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INTRODUCTION: Anxiety symptoms are the most common neuropsychiatric manifestation of Parkinson's disease (PD), contributing to decreased quality of life. Few longitudinal studies in PD samples have examined correlates of anxiety symptoms over time. Understanding predictor variables may help to identify novel targets for reducing anxiety in PD. The aim of this study was to identify predictors of anxiety symptoms over 3 years in a clinic-based PD cohort. METHODS: Our cohort included patients with PD at an academic medical center in the Southeastern United States (n = 105). Visits included assessment of motor, psychiatric, and cognitive features, including neuropsychological testing. For our multivariate model, we selected 11 predictor variables with the most existing evidence or theoretical support for an association with anxiety symptoms in PD. Multivariate linear mixed model regression was performed to determine which variables were significantly associated with anxiety symptoms over time. RESULTS: Over half of participants (57%) met the screening threshold for an anxiety disorder at some point during the study. Independent predictors of anxiety symptoms over time included symptoms of REM sleep behavior disorder (RBD) and dysautonomia. DISCUSSION: In this PD sample, RBD and dysautonomia symptoms were significantly associated with anxiety symptoms over time. Each of these relationships has been reported in one of two prior longitudinal studies. Unlike prior studies, cognitive impairment was not a significant predictor of anxiety symptoms in our sample. Future research should confirm the direction and mechanisms underlying these relationships, including the potential for anxiety symptom reduction through treatment for RBD and dysautonomia.
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Doença de Parkinson , Transtorno do Comportamento do Sono REM , Humanos , Estudos Longitudinais , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Doença de Parkinson/psicologia , Qualidade de Vida , Estudos de Coortes , Ansiedade/etiologia , Transtornos de Ansiedade/complicações , Transtorno do Comportamento do Sono REM/diagnósticoRESUMO
Background: Huntington's disease (HD) is a complex neurodegenerative disorder that causes impairment in cognitive, motor, and psychological function and requires subspecialty neurological and interdisciplinary care. Access to subspecialty care for HD is restricted by disability from the disease, lack of trained providers, and barriers to care for disadvantaged and rural populations. Program Description: Since 1999, the University of Virginia HD clinic has used telemedicine to provide clinical services, consultation, and staff training. Initially, encounters were scheduled with the neurologist on a case-by-case basis at outlying rural clinics and community hospitals. Since 2015, telemedicine visits have been conducted by the entire interdisciplinary HD team and access has been extended to homes and long-term care facilities. This infrastructure was used to conduct a virtual clinic 2 days after initiation of coronavirus disease (COVID) mitigation. The clinic has continued to provide subspecialty and interdisciplinary care through telemedicine while clinic access has been restricted. A total of 69 individuals have been seen in 127 telemedicine visits, 56 of which were conducted by the interdisciplinary team. Conclusions: Telemedicine can provide high-quality subspecialty neurological and interdisciplinary care for HD that offers continuity across a wide range of care settings, and can overcome both anticipated and unanticipated barriers to access.
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COVID-19 , Doença de Huntington , Telemedicina , Instituições de Assistência Ambulatorial , Humanos , Doença de Huntington/terapia , SARS-CoV-2RESUMO
OBJECTIVES: Huntington's disease (HD) is a neurodegenerative disorder that produces a bias toward risky, reward-driven decisions in situations where the outcomes of decisions are uncertain and must be discovered. However, it is unclear whether HD patients show similar biases in decision-making when learning demands are minimized and prospective risks and outcomes are known explicitly. We investigated how risk decision-making strategies and adjustments are altered in HD patients when reward contingencies are explicit. METHODS: HD (N=18) and healthy control (HC; N=17) participants completed a risk-taking task in which they made a series of independent choices between a low-risk/low reward and high-risk/high reward risk options. RESULTS: Computational modeling showed that compared to HC, who showed a clear preference for low-risk compared to high-risk decisions, the HD group valued high-risks more than low-risk decisions, especially when high-risks were rewarded. The strategy analysis indicated that when high-risk options were rewarded, HC adopted a conservative risk strategy on the next trial by preferring the low-risk option (i.e., they counted their blessings and then played the surer bet). In contrast, following a rewarded high-risk choice, HD patients showed a clear preference for repeating the high-risk choice. CONCLUSIONS: These results indicate a pattern of high-risk/high-reward decision bias in HD that persists when outcomes and risks are certain. The allure of high-risk/high-reward decisions in situations of risk certainty and uncertainty expands our insight into the dynamic decision-making deficits that create considerable clinical burden in HD.
