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BACKGROUND AND PURPOSE: Reduced facial expression of emotions is a very frequent symptom of Parkinson's disease (PD) and has been considered part of the motor features of the disease. However, the neural correlates of hypomimia and the relationship between hypomimia and other non-motor symptoms of PD are poorly understood. METHODS: The clinical and structural brain correlates of hypomimia were studied. For this purpose, cross-sectional data from the COPPADIS study database were used. Age, disease duration, levodopa equivalent daily dose, Unified Parkinson's Disease Rating Scale part III (UPDRS-III), severity of apathy and depression and global cognitive status were collected. At the imaging level, analyses based on gray matter volume and cortical thickness were used. RESULTS: After controlling for multiple confounding variables such as age or disease duration, the severity of hypomimia was shown to be indissociable from the UPDRS-III speech and bradykinesia items and was significantly related to the severity of apathy (ß = 0.595; p < 0.0001). At the level of neural correlates, hypomimia was related to motor regions brodmann area 8 (BA 8) and to multiple fronto-temporo-parietal regions involved in the decoding, recognition and production of facial expression of emotions. CONCLUSION: Reduced facial expressivity in PD is related to the severity of symptoms of apathy and is mediated by the dysfunction of brain systems involved in motor control and in the recognition, integration and expression of emotions. Therefore, hypomimia in PD may be conceptualized not exclusively as a motor symptom but as a consequence of a multidimensional deficit leading to a symptom where motor and non-motor aspects converge.
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Apatia , Doença de Parkinson , Humanos , Estudos Transversais , Hipocinesia , EncéfaloRESUMO
BACKGROUND: Identifying modifiable risk factors for cognitive impairment in the early stages of Parkinson's disease (PD) and estimating their impact on cognitive status may help prevent dementia (PDD) and the design of cognitive trials. METHODS: Using a standard approach for the assessment of global cognition in PD and controlling for the effects of age, education and disease duration, we explored the associations between cognitive status, comorbidities, metabolic variables and lifestyle variables in 533 PD participants from the COPPADIS study. RESULTS: Among the overall sample, 21% of participants were classified as PD-MCI (n = 114) and 4% as PDD (n = 26). The prevalence of hypertension, diabetes and dyslipidemia was significantly higher in cognitively impaired patients while no between-group differences were found for smoking, alcohol intake or use of supplementary vitamins. Better cognitive scores were significantly associated with regular physical exercise (p < 0.05) and cognitive stimulation (< 0.01). Cognitive performance was negatively associated with interleukin 2 (Il2) (p < 0.05), Il6 (p < 0.05), iron (p < 0.05), and homocysteine (p < 0.005) levels, and positively associated with vitamin B12 levels (p < 0.005). CONCLUSIONS: We extend previous findings regarding the positive and negative influence of various comorbidities and lifestyle factors on cognitive status in early PD patients, and reinforce the need to identify and treat potentially modifiable variables with the intention of exploring the possible improvement of the global cognitive status of patients with PD.
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Disfunção Cognitiva , Demência , Doença de Parkinson , Cognição , Disfunção Cognitiva/epidemiologia , Humanos , Estilo de Vida , Testes Neuropsicológicos , Doença de Parkinson/complicações , Doença de Parkinson/epidemiologiaRESUMO
BACKGROUND: Impulse control disorders (ICD) are a common and disrupting complication of Parkinson's disease (PD) treatment. Although their relationship with dopaminergic activity is well studied, their brain metabolic correlates are mostly unknown. METHODS: In this work we studied brain metabolism using brain 18F-FDG-PET. We performed a case-control study nested within a cohort of PD patients free of ICD at baseline to compare ICD patients right after ICD diagnosis and prior to any treatment modification with matched ICD-free patients. We also compared both PD groups with healthy controls. RESULTS: When compared with ICD-free PD patients, PD patients with recently diagnosed ICD showed higher glucose metabolism in widespread areas comprising prefrontal cortices, both amygdalae and default mode network hubs (p < 0.05, corrected). When compared to healthy controls, they did not show hypermetabolism, and the only hypometabolic region was the right caudate. In turn, ICD-free patients showed diffuse hypometabolism when compared to healthy controls. CONCLUSION: Our results suggest brain metabolism is more preserved in PD patients with ICD than patients without ICD. This metabolic preservation could be related to ICD development.
