmet need. Larger clinical trials investigating novel approaches including istradefylline are warranted.
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Enfermedad de Parkinson , Purinas/uso terapéutico , Antagonistas del Receptor de Adenosina A2 , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Calidad de VidaRESUMEN
BACKGROUND AND OBJECTIVES: The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR. METHODS: We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (ORIVW per 4.8 kg/m2 [95% CI]) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI. RESULTS: Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (ORIVW 0.82 [0.70-0.97], p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, ORIVW 0.71 [0.55-0.92]) and cases with shorter disease duration (≤7 years, ORIVW 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (ORIVW 0.85 [0.74-0.99], p = 0.032) than men (ORIVW 0.92 [0.80-1.04], p = 0.18), but the interaction was not statistically significant (p-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association. DISCUSSION: Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.
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Índice de Masa Corporal , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Enfermedad de Parkinson , Polimorfismo de Nucleótido Simple , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/epidemiología , Polimorfismo de Nucleótido Simple/genética , Femenino , Masculino , Persona de Mediana Edad , Anciano , Factores de RiesgoRESUMEN
BACKGROUND AND OBJECTIVES: Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations. METHODS: A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC). RESULTS: The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance (p < 5 × 10-8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (p < 0.025): (rs34311866: ß(SE)COURAGE = 0.477(0.203), p COURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: ß(SE)COURAGE+IPDGC = 0.720(0.122), p COURAGE+IPDGC = 3.13 × 10-9) and a novel BST1 locus (rs4698412: ß(SE)COURAGE+IPDGC = -0.526(0.096), p COURAGE+IPDGC = 4.41 × 10-8). DISCUSSION: Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.
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Coraje , Enfermedad de Parkinson , Edad de Inicio , Femenino , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. OBJECTIVE: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. METHODS: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (pâ=â0.017). RESULTS: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smokingâ=â0.74, 95%CIâ=â0.60-0.93, pâ=â0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. CONCLUSION: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.
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Café , Enfermedad de Parkinson , Anciano , Consumo de Bebidas Alcohólicas/epidemiología , Consumo de Bebidas Alcohólicas/genética , Estudio de Asociación del Genoma Completo , Humanos , Análisis de la Aleatorización Mendeliana , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/genética , Factores de Riesgo , Fumar/epidemiologíaRESUMEN
INTRODUCTION: Approximately 10% of patients with Parkinson disease (PD) present with early-onset disease (EOPD), defined as diagnosis before 50 years of age. Genetic factors are known to contribute to EOPD, with most commonly observed mutations in PRKN, PINK1, and DJ1 genes. The aim of our study was to analyze the frequency of PRKN, PINK1, and DJ1 mutations in an EOPD series from 4 neighboring European countries: Czech Republic, Germany, Poland, and Ukraine. METHODS: Diagnosis of PD was made based on UK Brain Bank diagnostic criteria in departments experienced in movement disorders (1 from Czech Republic, 1 from Germany, 9 from Poland, and 3 from Ukraine). EOPD was defined as onset at or before 50 years of age. Of the 541 patients recruited to the study, 11 were Czech, 38 German, 476 Polish, and 16 Ukrainian. All cohorts were fully screened with Sanger sequencing for PRKN, PINK1, and DJ1 and multiplex ligation-dependent probe amplification for exon dosage. RESULTS: PRKN homozygous or double heterozygous mutations were identified in 17 patients: 1 Czech (9.1%), 1 German (2.6%), 14 Polish (2.9%), and 1 Ukrainian (6.3%). PINK1 homozygous mutations were only identified in 3 Polish patients (0.6%). There were no homozygous or compound heterozygous DJ1 mutations in analyzed subpopulations. One novel variant in PRKN was identified in the Ukrainian series. CONCLUSION: In the analyzed cohorts, mutations in the genes PRKN, PINK1, and DJ1 are not frequently observed.