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Transtornos Cognitivos/etiologia , Doença de Huntington/complicações , Doença de Huntington/psicologia , Recompensa , Assunção de Riscos , Adulto , Tomada de Decisões/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of "synthetic association" with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for â¼50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for â¼83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder.
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Cromossomos Humanos Par 4 , Doença de Huntington/genética , Idade de Início , Alelos , Estudos de Casos e Controles , Efeito Fundador , Estudo de Associação Genômica Ampla/métodos , Haplótipos , Humanos , Mutação , Polimorfismo de Nucleotídeo Único , Repetições de TrinucleotídeosRESUMO
BACKGROUND: The aim of this study was to determine whether age of onset of Parkinson disease (PD) is associated with differences in PD risk and PD age of onset in parents and siblings. METHODS: Clinical and detailed family history data were available for 1,114 PD probands. RESULTS: Proband age of onset was not associated with differences in PD prevalence or PD age of onset in parents. Proband age of PD onset <50, compared with ≥ 50 years, was associated with significantly greater risk of PD in siblings (hazard ratio: 2.4; P=0.002; 95% confidence interval: 1.4, 4.1), and proband age of onset was significantly correlated with sibling age of onset (Somer's D=0.20; P=0.018). CONCLUSIONS: Proband age of PD onset is not associated with differences in parental PD risk. Siblings of PD patients with onset before age 50 are at increased risk of PD and are more likely to have early-onset disease.
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Idade de Início , Saúde da Família , Doença de Parkinson/genética , Adulto , Fatores Etários , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pais , Doença de Parkinson/epidemiologia , Prevalência , Estudos Retrospectivos , Fatores de Risco , IrmãosRESUMO
BACKGROUND: Thalamic deep brain stimulation (DBS) has largely replaced radiofrequency thalamotomy as the treatment of choice for disabling, medication-refractory essential tremor. Recently, the development of transcranial, high-intensity focused ultrasound has renewed interest in thalamic lesioning. The purpose of this study is to compare functional outcomes and quality of life in essential tremor patients treated with either bilateral Vim DBS or unilateral procedures (focused ultrasound or DBS). We hypothesized that all three would effectively treat the dominant hand and positively impact functional outcomes and quality of life as measured with the Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire. METHODS: This is a retrospective study of medication-refractory essential tremor patients treated at the University of Virginia with bilateral Vim DBS (n = 57), unilateral Vim DBS (n = 13), or unilateral focused ultrasound Vim thalamotomy (n = 15). Tremor was rated for all patients before and after treatment, using the Clinical Rating Scale for Tremor and Quality of Life in Essential Tremor Questionnaire. RESULTS: Patients undergoing bilateral DBS treatment had more baseline tremor and worse quality of life scores. Patients had significant improvements in tremor symptoms and quality of life with all three treatments. Both DBS procedures improved axial tremor. No difference was seen in the degree of improvement in upper extremity tremor score, disability, or overall quality of life between bilateral and either unilateral procedure. CONCLUSIONS: Bilateral thalamic DBS improves overall tremor more than unilateral DBS or focused ultrasound treatment; however, unilateral treatments are equally effective in treating contralateral hand tremor. Despite the greater overall tremor reduction with bilateral DBS, there is no difference in disability or quality of life comparing bilateral versus unilateral treatments.
