RESUMO
Impulse control disorders (ICDs) and related impulsive and compulsive behaviors (together called ICBs) have been increasingly recognized in the context of Parkinson's disease (PD) and treatment. The International Parkinson's and Movement Disorder Society commissioned a task force to assess available clinical screening instruments and rating scales, including their clinimetric properties, make recommendations regarding their utility, and suggest future directions in scale development and validation. The literature was systematically searched for scales measuring a range of reported ICBs in PD. A scale was designated "recommended" if the scale had been employed in PD studies, been used beyond the group that developed it, and had adequate clinimetric data published for PD. Numerous diagnostic screening tools and severity rating scales were identified for a range of ICBs, including compulsive medication use, punding/hobbyism, walkabout, pathological gambling, hypersexuality, compulsive or binge eating, compulsive buying, reckless driving, compulsive exercise, pyromania, trichotillomania, hoarding, kleptomania, intermittent explosive disorder, and internet addiction. For screening across the range of ICBs (except compulsive medication use), the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP) and QUIP-Rating Scale (QUIP-RS) are recommended, and for severity rating across the range of ICBs the QUIP-RS and the Ardouin Scale of Behavior in Parkinson's Disease are recommended. The Scale for Outcomes in Parkinson's Disease-Psychiatric Complications is recommended for rating of hypersexuality and the compulsive behaviors gambling/shopping. Further testing of established scales against gold standard diagnostic criteria is urgently required for all other individual ICBs in PD. © 2019 International Parkinson and Movement Disorder Society © 2019 International Parkinson and Movement Disorder Society.
Assuntos
Comportamento Compulsivo/diagnóstico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/diagnóstico , Comportamento Impulsivo/fisiologia , Doença de Parkinson/complicações , Escalas de Graduação Psiquiátrica , Comportamento Compulsivo/complicações , Comportamento Compulsivo/psicologia , Transtornos Disruptivos, de Controle do Impulso e da Conduta/complicações , Transtornos Disruptivos, de Controle do Impulso e da Conduta/psicologia , Humanos , Doença de Parkinson/psicologiaRESUMO
BACKGROUND: Palliative care is recommended for non-malignant illnesses, including Parkinson's disease. However, past research with healthcare workers highlights unmet palliative needs in this population and referral rates to Specialist Palliative Care are low. Some healthcare workers perceive a 'fear' in their patients about introducing palliative care. However, less is known about the views of people with Parkinson's disease and their carers about palliative care. AIM: (1) To explore the palliative care and related issues most affecting people with Parkinson's disease and their families and (2) to examine perceptions about/understanding of palliative care. DESIGN: This was a qualitative study; semi-structured interviews were conducted, transcribed and analysed using thematic analysis. SETTING/PARTICIPANTS: A total of 31 people participated, both people with Parkinson's disease ( n = 19) and carers ( n = 12), across three Movement Disorder Clinics in the Republic of Ireland. RESULTS: People with Parkinson's disease and their carers were unfamiliar with the term palliative care. When informed of the role of palliative care, most felt that they would benefit from this input. People with Parkinson's disease and carers experienced a high illness burden and wanted extra support. Crises requiring Specialist Palliative Care involvement may occur at diagnosis and later, with advancing illness. Participants wanted more information about palliative care and especially further supports to address their psychosocial needs. CONCLUSION: A holistic palliative care approach could address the complex physical and psychosocial symptoms experienced by people with Parkinson's disease and their carers, and people with Parkinson's disease and their carers are open to palliative care. Further research needs to explore how palliative care can be introduced into the routine care for people with Parkinson's disease.
Assuntos
Cuidadores/psicologia , Pessoal de Saúde/psicologia , Cuidados Paliativos/psicologia , Doença de Parkinson/psicologia , Doença de Parkinson/terapia , Preferência do Paciente/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Atitude do Pessoal de Saúde , Atitude Frente a Saúde , Feminino , Humanos , Irlanda , Masculino , Pessoa de Meia-Idade , Pesquisa QualitativaRESUMO
INTRODUCTION: Evidence from clinical and pathological studies suggests a role for both alpha-synuclein and amyloid-beta in the pathophysiology of dementia associated with PD. Recent work demonstrated improvement in memory and reduced amyloid-beta burden in transgenic murine Alzheimer's models given subcutaneous apomorphine. The aim of this work was to determine whether antemortem exposure to apomorphine was associated with lower levels of amyloid-beta in brain tissue in a clinicopathological study of PD. METHODS: The case notes of donors with pathologically proven PD who had (n = 36) and had not received apomorphine (n = 35) during life for motor complications were reviewed to determine presence or absence of cognitive impairment. The four groups were well matched for disease duration, age at death, sex, and apolipoprotein E4 genotype. The severity of amyloid-beta mature/diffuse plaque load, tau pathology, and alpha-synuclein pathology were all established. Cerebral amyloid angiopathy was determined based on a four-tier grading system. RESULTS: Within the cognitively normal cases, significantly reduced amyloid-beta deposition was present in those with antemortem apomorphine exposure; this finding was not replicated in those with cognitive impairment plus previous apomorphine use. In the apomorphine cognitively normal group only, a significant negative association was observed between maximum apomorphine dose received and amyloid-beta burden. Early and maximum doses of apomorphine plus apolipoprotein genotype and sex were significant predictors of total plaque load in an explanatory model. CONCLUSION: This exploratory study suggests that apomorphine may have a modifying effect on amyloid deposition in nondemented PD cases and thus may represent a potential therapy to reduce cognitive impairment in PD. © 2015 Movement Disorder Society.