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Transtornos Disruptivos, de Controle do Impulso e da Conduta , Doença de Parkinson , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Transtornos Disruptivos, de Controle do Impulso e da Conduta/diagnóstico por imagem , Transtornos Disruptivos, de Controle do Impulso e da Conduta/etiologia , Fluordesoxiglucose F18 , Humanos , Doença de Parkinson/diagnóstico por imagemRESUMO
Cognitive decline is a major disabling feature in Parkinson's disease (PD). Multimodal imaging studies have shown functional disruption in neurocognitive networks related to cognitive impairment. However, it remains unknown whether these changes are related to gray matter loss, or whether they outline network vulnerability in the early stages of cognitive impairment. In this work, we intended to assess functional connectivity and graph theoretical measures and their relation to gray matter loss in Parkinson's disease with mild cognitive impairment (PD-MCI). We recruited 53 Parkinson's disease patients and classified them for cognitive impairment using Level-1 Movement Disorders Society-Task Force Criteria. Voxel-based morphometry, functional connectivity and graph theoretical measures were obtained on a 3-Tesla MRI scanner. Loss of gray matter was observed in the default mode network (bilateral precuneus), without a corresponding disruption of functional or graph theoretical properties. However, functional and graph theoretical changes appeared in salience network nodes, without evidence of gray matter loss. Global cognition and executive scores showed a correlation with node degree in the right anterior insula. We also found a correlation between visuospatial scores and right supramarginal gyrus node degree. Our findings highlight the loss of functional connectivity and topological features without structural damage in salience network regions in PD-MCI. They also underline the importance of multimodal hubs in the transition to mild cognitive impairment. This functional disruption in the absence of gray matter atrophy suggests that the salience network is a key vulnerable system at the onset of mild cognitive impairment in PD.
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Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Idoso , Cognição/fisiologia , Disfunção Cognitiva/psicologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/psicologiaRESUMO
BACKGROUND: Minor hallucinations and well-structured hallucinations are considered in the severity continuum of the psychotic spectrum associated with Parkinson's disease. Although their chronological relationship is largely unknown, the spatial patterns of brain atrophy in these 2 forms of hallucinations partially overlap, suggesting they share similar pathophysiological processes. Functional connectivity studies show that disruption of functional networks involved in perception and attention could be relevant in the emergence of well-structured hallucinations. However, functional neuroimaging studies in patients with isolated minor hallucinations are lacking. The objectives of this study were to explore the structural and functional changes underlying minor hallucinations. METHODS: We compared patients with (n = 18) and without (n = 14) minor hallucinations using a multimodal structural (gray-matter volume voxel-based morphometry) and functional (seed-to-whole-brain resting-state functional MRI) neuroimaging study. RESULTS: Coincident with previously described structural changes in well-structured hallucinations in Parkinson's disease, patients with minor hallucinations exhibited gray-matter atrophy with significant voxel-wise differences in visuoperceptual processing areas and core regions of the default mode network. Functional connectivity changes consisted of altered connectivity within the default mode network, reduced negative correlation with task-positive network, and aberrant connectivity between posterior regions of the default mode network and visual-processing areas. These changes are in accordance with the attentional networks hypothesis proposed for well-structured hallucinations. CONCLUSIONS: Although longitudinal studies are needed to assess the potential role of minor hallucinations as an early clinical biomarker of progression to well-structured hallucinations, the present findings show that the 2 phenomena share similar structural and functional brain correlates. © 2018 International Parkinson and Movement Disorder Society.
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Atenção/fisiologia , Encéfalo/fisiopatologia , Rede Nervosa/fisiopatologia , Doença de Parkinson/fisiopatologia , Idoso , Encéfalo/patologia , Mapeamento Encefálico/métodos , Transtornos Cognitivos/fisiopatologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
BACKGROUND: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. OBJECTIVES: To perform the largest PD genome-wide association study restricted to a single country. METHODS: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. RESULTS: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. CONCLUSIONS: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society.