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Enfermedad de Parkinson/genética , Proteína Desglicasa DJ-1/genética , Proteínas Quinasas/genética , Ubiquitina-Proteína Ligasas/genética , Adulto , Anciano , Estudios de Cohortes , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
OBJECTIVE: To determine whether distinct microtubule-associated protein tau MAPT H1 subhaplotypes are associated with clinical and demographic features in Parkinson's disease. METHODS: A retrospective cohort study included 855 unrelated Caucasian patients with Parkinson's disease who were seen by Movement Disorder specialists at the Mayo Clinic Florida between 1998 and 2016. The primary outcome measures were specific demographic and clinical features of Parkinson's disease, including age at onset, disease progression, survival, motor signs, dementia, dystonia, dyskinesia, autonomic dysfunction, impulse control disorder, psychiatric features, REM sleep behavior disorder, restless legs syndrome, and Parkinson's disease subtype. Specific clinical features were measured at the initial visit and most recent visit. These outcomes were assessed for association with MAPT H1 subhaplotypes, which were defined by six haplotype tagging variants. RESULTS: Median onset age was 64 years (range: 22-94 years); 548 (64%) of patients were male. Significant associations (P < 0.0029) were observed between MAPT H1b and orthostatic hypotension (OR = 1.72, P = 0.001); between H1j and rest tremor (OR = 0.15; P < 0.001) as well as REM sleep behavior disorder (OR = 3.87, P < 0.001); between H1r and bradykinesia (OR = 0.11; P < 0.001); and between H1v and restless legs syndrome (OR = 4.02, P = 0.002). INTERPRETATION: Four MAPT H1 subhaplotypes, but not the H2 haplotype, were significantly associated with specific clinical features in Parkinson's disease. MAPT haplotypic structure may explain some of the phenotypic variability in disease. Replication of our findings will be critical to fully resolve the Parkinson's disease risk association signal at Chr17q21.
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Enfermedad de Parkinson/genética , Enfermedad de Parkinson/fisiopatología , Proteínas tau/genética , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Asociación Genética , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Functional magnetic resonance imaging (fMRI) in sighted individuals previously showed parahippocampal and fusiform activations during locomotor imagery, which were interpreted to reflect visuospatial navigation. Concurrent deactivations of multisensory vestibular and somatosensory cortical areas may reflect suppression of vestibular and somatosensory input, in order to prevent adverse interactions of sensory signals with the optimized automated locomotion pattern. In this fMRI study we compared blood oxygen level dependent (BOLD) activations and deactivations during the kinesthetic imagery of standing, walking, and running in seven congenitally totally blind subjects, seven sighted age-matched controls, and five subjects with age at onset of complete blindness > or =9 y or minimal residual vision. Imagined lying served as the rest condition. As opposed to their sighted controls, congenitally totally blind individuals activated multisensory vestibular areas in the posterior insula and superior temporal gyrus during imagined locomotion. Further, congenitally blind individuals did not show activations in parahippocampal and fusiform regions during locomotor tasks. In the intergroup comparisons, congenitally blind subjects exhibited higher BOLD activity levels than sighted subjects in multisensory vestibular (posterior insula and adjacent temporal sites), somatosensory (postcentral gyrus), and primary motor cortical areas, while sighted subjects showed higher activity levels in the parahippocampal and fusiform gyri. These findings indicate that blind subjects rely more on vestibular and somatosensory feedback for locomotion control than sighted subjects. This is accompanied by enhanced voluntary motor control and enhanced motor-kinesthetic processing. Thus, we provide neuroimaging evidence of distinct sensorimotor strategies in the blind for locomotor control.