Assuntos
Peptídeos beta-Amiloides/efeitos dos fármacos , Apomorfina/farmacologia , Encéfalo/metabolismo , Agonistas de Dopamina/farmacologia , Doença de Parkinson/metabolismo , Idoso , Idoso de 80 Anos ou mais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Feminino , Humanos , Masculino , Doença de Parkinson/tratamento farmacológicoRESUMO
BACKGROUND: An integrated palliative care approach is recommended in all life-limiting diseases, including Parkinson's disease (PD). However research shows that people with PD have unmet palliative care needs. The study aimed to explore multidisciplinary healthcare workers' (HCWs) views on palliative care for people with PD, identifying perceived barriers and facilitators. METHODS: A qualitative design was used; data was analysed using Thematic Analysis. Semi-structured interviews were conducted with 30 HCWs, working either with people with PD or in a palliative care setting in Ireland. RESULTS: A number of perceived barriers were evident helping to account for the previously reported unmet palliative care needs in PD. A lack of education about PD and palliative care meant that HCWs were unsure of the appropriateness of referral, and patients and carers weren't equipped with information to seek palliative care. A lack of communication between PD and palliative care specialists was seen to impede collaboration between the disciplines. Uncertainty about the timing of palliative care meant that it was often not introduced until a crisis point, despite the recognised need for early planning due to increased prevalence of dementia. CONCLUSIONS: Most HCWs recognised a need for palliative care for people with PD; however several barriers to implementing a palliative care approach in this population need to be addressed. Implications for clinical practice and policy include the need for an integrated model of care, and education for all HCWs, patients, carers, and the public on both the nature of advanced PD, and the potential of palliative care in support of patients and their family members.
Assuntos
Atitude do Pessoal de Saúde , Pessoal de Saúde , Acessibilidade aos Serviços de Saúde/normas , Cuidados Paliativos/estatística & dados numéricos , Doença de Parkinson/terapia , Idoso , Feminino , Grupos Focais , Humanos , Irlanda , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Fatores de Tempo , IncertezaRESUMO
There is increasing awareness that the medications used to treat the motor symptoms of Parkinson's disease (PD) contribute to the development of behavioral addictions, which have been clinically defined as impulsive-compulsive behaviors (ICBs). These features include pathological gambling, compulsive sexual behavior, binge eating, compulsive shopping, excessive hobbyism or punding, and the excessive use of dopaminergic medication. ICBs frequently have devastating effects on the social and occupational function of the affected individuals as well as their families. Although ICBs are an important clinical problem in PD, the number of studies in which these symptoms have been modeled in rodents is still limited. This may depend on uncertainties regarding, on one hand, the pathophysiology of these behaviors and, on the other hand, the experimental paradigms with which similar features can be induced in rodents. To help compose these uncertainties, we will here review the characteristics of ICBs in PD patients and then describe behavioral methods to approximate them in rodents. We will discuss both the challenges and the possibilities of applying these methods to animals with PD-like lesions, and review the recent progress made to this end. We will finally highlight important questions deserving further investigation. Rodent models having both face validity and construct validity to parkinsonian ICBs will be essential to further pathophysiological and therapeutic studies into this important area.