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Doença de Parkinson/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Mapeamento Cromossômico , Efeitos Psicossociais da Doença , Metilação de DNA , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Espanha , Ubiquitina-Proteína Ligases/genéticaRESUMO
Parkinson's disease (PD) can be divided into familial (Mendelian) and sporadic forms. A number of causal genes have been discovered for the Mendelian form, which constitutes 10-20% of the total cases. Genome-wide association studies have successfully uncovered a number of susceptibility loci for sporadic cases but those only explain a small fraction (6-7%) of PD heritability. It has been observed that some genes that confer susceptibility to PD through common risk variants also contain rare causing mutations for the Mendelian forms of the disease. These results suggest a possible functional link between Mendelian and sporadic PD and led us to investigate the role that rare and low-frequency variants could have on the sporadic form. Through a targeting approach, we have resequenced at 49× coverage the exons and regulatory regions of 38 genes (including Mendelian and susceptibility PD genes) in 249 sporadic PD patients and 145 unrelated controls of European origin. Unlike susceptibility genes, Mendelian genes show a clear general enrichment of rare functional variants in PD cases, observed directly as well as with Tajima's D statistic and several collapsing methods. Our findings suggest that rare variation on PD Mendelian genes may have a role in the sporadic forms of the disease.
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Doença de Parkinson/genética , Adulto , Idoso , Estudos de Casos e Controles , Éxons , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
BACKGROUND: The analysis of coverage depth in next-generation sequencing data allows the detection of gene dose alterations. We explore the frequency of such structural events in a Spanish cohort of sporadic PD cases. METHODS: Gene dose alterations were detected with the eXome-Hidden Markov Model (XHMM) software from depth of coverage in resequencing data available for 38 Mendelian and other risk PD loci in 394 individuals (249 cases and 145 controls) and subsequently validated by quantitative PCR. RESULTS: We identified 10 PD patients with exon dosage alterations in PARK2, GBA-GBAP1, and DJ1. Additional functional variants, including 2 novel nonsense mutations (p.Arg1552Ter in LRRK2 and p.Trp90Ter in PINK1), were confirmed by Sanger sequencing. This combined approach disclosed the genetic cause of 12 PD cases. CONCLUSIONS: Gene dose alterations related to PD can be correctly identified from targeting resequencing data. This approach substantially improves the detection rate of cases with causal genetic alterations. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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Doença de Parkinson/genética , Análise de Sequência de DNA/métodos , Estudos de Coortes , Variações do Número de Cópias de DNA , Humanos , EspanhaRESUMO
OBJECTIVES: The description of minor hallucinatory phenomena (presence, passage hallucinations) has widened the spectrum of psychosis in Parkinson's disease (PD). Minor hallucinatory phenomena seem to antedate the development of more severe hallucinations. Early detection of minor hallucinations may be useful for screening patients with more severe endophenotypes. Motivated by the observation of "de novo," drug-naive PD patients reporting minor hallucinations, we aimed to prospectively identify "de novo" untreated PD patients experiencing hallucinatory phenomena, and to compare their clinico-demographic characteristics with those of untreated PD patients without hallucinations and healthy controls. METHODS: Screening and description of psychosis was assessed by the Movement Disorders Society Unified Parkinson's Disease Rating Scale-Part I and a structured interview covering all types of psychotic phenomena reported in PD. Clinical, neuropsychological, and demographic data of PD patients with and without psychotic phenomena were compared with those of age- and education-matched healthy controls. RESULTS: Fifty drug-naive, "de novo" PD patients and 100 controls were prospectively included. Minor hallucinations were experienced in 42% (21 of 50) PD patients and 5% controls (P < 0.0001). Coexistence of passage and presence hallucinations was the most common finding. Unexpectedly, 33.3% of patients with minor hallucinations manifested these as a pre-motor symptom, starting 7 months to 8 years before first parkinsonian motor symptoms. The presence of minor hallucinations was significantly associated with presence of rapid eye movement sleep behavior disorder. CONCLUSIONS: In this first study to prospectively analyze the frequency of minor hallucinatory phenomena in incident, untreated PD patients, hallucinations appeared as a frequent early non-motor symptom that may even predate the onset of parkinsonism.