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Mapeo Encefálico/métodos , Encéfalo/fisiopatología , Potenciales Evocados , Imaginación , Locomoción , Imagen por Resonancia Magnética/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Neurostimulation of the subthalamic nucleus reduces levodopa-related motor complications in advanced Parkinson's disease. We compared this treatment plus medication with medical management. METHODS: In this randomized-pairs trial, we enrolled 156 patients with advanced Parkinson's disease and severe motor symptoms. The primary end points were the changes from baseline to six months in the quality of life, as assessed by the Parkinson's Disease Questionnaire (PDQ-39), and the severity of symptoms without medication, according to the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III). RESULTS: Pairwise comparisons showed that neurostimulation, as compared with medication alone, caused greater improvements from baseline to six months in the PDQ-39 (50 of 78 pairs, P=0.02) and the UPDRS-III (55 of 78, P<0.001), with mean improvements of 9.5 and 19.6 points, respectively. Neurostimulation resulted in improvements of 24 to 38 percent in the PDQ-39 subscales for mobility, activities of daily living, emotional well-being, stigma, and bodily discomfort. Serious adverse events were more common with neurostimulation than with medication alone (13 percent vs. 4 percent, P<0.04) and included a fatal intracerebral hemorrhage. The overall frequency of adverse events was higher in the medication group (64 percent vs. 50 percent, P=0.08). CONCLUSIONS: In this six-month study of patients under 75 years of age with severe motor complications of Parkinson's disease, neurostimulation of the subthalamic nucleus was more effective than medical management alone. (ClinicalTrials.gov number, NCT00196911 [ClinicalTrials.gov].).
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Antiparkinsonianos/uso terapéutico , Estimulación Encefálica Profunda , Enfermedad de Parkinson/terapia , Calidad de Vida , Actividades Cotidianas , Anciano , Antiparkinsonianos/efectos adversos , Estimulación Encefálica Profunda/efectos adversos , Discinesias/etiología , Discinesias/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Patients with unilateral vestibular failure (UVF) experience oscillopsia (apparent motion of the visual scene) during rapid head movements due to increased retinal slip caused by vestibulo-ocular reflex impairment. Oscillopsia is always smaller than the net retinal slip and decreases over time in patients with acquired vestibular loss; this correlates with increased thresholds for visual motion detection and increased tolerance to retinal slip. We investigated the underlying cortical adaptive processes using visual motion stimulation during blood oxygen level-dependent (BOLD) fMRI. Optokinetic nystagmus was elicited in seven patients with right-sided and seven patients with left-sided unilateral vestibular neurectomy and in seven age- and gender-matched healthy controls. Patients showed diminished activation of bilateral visual cortex areas (including the motion-sensitive area MT/V5, cuneus, middle occipital, fusiform and lingual areas) and ocular motor regions compared to their controls during visual motion stimulation. Concurrent BOLD signal decreases of temporo-parietal and insular multisensory cortical areas occurred in controls and patients. The diminished activation of visual motion processing areas plausibly reflects an adaptive mechanism that suppresses distressing oscillopsia in patients with UVF and thereby stabilizes the perceived visual surroundings. This study provides for the first time neuroimaging evidence of suppressed cortical visual motion processing in patients with vestibulopathy.
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Percepción de Movimiento , Trastornos de la Percepción/etiología , Reflejo Vestibuloocular , Vestíbulo del Laberinto/cirugía , Mapeo Encefálico/métodos , Femenino , Movimientos de la Cabeza , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Plasticidad Neuronal , Nistagmo Optoquinético , Trastornos de la Percepción/fisiopatología , Estimulación Luminosa/métodos , Vestíbulo del Laberinto/fisiopatología , Corteza Visual/fisiopatologíaRESUMEN
INTRODUCTION: Tremor dominant (TD), postural instability/gait difficulty (PIGD), and akinetic-rigid (AR) subtypes are widely used in classifying patients with Parkinson's disease (PD). METHODS: We compared clinical characteristics between PD subtypes in a large retrospective cohort. Between 1998 and 2016, we included a total of 1003 patients with PD in this retrospective study. Six hundred ninety-four patients had more than one visit. Data were collected regarding motor/non-motor symptoms at the initial/final visits. Based on the prominent symptom at the initial visit, we classified patients into one of the four subtypes: TD, AR, gait difficulty, and mixed. Rapid progression was defined by emergence of falls, dementia, or dependency within 5years after onset. RESULTS: TD was the most prevalent subtype (44%), followed by AR (29%), mixed (18%), and gait difficulty (9%). Rapid progression was observed more frequently in gait difficulty compared to AR (OR: 3.59 P<0.001). Hallucinations at the final visit were more likely to occur in AR (OR: 2.36, P=0.005) and mixed (OR: 3.28, P<0.001) compared to TD. CONCLUSIONS: Our findings provide support for a distinction of four different PD subtypes: TD, AR, gait difficulty, and mixed. The gait difficulty subtype was distinguishable from the AR subtype.