Assuntos
Comportamento Compulsivo , Comportamento Impulsivo , Transtornos Parkinsonianos/psicologia , Animais , Comportamento Compulsivo/fisiopatologia , Humanos , Comportamento Impulsivo/fisiologia , Transtornos Parkinsonianos/fisiopatologia , RoedoresRESUMO
Preclinical animal models implicate serotonin neurons in the pathophysiology of levodopa (l-dopa)-induced dyskinesias in Parkinson's disease (PD), but effective treatment remains elusive. We examined the relationship between serotonin and l-dopa-induced dyskinesias in a pathologically confirmed cohort of PD patients. We obtained brain tissue from 44 PD cases and 17 age-matched controls and assessed monoamine levels and the serotonin and dopamine transporters in the striatum, and the extent of dopaminergic and serotonergic cell preservation in the substantia nigra (SN) and the dorsal raphe nuclei (DRN), respectively. As expected, PD patients demonstrated a severe loss of all dopaminergic markers, including dopamine (P < 0.0001) and the dopamine transporter (P < 0.0001) in the striatum, and dopaminergic neurons (P < 0.001) in the SN, compared with controls. Marked serotonin loss was observed in the caudate (but not putamen) in PD patients compared with controls (P < 0.001), but no difference was found in the levels of the serotonin transporter in the striatum or density of serotonergic neurons in the DRN between these groups, suggesting a functional but not structural change in the serotonergic system in PD. No difference was seen in levels of serotonergic and dopaminergic markers in the striatum between PD patients with and without dyskinesias, or between cases separated according to the clinical severity of their dyskinesias. The absence of a correlation between striatal serotonin markers and the incidence and severity of l-dopa-induced dyskinesias suggests that an intact and functioning serotonergic system is not a risk factor for developing dyskinesias in PD.
Assuntos
Biomarcadores/metabolismo , Discinesia Induzida por Medicamentos/metabolismo , Levodopa/efeitos adversos , Doença de Parkinson/metabolismo , Idoso , Idoso de 80 Anos ou mais , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/uso terapêutico , Estudos de Casos e Controles , Núcleo Caudado/metabolismo , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Feminino , Humanos , Levodopa/uso terapêutico , Masculino , Putamen/metabolismo , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Substância Negra/metabolismoAssuntos
Transtornos Disruptivos, de Controle do Impulso e da Conduta/diagnóstico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/epidemiologia , Dopaminérgicos/efeitos adversos , Doença de Parkinson/diagnóstico , Doença de Parkinson/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos Disruptivos, de Controle do Impulso e da Conduta/induzido quimicamente , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Prognóstico , Reino Unido/epidemiologiaRESUMO
Hypersexuality with compulsive sexual behaviour is a significant source of morbidity for patients with Parkinson's disease receiving dopamine replacement therapies. We know relatively little about the pathophysiology of hypersexuality in Parkinson's disease, and it is unknown how visual sexual stimuli, similar to the portrayals of sexuality in the mainstream mass media may affect the brain and behaviour in such susceptible individuals. Here, we have studied a group of 12 patients with Parkinson's disease with hypersexuality using a functional magnetic resonance imaging block design exposing participants to both sexual, other reward-related and neutral visual cues. We hypothesized that exposure to visual sexual cues would trigger increased sexual desire in patients with Parkinson's disease with hypersexuality that would correspond to changes in brain activity in regions linked to dopaminergically stimulated sexual motivation. Patients with Parkinson's disease with hypersexuality were scanned ON and OFF dopamine drugs, and their results were compared with a group of 12 Parkinson's disease control patients without hypersexuality or other impulse control disorders. Exposure to sexual cues significantly increased sexual desire and hedonic responses in the Parkinson's disease hypersexuality group compared with the Parkinson's disease control patients. These behavioural changes corresponded to significant blood oxygen level-dependent signal changes in regions within limbic, paralimbic, temporal, occipital, somatosensory and prefrontal cortices that correspond to emotional, cognitive, autonomic, visual and motivational processes. The functional imaging data showed that the hypersexuality patients' increased sexual desire correlated with enhanced activations in the ventral striatum, and cingulate and orbitofrontal cortices. When the patients with Parkinson's disease with hypersexuality were OFF medication, the functional imaging data showed decreases in activation during the presentation of sexual cues relative to rest. These deactivations were not observed when the patients were ON medication, suggesting that dopamine drugs may release inhibition within local neuronal circuits in the cerebral cortex that may contribute to compulsive sexual behaviour. The findings of this study have implications with respect to the potential influence of cue exposure via exposure to mass media in enhancing libido, which in this group of vulnerable patients can lead to devastating social consequences and occasionally, custodial sentences. Stimulation through exposure to sexual visual cues in patients with Parkinson's disease with hypersexuality provides a motivational impetus for seeking this reward behaviour through activations and deactivations of cerebral cortex.