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Estimulação Encefálica Profunda/métodos , Tremor Essencial/diagnóstico , Tremor Essencial/terapia , Qualidade de Vida/psicologia , Tálamo , Idoso , Tremor Essencial/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Ultrassonografia de IntervençãoRESUMO
Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3' UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations.
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Doença de Huntington/genética , Polimorfismo Genético , Receptores Dopaminérgicos/genética , Receptores de N-Metil-D-Aspartato/genética , Idade de Início , Catecol O-Metiltransferase/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Estudos de Associação Genética , Humanos , Doença de Huntington/epidemiologia , Vias Neurais/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D4/genéticaRESUMO
Background: Palliative care practices, including communication about patient-centered goals of care and advance care planning (ACP), have the potential to enhance care throughout the course of Huntington's disease (HD) and related disorders. The goal of our project was to develop a pilot program that integrates primary palliative care practices with interdisciplinary care for HD. Objectives: (1) To train HD team members to facilitate goals of care and ACP conversations at all stages of HD; (2) To create materials for care planning in HD focused on patient-centered goals of care and health-related quality of life; and (3) To modify clinic workflow to include goals of care and ACP discussions. Methods: We defined planning domains to expand care planning beyond end-of-life concerns. We created a patient and family guide to advance care planning in HD. We conducted VitalTalk communications training with the HD team. We modified the interdisciplinary clinic workflow to include ACP and developed an EMR template for documentation. Results: After communication training, more team members felt well prepared to discuss serious news (12.5% to 50%) and manage difficult conversations (25% to 62.5%). The proportion of clinic visits including advance care planning discussions increased from 12.5% to 30.6% during the pilot phase. Conclusions: Provision of primary palliative care for HD in an interdisciplinary clinic is feasible. Integration of palliative care practices into HD specialty care requires additional training and modification of clinic operations.
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Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive and behavioral disturbances, caused by the expansion of a CAG trinucleotide repeat in the HD gene. The CAG allele size is the major determinant of age at onset (AO) of motor symptoms, although the remaining variance in AO is highly heritable. The rs7665116 SNP in PPARGC1A, encoding the mitochondrial regulator PGC-1α, has been reported to be a significant modifier of AO in three European HD cohorts, perhaps due to affected cases from Italy. We attempted to replicate these findings in a large collection of (1,727) HD patient DNA samples of European origin. In the entire cohort, rs7665116 showed a significant effect in the dominant model (p value = 0.008) and the additive model (p value = 0.009). However, when examined by origin, cases of Southern European origin had an increased rs7665116 minor allele frequency (MAF), consistent with this being an ancestry-tagging SNP. The Southern European cases, despite similar mean CAG allele size, had a significantly older mean AO (p < 0.001), suggesting population-dependent phenotype stratification. When the generalized estimating equations models were adjusted for ancestry, the effect of the rs7665116 genotype on AO decreased dramatically. Our results do not support rs7665116 as a modifier of AO of motor symptoms, as we found evidence for a dramatic effect of phenotypic (AO) and genotypic (MAF) stratification among European cohorts that was not considered in previously reported association studies. A significantly older AO in Southern Europe may reflect population differences in genetic or environmental factors that warrant further investigation.
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Proteínas de Choque Térmico/genética , Doença de Huntington/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Adulto , Idade de Início , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Genética Populacional , Humanos , Proteína Huntingtina , Doença de Huntington/epidemiologia , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Expansão das Repetições de TrinucleotídeosRESUMO
Huntington's disease is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat whose length is the major determinant of age at onset but remaining variation appears to be due in part to the effect of genetic modifiers. GRIK2, which encodes GluR6, a mediator of excitatory neurotransmission in the brain, has been suggested in several studies to be a modifier gene based upon a 3' untranslated region TAA trinucleotide repeat polymorphism. Prior to investing in detailed studies of the functional impact of this polymorphism, we sought to confirm its effect on age at onset in a much larger dataset than in previous investigations. We genotyped the HD CAG repeat and the GRIK2 TAA repeat in DNA samples from 2,911 Huntington's disease subjects with known age at onset, and tested for a potential modifier effect of GRIK2 using a variety of statistical approaches. Unlike previous reports, we detected no evidence of an influence of the GRIK2 TAA repeat polymorphism on age at motor onset. Similarly, the GRIK2 polymorphism did not show significant modifier effect on psychiatric and cognitive age at onset in HD. Comprehensive analytical methods applied to a much larger sample than in previous studies do not support a role for GRIK2 as a genetic modifier of age at onset of clinical symptoms in Huntington's disease.