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Alucinações/etiologia , Doença de Parkinson/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Estatísticas não ParamétricasRESUMO
The H1 haplotype of the 17q21.31 inversion polymorphism has been consistently associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson's disease in Caucasians. Recently, large polymorphic segmental duplications resulting into complex rearrangements at this locus with a high diversity range in human populations have been revealed. We sought to explore whether the two multi-allelic copy number variants that are present in the H1 clade (with segmental duplications of 300 and 218 kilobases in length) could be responsible for the known H1-related risk of developing these neurodegenerative disorders. A total of 857 Spanish subjects including 330 patients with Parkinson's disease, 96 with progressive supranuclear palsy, 55 with corticobasal degeneration, 51 dementia with Lewy bodies, and 325 neurologically healthy controls, were genotyped for the H1/H2 haplotype. Subsequently, the two copy number variants that are characteristic of the H1 haplotype were evaluated through a high-resolution approach based on droplet digital polymerase chain reaction, in all H1 homozygous subjects. The H1 allele was significantly overrepresented in all diagnostic groups compared with controls (Parkinson's disease, P = 0.0001; progressive supranuclear palsy, P = 1.22 × 10(-6) ; corticobasal degeneration, P = 0.0002; and dementia with Lewy bodies, P = 0.032). However, no dosage differences were found for any of the two copy number variants analyzed. The H1 haplotype is associated with the risk of several neurodegenerative disorders, including dementia with Lewy bodies. However, common structural diversity within the 17q21.31-H1 clade does not explain this genetic association.
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Cromossomos Humanos Par 17/genética , Variações do Número de Cópias de DNA/genética , Doenças Neurodegenerativas/genética , Idoso , Estudos de Casos e Controles , Demografia , Feminino , Frequência do Gene/genética , Humanos , MasculinoRESUMO
Apathy is one of the most common and debilitating nonmotor manifestations of Parkinson's disease (PD) and is characterized by diminished motivation, decreased goal-directed behavior, and flattened affect. Despite its high prevalence, its underlying mechanisms are still poorly understood, having been associated with executive dysfunction, and impaired emotional processing and decision making. Apathy, as a syndrome, has recently been associated with reduced activation in the ventral striatum, suggesting that early- to middle-stage Parkinson's disease patients with this manifestation may have a compromised mesocorticolimbic dopaminergic pathway and impaired incentive processing. To test this hypothesis, we measured the amplitude of the feedback-related negativity, an event-related brain potential associated with performance outcome valence, following monetary gains and losses in human PD patients (12 women) and healthy controls (6 women) performing a gambling task. Early- to middle-stage PD patients presenting clinically meaningful symptoms of apathy were compared with nonapathetic PD patients and healthy controls. Patients with cognitive impairment, depression, and other psychiatric disturbances were excluded. Results showed that the amplitude of the feedback-related negativity, measured as the difference wave in the event-related brain potential between gains and losses, was significantly reduced in PD patients with apathy compared with nonapathetic patients and healthy controls. These findings indicate impaired incentive processing and suggest a compromised mesocorticolimbic pathway in cognitively intact PD patients with apathy.
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Apatia/fisiologia , Encéfalo/fisiopatologia , Potenciais Evocados/fisiologia , Motivação/fisiologia , Doença de Parkinson/fisiopatologia , Afeto/fisiologia , Idoso , Mapeamento Encefálico , Tomada de Decisões/fisiologia , Feminino , Jogo de Azar , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/psicologia , Tempo de Reação/fisiologiaRESUMO
OBJECTIVE: The effects of stimulation frequency on verbal fluency (VF) following subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) are not well understood. The present study examines the impact stimulation frequency has on VF following bilateral STN-DBS in PD. METHODS: Prospective study of 38 consecutive patients with PD with low frequency STN-DBS (LFS) (n = 10) and high frequency STN-DBS (HFS) (n = 14), and a non-operated PD control group consisting of patients with fluctuating response to dopaminergic medication (n = 14) homogeneous in age, education, disease duration, and global cognitive function. Patients were evaluated on VF tasks (letter, semantic, action verbs, alternating). A one-way analysis of variance (ANOVA) was conducted to assess distinctions between groups. Pre- and post-surgical comparisons of fluencies were performed for operated groups. A mixed ANOVA was applied to the data to evaluate the interaction between treatment (HFS vs. LFS) and time (pre- vs. post-surgery). Strategy use (clustering and switching) was evaluated. RESULTS: Semantic and letter fluency performance revealed significant differences between HFS and LFS groups. Pre- and post-surgical comparisons revealed HFS negatively affected letter, semantic, and action fluencies, but LFS had no effect on VF. No interaction effect or main effect of treatment was found. Main effect of time was significant for semantic and action fluencies indicating a decrease in postoperative fluency performance. Patients with LFS produced larger average cluster sizes than patients with HFS. CONCLUSION: LFS may be less detrimental to VF, but these findings suggest that VF decline following STN-DBS is not caused by stimulation frequency alone.