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Sinais (Psicologia) , Transtornos Disruptivos, de Controle do Impulso e da Conduta/induzido quimicamente , Agonistas de Dopamina/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Comportamento Sexual/efeitos dos fármacos , Adulto , Idoso , Córtex Cerebral/metabolismo , Estudos Cross-Over , Transtornos Disruptivos, de Controle do Impulso e da Conduta/metabolismo , Transtornos Disruptivos, de Controle do Impulso e da Conduta/psicologia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , Doença de Parkinson/psicologia , Estimulação Luminosa/métodos , Comportamento Sexual/fisiologia , Comportamento Sexual/psicologia , Resultado do TratamentoRESUMO
BACKGROUND: Clinical heterogeneity in the development of levodopa-induced dyskinesias (LID) suggests endogenous factors play a significant role in determining their overall prevalence. OBJECTIVE: We hypothesised that single nucleotide polymorphisms (SNPs) in specific genes may result in a clinical phenotype conducive to an increased risk of LID. METHODS: We examined the influence of SNPs in the catechol-O-methyltransferase (COMT), monoamine oxidase A (MAO-A) and brain-derived neurotrophic factor (BDNF) genes on LID in a cohort of 285 pathologically confirmed Parkinson's disease patients, using data from their complete disease course. RESULTS: Dyskinetic patients demonstrated younger age at disease onset (60.3 vs. 66.4 years, p < 0.0001), a longer disease duration (17.0 vs. 12.0 years, p < 0.0001) and a higher maximum daily levodopa equivalent dose (LED; 926.7 vs. 617.1 mg/day, p < 0.0001) than patients without dyskinesias. No individual SNP was found to influence prevalence or time to onset of dyskinesias, including after adjustment for known risk factors. We observed that patients carrying alleles conferring both high COMT activity and increased MAO-A mRNA expression received significantly higher maximum and mean daily LEDs than those with low enzyme activity/mRNA expression (max LED: 835 ± 445 vs. 508 ± 316 mg; p = 0.0056, mean LED: 601 ± 335 vs. 398 ± 260 mg; p = 0.025). CONCLUSIONS: Individual SNPs in BDNF, COMT and MAO-A genes did not influence prevalence or time to onset of dyskinesias in this cohort. The possibility that combined COMT and MAO-A genotype is a significant factor in determining an individual's lifetime levodopa exposure warrants further investigation.
Assuntos
Antiparkinsonianos/administração & dosagem , Discinesia Induzida por Medicamentos/genética , Levodopa/efeitos adversos , Doença de Parkinson/genética , Idoso , Antiparkinsonianos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/genética , Catecol O-Metiltransferase/genética , Estudos de Coortes , Discinesia Induzida por Medicamentos/epidemiologia , Feminino , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Monoaminoxidase/genética , Doença de Parkinson/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Prevalência , Fatores de TempoRESUMO
BACKGROUND: Diagnosing psychogenic non-epileptic seizures (PNES) remains challenging. The majority of 'PNES status' cases are likely to be seen in the emergency department or similar non-specialised units, where patients are initially assessed and managed by physicians of varying expertise in neurology. METHODS: 216 participants including medical students and doctors of all grades from a wide range of medical disciplines were shown video recordings of six patients with PNES and six other patients with convulsive epileptic seizures (ES). Participants were asked to choose between PNES and ES as a diagnosis and to rate their confidence in each diagnosis, both before and after a 15-minute teaching presentation on PNES and ES. RESULTS: Pre-teaching sensitivity for diagnosing PNES was 0.77, specificity 0.55. The positive predictive value (PPV) of diagnosing PNES was 0.63, and was 0.7 for ES. Diagnostic accuracy increased with increasing clinical grades (p=0.022), as did clinical confidence (p<0.0005). Clinical accuracy and clinical confidence increased post-teaching (p<0.0005). Sensitivity for diagnosing PNES post-teaching improved to 0.88, specificity to 0.67. The PPV of diagnosing PNES increased to 0.72, and to 0.84 for ES. CONCLUSIONS: Diagnosing PNES can be improved by clinical experience in neurology and focussed teaching interventions.