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Códon de Terminação/genética , Doença de Huntington/genética , Receptores de Ácido Caínico/genética , Repetições de Trinucleotídeos/genética , Regiões 3' não Traduzidas/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Adulto Jovem , Receptor de GluK2 CainatoRESUMO
BACKGROUND: The objective of this study was to confirm whether an association between handedness and the side of symptom onset exists and to evaluate the impact of this association on specific clinical characteristics of Parkinson's disease (PD). METHODS: 1173 PD patients were identified from a clinical database. Patients with asymmetrical onset (n=1015) were divided into those with dominant-side onset and those with non-dominant-side onset, and the clinical characteristics of the two subgroups were compared. RESULTS: In our PD sample, 86.5% of patients presented asymmetrically. There was a significant association between handedness and the side of the initial symptom; that is, the dominant side was affected first in the majority of both left- and right-handed patients. Compared with patients with non-dominant side onset, more patients with dominant-side onset presented with bradykinesia, while fewer patients presented with gait difficulty. Patients with dominant-side onset were diagnosed and began dopaminergic medication after a longer symptom duration than patients with non-dominant-side onset. The only difference in Unified Parkinson Disease Rating Scale scores between the two groups was in a subscore addressing dominant-hand tasks. CONCLUSIONS: An association exists between the dominant hand and the side of the initial motor symptom in PD. Whether the initial symptom occurs on the dominant or non-dominant side has implications for the reported first symptom, the time to diagnosis and the time to dopaminergic treatment initiation. The side of disease onset does not affect the severity of disease, as measured by the Unified Parkinson Disease Rating Scale.
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Dominância Cerebral , Lateralidade Funcional , Doença de Parkinson/diagnóstico , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exame NeurológicoRESUMO
BACKGROUND: Huntington disease (HD) is an inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive symptoms. Little is known about the effects of environmental factors on HD symptom onset and severity. OBJECTIVE: To evaluate the relationship between education level and age of diagnosis, symptom onset, and symptom severity in HD. METHODS: This study evaluated 4537 adult-onset, motor-manifest HD participants from the Enroll-HD global registry. Education level was assessed using International Standard Classification of Education categories, stratified into three education groups corresponding to pre-secondary, secondary, and post-secondary educational attainment. Motor and behavioral symptoms of HD, cognition, and functional capacity were measured using baseline Unified Huntington's Disease Rating Scale (UHDRS), Mini-Mental State Exam (MMSE), Symbol Digit Modalities Test (SDMT), verbal fluency, and Stroop assessments. RESULTS: After adjusting for CAG repeats, higher level of education predicted lower age of onset of motor symptoms, depression, irritability, and cognitive impairment (all P-values < 0.001). After adjusting for age of enrollment and CAG repeats, the highest education level predicted the lowest UHDRS motor scores, higher UHDRS total functional capacity and functional assessment scores, and higher SDMT, MMSE, verbal fluency, and Stroop assessment scores (all P-values < 0.001). CONCLUSIONS: HD participants with higher education levels have earlier age of diagnosis and age of symptom onset, but lower motor exam scores and higher functional assessment scores. Earlier recognition of symptoms in more highly educated participants may explain earlier symptom onset and diagnosis. Better performance on motor and functional assessments may be explained by higher cognitive reserve in those with greater education.