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Lack of validated data on cutoff scores for mild cognitive impairment (MCI) and sensitivity to change in predementia stages of Parkinson's disease (PD) limit the utility of instruments measuring global cognition as screening and outcome measures in therapeutic trials. Investigators who were blinded to PD-Cognitive Rating Scale (PD-CRS) scores classified a cohort of prospectively recruited, nondemented patients into a PD with normal cognition (PD-NC) group and a PD with MCI (PD-MCI) group using Clinical Dementia Rating (CDR) and the Mattis Dementia Rating Scale-2 (MDRS-2). The discriminative power of the PD-CRS for PD-MCI was examined in a representative sample of 234 patients (145 in the PD-NC group; 89 in the PD-MCI group) and in a control group of 98 healthy individuals. Sensitivity to change in the PD-CRS score (the minimal clinically important difference was examined with the Clinical Global Impression of Change scale and was calculated with a combination of distribution-based and anchor-based approaches) was explored in a 6-month observational multicenter trial involving a subset of 120 patients (PD-NC, 63; PD-MCI, 57). Regression analysis demonstrated that PD-CRS total scores (P < 0.001) and age (P = 0.01) independently differentiated PD-NC from PD-MCI. Area under the receiver operating characteristic curve (AUC) analysis (AUC, 0.85; 95% confidence interval, 0.80-0.90) indicated that a score ≤ 81 of 134 was the optimal cutoff point on the total score for the PD-CRS (sensitivity, 79%; specificity, 80%; positive predictive value, 59%; negative predictive value, 91%). A range of change from 10 to 13 points on the PD-CRS total score was indicative of clinically significant change. These findings suggest that the PD-CRS is a useful tool to identify PD-MCI and to track cognitive changes in nondemented patients with PD.
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Disfunção Cognitiva/psicologia , Doença de Parkinson/psicologia , Psicometria/métodos , Idoso , Disfunção Cognitiva/etiologia , Interpretação Estatística de Dados , Progressão da Doença , Feminino , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/complicações , Estudos Prospectivos , Curva ROC , Reprodutibilidade dos TestesRESUMO
Background: We describe our experience of using perampanel to treat essential tremor (ET) over 12 months. Methods: We enrolled 50 ET patients in an open-label trial. Perampanel was titrated to 4 mg/day as adjuvant therapy. The main outcome measures were baseline, +1, +3, +6, and + 12 month scores of the Tremor Clinical Rating Scale (TCRS) and the Glass scale (GS). Results: Twenty patients withdrew because of adverse effects. At +1 month, 27 of 30 patients improved: 68% reduction in both TCRS 1 + 2 (P < 0.001) and TCRS 3 (P < 0.001); TCRS 4 + 1.8 and GS 1.1 point reduction. By +12 months non-persistence of therapeutic effect occurred in 70% of patients: the mean reduction in TCRS 1 + 2 was 33% (P = 0.03), TCRS 3 (0.04), TCRS 4 + 0.8, GS 0.2 points reduction. Conclusions: We report important peramapanel acute tremorolytic effects, but poor tolerance to adverse effects and a non-sustained therapeutic effect in most patients.
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Mutations in the glucocerebrosidase gene are associated with Parkinson's disease and Lewy body dementia. However, whether these alterations have any effect on the clinical course of Parkinson's disease is not clear. The glucocerebrosidase coding region was fully sequenced in 225 Parkinson's disease patients, 17 pathologically confirmed Lewy body dementia patients, and 186 controls from Spain. Twenty-two Parkinson's disease patients (9.8%) and 2 Lewy body dementia patients (11.8%) carried mutations in the glucocerebrosidase gene, compared with only 1 control (0.5%); P = .016 and P = .021 for Parkinson's disease and Lewy body dementia, respectively. The N370S and the L444P mutations represented 50% of the alterations. Two novel variants, L144V and S488T, and 7 previously described alterations were also found. Alterations in glucocerebrosidase were associated with a significant risk of dementia during the clinical course of Parkinson's disease (age at onset, years of evolution, and sex-adjusted odds ratio, 5.8; P = .001). Mutation carriers did not show worse motor symptoms, had good response to L-dopa, and tended to present the intermediate parkinsonian phenotype. Our findings suggest that mutations in the glucocerebrosidase gene not only increase the risk of both Parkinson's disease and Lewy body dementia but also strongly influence the course of Parkinson's disease with respect to the appearance of dementia.