Assuntos
Competência Clínica/estatística & dados numéricos , Epilepsia/diagnóstico , Convulsões/diagnóstico , Diagnóstico Diferencial , Epilepsia/psicologia , Humanos , Médicos/psicologia , Convulsões/psicologia , Sensibilidade e Especificidade , Estudantes de Medicina/psicologia , Ensino/métodos , Gravação em VídeoRESUMO
Conventional magnetic resonance imaging (cMRI) is often used to aid the diagnosis of progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), but its ability to predict the histopathological diagnosis has not been systematically studied. cMRI from 48 neuropathologically confirmed cases, including PSP (n = 22), MSA (n = 13), Parkinson's disease (PD) (n = 7), and corticobasal degeneration (n = 6), and controls (n = 9) were assessed blinded to clinical details and systematically rated for reported abnormalities. Clinical diagnosis and macroscopic postmortem findings were retrospectively assessed. Radiological assessment of MRI was correct in 16 of 22 (72.7%) PSP cases and 10 of 13 (76.9%) MSA cases with substantial interrater agreement (Cohen's kappa 0.708; P < .001); no PSP case was misclassified as MSA or vice versa. MRI was less sensitive but more specific than clinical diagnosis in PSP and both more sensitive and specific than clinical diagnosis in MSA. The "hummingbird" and "morning glory" signs were highly specific for PSP, and "the middle cerebellar peduncle sign" and "hot cross bun" for MSA, but sensitivity was lower (up to 68.4%) and characteristic findings may not be present even at autopsy. cMRI, clinical diagnosis, and macroscopic examination at postmortem have similar sensitivity and specificity in predicting a neuropathological diagnosis. We have validated specific radiological signs in pathologically confirmed PSP and MSA. However, the low sensitivity of these and macroscopic findings at autopsy suggest a need for imaging techniques sensitive to microstructural abnormalities without regional atrophy.
Assuntos
Imageamento por Ressonância Magnética , Atrofia de Múltiplos Sistemas/patologia , Paralisia Supranuclear Progressiva/patologia , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico , Estudos Retrospectivos , Sensibilidade e Especificidade , Paralisia Supranuclear Progressiva/diagnósticoRESUMO
Links between impulsive-compulsive behaviors (ICBs) in treated Parkinson's disease (PD), behavioral addictions, and substance abuse have been postulated, but no direct comparisons have been carried out so far. We directly compared patients with PD with and without ICBs with illicit drug abusers, pathological gamblers, and age-matched healthy controls using the beads task, a test of reflection impulsivity, and a working memory task. We found that all patients with PD made more impulsive and irrational choices than the control group. PD patients who had an ICB showed similar behavior to illicit substance abusers, whereas patients without ICBs more closely resembled pathological gamblers. In contrast, we found no difference in working memory performance within the PD groups. However, PD patients without ICBs remembered distractors significantly less than all other patients during working memory tests. We were able to correctly classify 96% of the PD patients with respect to whether or not they had an ICB by analyzing three trials of the 80/20 loss condition of the beads task with a negative prediction value of 92.3%, and we propose that this task may prove to be a powerful screening tool to detect an ICB in PD. Our results also suggest that intact cortical processing and less distractibility in PD patients without ICBs may protect them from developing behavioral addictions.
Assuntos
Comportamento Aditivo/psicologia , Tomada de Decisões , Comportamento Impulsivo/etiologia , Comportamento Impulsivo/psicologia , Doença de Parkinson/complicações , Doença de Parkinson/psicologia , Idoso , Antiparkinsonianos/uso terapêutico , Comportamento Aditivo/etiologia , Comportamento de Escolha , Escolaridade , Feminino , Jogo de Azar , Humanos , Masculino , Memória de Curto Prazo , Pessoa de Meia-Idade , Testes Neuropsicológicos , Desempenho Psicomotor , Reprodutibilidade dos Testes , Transtornos Relacionados ao Uso de Substâncias/psicologiaRESUMO
The relative importance of Lewy- and Alzheimer-type pathologies to dementia in Parkinson's disease remains unclear. We have examined the combined associations of α-synuclein, tau and amyloid-ß accumulation in 56 pathologically confirmed Parkinson's disease cases, 29 of whom had developed dementia. Cortical and subcortical amyloid-ß scores were obtained, while tau and α-synuclein pathologies were rated according to the respective Braak stages. Additionally, cortical Lewy body and Lewy neurite scores were determined and Lewy body densities were generated using morphometry. Non-parametric statistics, together with regression models, receiver-operating characteristic curves and survival analyses were applied. Cortical and striatal amyloid-ß scores, Braak tau stages, cortical Lewy body, Lewy neurite scores and Lewy body densities, but not Braak α-synuclein stages, were all significantly greater in the Parkinson's disease-dementia group (P<0.05), with all the pathologies showing a significant positive correlation to each other (P<0.05). A combination of pathologies [area under the receiver-operating characteristic curve=0.95 (0.88-1.00); P<0.0001] was a better predictor of dementia than the severity of any single pathology. Additionally, cortical amyloid-ß scores (r=-0.62; P=0.043) and Braak tau stages (r=-0.52; P=0.028), but not Lewy body scores (r=-0.25; P=0.41) or Braak α-synuclein stages (r=-0.44; P=0.13), significantly correlated with mini-mental state examination scores in the subset of cases with this information available within the last year of life (n=15). High cortical amyloid-ß score (P=0.017) along with an older age at onset (P=0.001) were associated with a shorter time-to-dementia period. A combination of Lewy- and Alzheimer-type pathologies is a robust pathological correlate of dementia in Parkinson's disease, with quantitative and semi-quantitative assessment of Lewy pathology being more informative than Braak α-synuclein stages. Cortical amyloid-ß and age at disease onset seem to determine the rate to dementia.