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BACKGROUND: There is evidence that cortical cholinergic denervation contributes to gait and balance impairment in Parkinson's Disease (PD), especially reduced gait speed. OBJECTIVES: The objective of this study was to determine the relationship between cholinergic basal forebrain gray matter density (GMD) and gait in PD patients. METHODS: We investigated 66 PD patients who underwent a pre-surgical evaluation for a neurosurgical procedure to treat motor symptoms of PD. As part of this evaluation patients had a brain MRI and formal gait assessments. By applying probabilistic maps of the cholinergic basal forebrain to voxel-based morphometry of brain MRI, we calculated gray matter density (GMD) for cholinergic nucleus 4 (Ch4), cholinergic nucleus 1, 2, and 3 (Ch123), and the entire cortex. RESULTS: Reduced Ch4 GMD was associated with reduced Fast Walking Speed in the "on" medication state (FWSON, p = 0.004). Bilateral cortical GMD was also associated with FWSON (p = 0.009), but Ch123 GMD was not (p = 0.1). Bilateral cortical GMD was not associated with FWSON after adjusting for Ch4 GMD (p = 0.44). While Ch4 GMD was not associated with improvement in Timed Up and Go (TUG) or Cognitive TUG in the "on" medication state, reduced Ch4 GMD was associated with greater percent worsening based on dual tasks (p = 0.021). CONCLUSIONS: Reduced Ch4 GMD is associated with slower gait speed in PD and greater percent worsening in TUG during dual tasks in patients with PD. These findings have implications for planning of future clinical trials investigating cholinergic therapies to improve gait impairment in PD.
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Transtornos Neurológicos da Marcha , Doença de Parkinson , Atrofia , Colinérgicos , Marcha , Transtornos Neurológicos da Marcha/diagnóstico por imagem , Transtornos Neurológicos da Marcha/etiologia , Humanos , Testes Neuropsicológicos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagemRESUMO
The activities of daily living (ADL) subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) captures the impact of Parkinson's disease (PD) on daily function and may be less affected than other subsections by variability associated with drug cycle and motor fluctuations. We examined UPDRS mentation, ADL and motor subscores in 888 patients with idiopathic PD. Multiple linear regression analyses determined the association between disease duration and UPDRS subscores as a function of medication status at examination and in a subset of patients with multiple examinations. Independent of medication status and across cross-sectional and longitudinal analyses, ADL subscores showed a stronger and more stable association with disease duration than other UPDRS subscores after adjusting for age of disease onset. The association between disease duration and the motor subscore depended on medication status. The strong association between ADL subscore and disease duration in PD suggests that this measure may serve as a better marker of disease progression than signs and symptoms assessed in other UPDRS sections.
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Atividades Cotidianas , Doença de Parkinson/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antiparkinsonianos/uso terapêutico , Estudos Transversais , Progressão da Doença , Feminino , Seguimentos , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Desempenho Psicomotor , Resultado do TratamentoRESUMO
OBJECTIVE: To determine the feasibility and educational value of an arts-based curriculum for neurology residents, with the following specific learning objectives: to enhance communication and observational skills, increase awareness of point of view, and deepen appreciation of the narrative content of illness. METHODS: Narrative medicine and visual thinking exercises, adopted from the study of literature and art history, were offered as monthly sessions in the neurology residents' conference schedule. Participants completed an institutional review board-approved anonymous evaluation using a 5-point Likert scale to rate course effectiveness and perform a retrospective pre- and post-self-assessment of communication and visual observation skills. They also provided free text feedback on the course. RESULTS: All participants rated the course highly and found the exercises effective in enhancing awareness of language and observational skills. Eighty percent of participants rated their listening and observation skills as above average after participation, which improved from 63% and 45%, respectively, before the sessions. Comments on the course cited the importance of reflection, focused attention, awareness of multiple perspectives, and appreciation of colleagues. CONCLUSIONS: Arts-based graduate medical education is feasible and effective in teaching residents to listen and observe more closely. Narrative medicine and visual thinking exercises highlight these skills and promote professional growth, providing an opportunity to reflect and find meaning in clinical work.