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Trastornos Neurológicos de la Marcha/fisiopatología , Enfermedad de Parkinson/clasificación , Enfermedad de Parkinson/fisiopatología , Trastornos de la Sensación/fisiopatología , Temblor/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Trastornos Neurológicos de la Marcha/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/epidemiología , Equilibrio Postural/fisiología , Prevalencia , Estudios Retrospectivos , Trastornos de la Sensación/diagnóstico , Estadísticas no Paramétricas , Temblor/diagnóstico , Adulto JovenRESUMEN
OBJECTIVE: To ascertain the genetic cause of a consanguineous family from Syria suffering from a sterile brain inflammation mimicking a mild nonprogressive form of MS. METHODS: We used homozygosity mapping and next-generation sequencing to detect the disease-causing gene in the affected siblings. In addition, we performed RNA and protein expression studies, enzymatic activity assays, immunohistochemistry, and targeted sequencing of further MS cases from Austria, Germany, Canada and Jordan. RESULTS: In this study, we describe the identification of a homozygous missense mutation (c.82T>G, p.Cys28Gly) in the tripeptidyl peptidase II (TPP2) gene in all 3 affected siblings of the family. Sequencing of all TPP2-coding exons in 826 MS cases identified one further homozygous missense variant (c.2027C>T, p.Thr676Ile) in a Jordanian MS patient. TPP2 protein expression in whole blood was reduced in the affected siblings. In contrast, TPP2 protein expression in postmortem brain tissue from MS patients without TPP2 mutations was highly upregulated. CONCLUSIONS: The homozygous TPP2 mutation (p.Cys28Gly) is likely responsible for the inflammation phenotype in this family. TPP2 is an ubiquitously expressed serine peptidase that removes tripeptides from the N-terminal end of longer peptides. TPP2 is involved in various biological processes including the destruction of major histocompatibility complex Class I epitopes. Recessive loss-of-function mutations in TPP2 were described in patients with Evans syndrome, a rare autoimmune disease affecting the hematopoietic system. Based on the gene expression results in our MS autopsy brain samples, we further suggest that TPP2 may play a broader role in the inflammatory process in MS.
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Biomarkers are helpful for early diagnosis, assessment of disorder severity, prognosis, and prediction of response to therapy. Given that early therapeutic intervention may be useful in forestalling or slowing neurodegenerative conditions, employing reliable biomarkers to identify asymptomatic individuals who are destined to develop clinical Parkinson's disease (PD) is critical. Two important observations have been repeatedly found in persons who eventually develop clinical PD: (1) significant neuronal loss occurs in the substantia nigra and (2) the presence of nonmotor symptoms (NMS). Each of these findings occurs prior to the development of motor signs and symptoms, often preceding the clinical diagnosis of PD by a decade or more. As such, NMS themselves, and factors associated with their development may be useful clinical biomarkers for predicting future development of motor PD. Recently, research criteria for prodromal PD, defined as presence of motor and/or NMS, but not yet fulfilling the classic PD diagnosis, have been proposed by the International Parkinson and Movement Disorder Society Task Force. Although there are a small number of biomarkers associated with NMS of PD, in this chapter, discussion follows concerning the expanding literature associated with clinical, biochemical, imaging, and genetic biomarkers of NMS in patients with PD.