Assuntos
Doença de Alzheimer/complicações , Demência/complicações , Doença por Corpos de Lewy/complicações , Doença de Parkinson/complicações , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Demência/genética , Feminino , Humanos , Doença por Corpos de Lewy/genética , Masculino , Entrevista Psiquiátrica Padronizada , Doença de Parkinson/genética , Curva ROC , Estatística como Assunto , alfa-Sinucleína/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Angiogenesis and increased permeability of the blood-brain barrier have been reported to occur in animal models of Parkinson's disease and l-dopa-induced dyskinesia, but the significance of these phenomena has remained unclear. Using a validated rat model of l-dopa-induced dyskinesia, this study demonstrates that chronic treatment with l-dopa dose dependently induces the expression of vascular endothelial growth factor in the basal ganglia nuclei. Vascular endothelial growth factor was abundantly expressed in astrocytes and astrocytic processes in the proximity of blood vessels. When co-administered with l-dopa, a small molecule inhibitor of vascular endothelial growth factor signalling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood-brain barrier permeability induced by the treatment. The occurrence of angiogenesis and vascular endothelial growth factor upregulation was verified in post-mortem basal ganglia tissue from patients with Parkinson's disease with a history of dyskinesia, who exhibited increased microvascular density, microvascular nestin expression and an upregulation of vascular endothelial growth factor messenger ribonucleic acid. These congruent findings in the rat model and human patients indicate that vascular endothelial growth factor is implicated in the pathophysiology of l-dopa-induced dyskinesia and emphasize an involvement of the microvascular compartment in the adverse effects of l-dopa pharmacotherapy in Parkinson's disease.
Assuntos
Antiparkinsonianos/efeitos adversos , Encéfalo/efeitos dos fármacos , Discinesia Induzida por Medicamentos/etiologia , Levodopa/efeitos adversos , Transtornos Parkinsonianos/patologia , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Animais , Antígenos CD/metabolismo , Antígenos de Superfície/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Comportamento Animal/efeitos dos fármacos , Benserazida/efeitos adversos , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/fisiopatologia , Encéfalo/citologia , Bromodesoxiuridina/metabolismo , Contagem de Células , Células Cultivadas , Modelos Animais de Doenças , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Discinesia Induzida por Medicamentos/tratamento farmacológico , Discinesia Induzida por Medicamentos/patologia , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Laminina/metabolismo , Masculino , Neovascularização Patológica/induzido quimicamente , Neovascularização Patológica/tratamento farmacológico , Proteínas do Tecido Nervoso/metabolismo , Transtornos Parkinsonianos/tratamento farmacológico , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
The exact pathogenesis of visual hallucinations in Parkinson's disease is not known but an integrated model has been proposed that includes impaired visual input and central visual processing, impaired brainstem regulation of sleep-wake cycle with fluctuating vigilance, intrusion of rapid eye movement dream imagery into wakefulness and emergence of internally generated imagery, cognitive dysfunction and influence of dopaminergic drugs. In a clinical study, we assessed motor and non-motor function, including sleep, mood, autonomic and global, frontal and visuoperceptive cognitive function in patients with and without visual hallucinations. A subgroup of patients underwent detailed ophthalmological assessment. In a separate pathological study, histological specimens were obtained from cases of pathologically proven Parkinson's disease and a retrospective case notes review was made for reporting of persistent formed visual hallucinations. An assessment of Lewy body and Lewy neurite pathology was carried out in five cortical regions as recommended by diagnostic criteria for dementia with Lewy Bodies and in brainstem nuclei. Ninety-four patients (mean age 67.5 ± 9.5 years) participated in the clinical study of whom 32% experienced visual hallucinations. When corrected for multiple comparisons, patients with visual hallucinations had significantly greater disease duration, treatment duration, motor severity and complications, sleep disturbances, in particular excessive daytime somnolence and rapid eye movement sleep behavioural disorder, disorders of mood, autonomic dysfunction and global, frontal and visuoperceptive cognitive dysfunction. Of the 94 patients, 50 (53%) underwent ophthalmological assessment. There were no differences in ocular pathology between the visual hallucination and non-visual hallucination groups. In a logistic regression model the four independent determinants of visual hallucinations were rapid eye movement sleep behavioural disorder (P = 0.026), autonomic function (P = 0.004), frontal cognitive function (P = 0.020) and a test of visuoperceptive function (object decision; P = 0.031). In a separate study, post-mortem analysis was performed in 91 subjects (mean age at death 75.5 ± 8.0 years) and persistent visual hallucinations were documented in 63%. Patients in the visual hallucinations group had similar disease duration but had significantly higher Lewy body densities in the middle frontal (P = 0.002) and middle temporal gyri (P = 0.033) and transentorhinal (P = 0.005) and anterior cingulate (P = 0.020) cortices but not parietal cortex (P = 0.22). Using a comprehensive assessment of the clinical, demographic and ophthalmological correlates of visual hallucinations in Parkinson's disease, the combined data support the hypothesized model of impaired visual processing, sleep-wake dysregulation and brainstem dysfunction, and cognitive, particularly frontal, impairment all independently contributing to the pathogenesis of visual hallucinations in Parkinson's disease. These clinical data are supported by the pathological study, in which higher overall cortical Lewy body counts, and in particular areas implicated in visuoperception and executive function, were associated with visual hallucinations.