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Arte , Currículo , Educação de Pós-Graduação em Medicina/métodos , Literatura , Medicina Narrativa , Neurologia/educação , Competência Clínica , Comunicação , Humanos , Internato e Residência , ObservaçãoRESUMO
Background: We investigated whether the characteristics of Parkinson's disease (PD) patients differ based on the primary indication for deep brain stimulation (DBS). Methods: We reviewed data for 149 consecutive PD patients who underwent DBS at the University of Virginia. Patients were categorized based on primary surgical indication, and clinical characteristics were compared between groups. Results: Twenty-nine (93.5%) of 31 PD patients who underwent DBS for medication refractory tremor were men, and 66 (62.3%) of 106 PD patients who underwent DBS for motor fluctuations were men (p = 0.001). Other primary indications for DBS were tremor and fluctuations (n = 5), medication intolerance (n = 5), and dystonia (n = 2). Discussion: Patients who underwent DBS for medication refractory tremor were predominantly men, while patients who had DBS for motor fluctuations approximated the gender distribution of PD. Possible explanations are that men with PD are more likely to develop medication refractory tremor or undergo surgery for medication refractory tremor in PD compared to women.
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Estimulação Encefálica Profunda/estatística & dados numéricos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/terapia , Tremor/fisiopatologia , Tremor/terapia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Estudos Retrospectivos , Fatores Sexuais , Tremor/etiologiaRESUMO
BACKGROUND: Dopamine therapy in Parkinson disease (PD) can have differential effects on inhibitory action control, or the ability to inhibit reflexive or impulsive actions. Dopamine agonist (DAAg) medications, which preferentially target D2 and D3 receptors, can either improve or worsen control of impulsive actions in patients with PD. We have reported that the direction of this effect depends on baseline levels of performance on inhibitory control tasks. This observation suggests that there may exist certain biologic determinants that contribute to these patient-specific differences. We hypothesized that one important factor might be functional polymorphisms in D2-like receptor genes. AIM: The goal of this study was to determine whether the direction of DAAg effects on inhibitory control depends on functional polymorphisms in the DRD2 and DRD3 genes. METHODS: Twenty-eight patients with PD were genotyped for known functional polymorphisms in DRD2 (rs6277 and rs1800497) and DRD3 (rs6280) receptors. These patients then completed the Simon conflict task both on and off DAAg therapy in a counterbalanced manner. RESULTS: We found that patients with the rs1800497 Taq1A (A1) polymorphism (A1/A1 or A1/A2: 11 subjects) showed improved proficiency to suppress impulsive actions when on DAAg; conversely, patients with the A2/A2 allele (14 patients) became less proficient at suppressing incorrect response information on DAAg therapy (Group × Medication, F(1, 23) = 5.65, p < 0.05). Polymorphisms in rs6277 and rs6280 were not associated with a differential medication response. CONCLUSION: These results suggest that certain DRD polymorphisms may determine the direction of DAAg effects on critical cognitive control processes impaired in PD. Our findings have implications for understanding pharmacogenomics interactions on a larger scale and the role these may play in the wide variability of treatment effects seen in the PD population.