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Biomarcadores , Disfunción Cognitiva/diagnóstico , Estreñimiento/diagnóstico , Depresión/diagnóstico , Hipotensión Ortostática/diagnóstico , Trastornos del Olfato/diagnóstico , Enfermedad de Parkinson/diagnóstico , Síntomas Prodrómicos , Trastorno de la Conducta del Sueño REM/diagnóstico , Disfunción Cognitiva/etiología , Estreñimiento/etiología , Depresión/etiología , Humanos , Hipotensión Ortostática/etiología , Trastornos del Olfato/etiología , Enfermedad de Parkinson/complicaciones , Trastorno de la Conducta del Sueño REM/etiologíaRESUMEN
OBJECTIVE: To study whether and how fear of litigation and defensive medicine are communicated during residency training and to assess whether this affects residents' attitudes. METHODS: Neurology residents in the US (n=25) and, as a control group, Neurology residents training in Germany (n=42) were asked to rate multiple items regarding litigation, defensive strategies and how often these issues are raised by teaching physicians. Statistic analysis was performed using nonparametric tests. RESULTS: Residents in both countries indicated that litigation is an "important problem", although US residents stated this significantly more often (p<0.001). Initiation of tests motivated mainly by fear of litigation (p=0.004) and explicit teaching of defensive strategies by teaching physicians (p<0.02) were reported more often by US residents. CONCLUSION: Neurology residents in both the US and Germany perceive a litigational threat, but significantly less so in Germany. This difference may result at least in part from teaching of defensive strategies reported more often in US programs.
Asunto(s)
Medicina Defensiva , Internado y Residencia , Neurología/educación , Pautas de la Práctica en Medicina , Medicina Defensiva/educación , Medicina Defensiva/legislación & jurisprudencia , Medicina Defensiva/métodos , Humanos , Responsabilidad Legal , Encuestas y Cuestionarios , Estados UnidosRESUMEN
Whereas positron emission tomography (PET) with the antagonist ligand [(18)F]fallypride reveals the composite of dopamine D2 and D3 receptors in brain, treatment of Parkinson's disease (PD) patients with the D3-prefering agonist pramipexole should result in preferential occupancy in the nucleus accumbens, where the D3-subtype is most abundant. To test this prediction we obtained pairs of [(18)F]fallypride PET recordings in a group of nine PD patients, first in a condition of treatment as usual with pramipexole (ON-Sifrol; 3 × 0.7 mg p.d.), and again at a later date, after withholding pramipexole 48-72 h (OFF-Sifrol); in that condition the serum pramipexole concentration had declined by 90% and prolactin levels had increased four-fold, in conjunction with a small but significant worsening of PD motor symptoms. Exploratory comparison with historical control material showed 14% higher dopamine D2/3 availability in the more-affected putamen of patients OFF medication. On-Sifrol there was significant (p Ë 0.01) occupancy at [(18)F]fallypride binding sites in globus pallidus (8%) thalamus (9%) and substantia nigra (19%), as well as marginally significant occupancy in frontal and temporal cortex of patients. Contrary to expectation, comparison of ON- and OFF-Sifrol results did not reveal any discernible occupancy in nucleus accumbens, or elsewhere in the extended striatum; present methods should be sensitive to a 10% change in dopamine D2/3 receptor availability in striatum; the significant findings elsewhere in the basal ganglia and in cerebral cortex are consistent with a predominance of D3 receptors in those structures, especially in substantia nigra, and imply that therapeutic effects of pramipexole may be obtained at sites outside the extended striatum.
Asunto(s)
Benzotiazoles/farmacología , Agonistas de Dopamina/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D3/efectos de los fármacos , Anciano , Benzamidas/farmacología , Antagonistas de Dopamina/farmacología , Femenino , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía de Emisión de Positrones , Pramipexol , RadiofármacosRESUMEN
The differential effects of visual hemifield motion stimulation during fixation of a stationary target were compared under two conditions: fixation straight ahead without any further instructions and fixation straight ahead with attention shifted to the "dark hemifield." Data from nine right-handed volunteers revealed that striate and extrastriate right hemispheric visual areas exhibited larger activations during left hemifield motion stimulation when attention was shifted to the right dark hemifield. Montreal Neurological Institute (MNI) coordinates (26, -98, -4) of the additional clusters activated in the latter condition corresponded best to the kinetic occipital region, which is known to process both shape and motion information, and to parts of area V3 posterior to V3A, which has been shown repeatedly to mediate motion perception. A simple computational model of transhemispheric visuovisual interaction is proposed. The basic mechanism of this model is a central predictor formed by a feedback loop that detects a mismatch between input to the two hemispheres. Predicted stimulation is then compared with the actual input. If the sensed motion of a visual hemifield is larger than the predicted net motion in the model, activation of the respective neural population is increased; conversely, a smaller actual motion causes less activation.