Assuntos
Encéfalo/fisiopatologia , Alucinações/etiologia , Doença de Parkinson/complicações , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Cognição/fisiologia , Transtornos Cognitivos/complicações , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Feminino , Alucinações/patologia , Alucinações/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologiaRESUMO
Impulsive-compulsive behaviours are a significant source of morbidity for patients with Parkinson's disease receiving dopaminergic therapy. The development of these behaviours may reflect sensitization of the neural response to non-drug rewards, similar to that proposed for sensitization to drug rewards in addiction. Here, by using (11)C-raclopride positron emission tomography imaging, we investigated the effects of reward-related cues and L-dopa challenge in patients with Parkinson's disease with and without impulsive-compulsive behaviours on striatal levels of synaptic dopamine. Eighteen patients (11 with and seven without impulsive-compulsive behaviours) underwent three (11)C-raclopride positron emission tomography scans. The impulsive-compulsive behaviours included hypersexuality, binge eating, punding, compulsive use of dopamine replacement therapy, compulsive buying and pathological gambling, with eight patients exhibiting more than one impulsive-compulsive behaviour. There were no significant differences in baseline dopamine D2 receptor availability between the Parkinson's disease groups. No differences were found when comparing the percentage change of raclopride binding potential between the two Parkinson's disease groups following L-dopa challenge with neutral cues. The group with Parkinson's disease with impulsive-compulsive behaviours had a greater reduction of ventral striatum (11)C-raclopride binding potential following reward-related cue exposure, relative to neutral cue exposure, following L-dopa challenge (16.3% compared with 5.8% in Parkinson's disease controls, P = 0.016). The heightened response of striatal reward circuitry to heterogeneous reward-related visual cues among a group of patients with different impulsive-compulsive behaviours is consistent with a global sensitization to appetitive behaviours with dopaminergic therapy in vulnerable individuals. Our findings are relevant for the broader debate on the relation between impulsive-compulsive behaviours and addictions and may have important implications with regards to advertisement legislation in an effort to prevent the onset of behavioural addictions.
Assuntos
Comportamento Compulsivo/metabolismo , Corpo Estriado/metabolismo , Dopamina/metabolismo , Comportamento Impulsivo/metabolismo , Doença de Parkinson/metabolismo , Idoso , Mapeamento Encefálico , Comportamento Compulsivo/complicações , Comportamento Compulsivo/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Sinais (Psicologia) , Feminino , Humanos , Comportamento Impulsivo/complicações , Comportamento Impulsivo/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , CintilografiaRESUMO
BACKGROUND: Little is known about the cognitive and neuropsychiatric profile associated with punding and hobbyism in Parkinson's disease (PD). OBJECTIVE: To compare the clinical and neuropsychological features of PD patients with punding and hobbyism to PD controls. METHODS: The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) was used as a screening tool, and a structured interview was used to diagnose punding/hobbyism. Clinical and neuropsychological assessment was conducted with validated questionnaires/scales. RESULTS: Twenty-one patients with PD and punding (PD + pu) were compared to 26 with hobbyism (PD + h) and 25 PD controls. PD + pu patients showed higher levels of anxiety, non-motor symptoms and motor symptoms, and lower Frontal Assessment Battery scores. The PD + h group exhibited similar levels of anxiety and motor fluctuations to the PD + pu group. CONCLUSION: PD + pu showed increased anxiety and frontal lobe dysfunction, similar to PD + h. Hobbyism could be a prodromal phase with increased risk of leading to punding.