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Agonistas de Dopamina/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Polimorfismo Genético/genética , Receptores de Dopamina D2/genética , Alelos , Agonistas de Dopamina/uso terapêutico , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Considering that psychosis in Parkinson disease (PD) is associated with worse outcomes, including dementia, we aimed to study the characteristics, correlates, and assessment of PD psychosis in those without dementia. METHODS: 101 PD subjects without dementia (Montreal Cognitive Assessment ≥21/30) were recruited to participate in a study of neuropsychiatric symptoms in PD. This study included a baseline standard neurological exam and common PD symptom assessments. Using the Scale for the Assessment of Positive Symptoms (SAPS) and separate assessment of visual illusions and sense of presence, NINDS-NIMH criteria for PD psychosis were applied. RESULTS: Of the 33 (32.7%) PD subjects who met diagnostic criteria for psychosis in PD, visual illusions were most common (72.7%), followed by visual hallucinations (39.4%). Adjusted for presence of REM sleep behavior disorder (RBD) (p = 0.097), use of dopamine agonists (OR = 3.7, p = 0.012) and greater autonomic symptom burden (OR = 1.1 (per 1-unit change in score on SCOPA-AUT), p = 0.012) were associated with greater risk of psychosis. Use of dopamine agonists (OR = 5.0, p = 0.007), higher MDS-UPDRS Part II score (OR = 1.1, p = 0.010), and presence of RBD (OR = 4.8, p = 0.012) were independent predictors of visual hallucinations and visual illusions. MDS-UPDRS item 1.2 score ≥1 had highly correlated with the SAPS score (r = 0.65, p < 0.0001), but was 42% sensitive and 96% specific for identifying psychosis. CONCLUSION: This study confirms the association between dopamine agonists and psychosis in PD patients without dementia. The association of RBD, autonomic symptoms, and MDS-UPDRS Part II scores with psychosis underscore its link to brainstem dysfunction and greater PD motor symptom severity.
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Doença de Parkinson/complicações , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/etiologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Delusões/etiologia , Feminino , Alucinações/etiologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Transtorno do Comportamento do Sono REM/etiologiaRESUMO
Importance: Clinical trials have confirmed the efficacy of focused ultrasound (FUS) thalamotomy in essential tremor, but its effectiveness and safety for managing tremor-dominant Parkinson disease (TDPD) is unknown. Objective: To assess safety and efficacy at 12-month follow-up, accounting for placebo response, of unilateral FUS thalamotomy for patients with TDPD. Design, Setting, and Participants: Of the 326 patients identified from an in-house database, 53 patients consented to be screened. Twenty-six were ineligible, and 27 were randomized (2:1) to FUS thalamotomy or a sham procedure at 2 centers from October18, 2012, to January 8, 2015. The most common reasons for disqualification were withdrawal (8 persons [31%]), and not being medication refractory (8 persons [31%]). Data were analyzed using intention-to-treat analysis, and assessments were double-blinded through the primary outcome. Interventions: Twenty patients were randomized to unilateral FUS thalamotomy, and 7 to sham procedure. The sham group was offered open-label treatment after unblinding. Main Outcomes and Measures: The predefined primary outcomes were safety and difference in improvement between groups at 3 months in the on-medication treated hand tremor subscore from the Clinical Rating Scale for Tremor (CRST). Secondary outcomes included descriptive results of Unified Parkinson's Disease Rating Scale (UPDRS) scores and quality of life measures. Results: Of the 27 patients, 26 (96%) were male and the median age was 67.8 years (interquartile range [IQR], 62.1-73.8 years). On-medication median tremor scores improved 62% (IQR, 22%-79%) from a baseline of 17 points (IQR, 10.5-27.5) following FUS thalamotomy and 22% (IQR, -11% to 29%) from a baseline of 23 points (IQR, 14.0-27.0) after sham procedures; the between-group difference was significant (Wilcoxon P = .04). On-medication median UPDRS motor scores improved 8 points (IQR, 0.5-11.0) from a baseline of 23 points (IQR, 15.5-34.0) following FUS thalamotomy and 1 point (IQR, -5.0 to 9.0) from a baseline of 25 points (IQR, 15.0-33.0) after sham procedures. Early in the study, heating of the internal capsule resulted in 2 cases (8%) of mild hemiparesis, which improved and prompted monitoring of an additional axis during magnetic resonance thermometry. Other persistent adverse events were orofacial paresthesia (4 events [20%]), finger paresthesia (1 event [5%]), and ataxia (1 event [5%]). Conclusions and Relevance: Focused ultrasound thalamotomy for patients with TDPD demonstrated improvements in medication-refractory tremor by CRST assessments, even in the setting of a placebo response. Trial Registration: ClinicalTrials.gov identifier NCT01772693.