RESUMO
Mutations in the glucocerebrosidase (GBA) gene have been implicated in increased formation of Lewy bodies (LBs) in Parkinson's disease (PD). We found GBA mutation status not to be significantly associated with the density of cortical LBs, after adjusting for sex, age at death, duration of PD and presence of dementia. Comparison of GBA carriers to PD controls found no difference in Alzheimer's disease pathological findings. Our results do not support GBA carriers to have a more advanced neuropathologic disease i.e. increased density of protein aggregates.
Assuntos
Glucosilceramidase/genética , Corpos de Lewy/patologia , Doença de Parkinson/enzimologia , Doença de Parkinson/genética , Adulto , Idoso , Glucosilceramidase/metabolismo , Heterozigoto , Humanos , Corpos de Lewy/genética , Corpos de Lewy/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Doença de Parkinson/patologiaRESUMO
OBJECTIVE: Striatal serotonin projections have been implicated in levodopa-induced dyskinesia by providing an unregulated source of dopamine release. We set out to determine whether these projections are affected by levodopa treatment in a way that would favor the occurrence of dyskinesia. METHODS: As an index of terminal serotonin innervation density, we measured radioligand binding to the plasma membrane serotonin transporter (SERT) in levodopa-treated dyskinetic and nondyskinetic subjects, using brain tissue from both rat and monkey models of Parkinson disease as well as parkinsonian patients. In addition, striatal tissue from dyskinetic rats was used for morphological and ultrastructural analyses of serotonin axon terminals, and for studies of stimulated [³H]dopamine release. RESULTS: Across all conditions examined, striatal levels of SERT radioligand binding were significantly elevated in dyskinetic subjects compared to nondyskinetic cases. In the rat striatum, dyskinesiogenic levodopa treatment had induced sprouting of serotonin axon varicosities having a relatively high synaptic incidence. This response was associated with increased depolarization-induced [³H]dopamine release and with a stronger release potentiation by brain-derived neurotrophic factor. INTERPRETATION: This study provides the first evidence that L-dopa treatment induces sprouting of serotonin axon terminals, with an increased incidence of synaptic contacts, and a larger activity-dependent potentiation of dopamine release in the dopamine-denervated striatum. Treatment-induced plasticity of the serotonin innervation may therefore represent a previously unappreciated cause of altered dopamine dynamics. These results are important for understanding the mechanisms by which L-dopa pharmacotherapy predisposes to dyskinesia, and for defining biomarkers of motor complications in Parkinsons disease.
Assuntos
Discinesia Induzida por Medicamentos/patologia , Levodopa/efeitos adversos , Plasticidade Neuronal/efeitos dos fármacos , Terminações Pré-Sinápticas/patologia , Serotonina/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Idoso , Animais , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Corpo Estriado/ultraestrutura , Modelos Animais de Doenças , Dopamina/metabolismo , Feminino , Humanos , Macaca fascicularis , Masculino , Oxidopamina , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/ultraestrutura , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismoRESUMO
A number of recent studies have described cases with tau-positive globular oligodendroglial inclusions (GOIs) and such cases have overlapping pathological features with progressive supranuclear palsy (PSP), but present with clinical features of motor neuron disease (MND) and/or frontotemporal dementia (FTD). These two clinical phenotypes have been published independently and as a result, have come to be considered as distinct disease entities. We describe the clinicopathological and biochemical features of two cases with GOIs: one with clinical symptoms suggestive of MND and the other with FTD. Histological changes in our two cases were consistent with their clinical symptoms; the MND case had severe neurodegeneration in the primary motor cortex and corticospinal tract, whereas the FTD case had severe involvement of the frontotemporal cortices and associated white matter. Immunohistochemistry in both cases revealed significant 4-repeat (4R) tau pathology primarily in the form of GOIs, but also in astrocytes and neurons. Astrocytic tau pathology was morphologically similar to that seen in PSP, but in contrast was consistently negative for Gallyas silver staining. Tau-specific western blotting revealed 68, 64 and 35 kDa bands, showing further overlap with PSP. The underlying neuropathological features of these two cases were similar, with the major difference relating to the regional distribution of pathology and resulting clinical symptoms and signs. The globular nature of glial inclusions and the non-fibrillar properties of tau in astrocytes are characteristic features that allow them to be distinguished from PSP and other tauopathies. We, therefore, propose the term globular glial tauopathy as an encompassing term to classify this emerging class of 4R tauopathy.