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Predisposição Genética para Doença/genética , Glucosilceramidase/genética , Doença por Corpos de Lewy/genética , Mutação/genética , Transtornos Parkinsonianos/genética , Adulto , Idoso , Análise de Variância , Distribuição de Qui-Quadrado , Análise Mutacional de DNA , Progressão da Doença , Feminino , Genótipo , Humanos , Doença por Corpos de Lewy/complicações , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtornos Parkinsonianos/complicações , Fatores de RiscoRESUMO
Frontal subcortical cognitive defects are predominant in Parkinson's disease (PD). Temporal lobe dysfunction seems more relevant for progression to dementia. We aimed to study the relative importance of temporal lobe defects versus executive impairment in the progression to dementia in PD by using proton magnetic resonance spectroscopy ((1)H-MRS). The (1)H-MRS features of PD patients with intact cognition (PD-CgInt; n = 16), mild cognitive impairment (MCI; n = 15) and dementia (PDD; n = 15) were compared, to delineate the metabolic alterations correlating with cognitive status. Metabolite concentrations were acquired from voxels localized to the hippocampus and dorsolateral prefrontal cortex (DL-PFC). Cognitive status was established following the Movement Disorder Society PDD criteria, administering the Clinical Dementia Rating Scale and Mattis Dementia Rating Scale. The Parkinson's Disease Cognitive Rating Scale (PD-CRS) was used to correlate (1)H-MRS with neuropsychology. N-acetylaspartate (NAA) concentrations in the right DL-PFC were decreased in PD-MCI compared with PD-CgInt patients (p = 0.002), and correlated with frontal subcortical tasks. Decreased NAA concentrations in the left hippocampus in PDD compared to PD-MCI (p = 0.03) correlated with confrontation naming. The present findings support that executive impairment is related to dorsolateral prefrontal dysfunction from the early stages, while progression to dementia is linked to the additional impairment of temporal lobe structures. The PD-CRS was able to capture the differential impairment of prefrontal versus temporal cortical areas.
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Química Encefálica/fisiologia , Disfunção Cognitiva/metabolismo , Demência/metabolismo , Doença de Parkinson/metabolismo , Idoso de 80 Anos ou mais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/química , Ácido Aspártico/metabolismo , Cognição/fisiologia , Interpretação Estatística de Dados , Demência/etiologia , Progressão da Doença , Função Executiva , Feminino , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/complicações , Córtex Pré-Frontal/química , Córtex Pré-Frontal/metabolismo , Escalas de Graduação Psiquiátrica , Desempenho Psicomotor/fisiologia , Lobo Temporal/química , Lobo Temporal/metabolismo , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Minor hallucinations in Parkinson's disease are associated with connectivity changes in attentional networks and increased risk of structured hallucinations. However, the clinical translation of these abnormalities in attention processes is not well-defined, and commonly used neuropsychological tests are not able to detect significant deficits in Parkinson's disease patients with isolated minor hallucinations. OBJECTIVES: To analyze the behavioral and electrophysiological correlates of minor hallucinations in Parkinson's disease during an attentional task assessing response inhibition and interference control. METHODS: Fifty-five non-demented Parkinson's disease patients with (PD-mH; n = 27) and without minor hallucinations (PD-NH; n = 28) were included in the analysis. An Ericksen flanker task was performed to compare the effect of presenting congruent and incongruent stimuli on accuracy, reaction times and stimulus-locked event-related potentials morphology. RESULTS: Although both groups showed equivalent performance in a standard neuropsychological assessment, in the flanker task accuracy rates were lower in the PD-mH group in incongruent trials (p = 0.005). In the event-related potentials, PD-mH patients showed increased amplitude of the N2 at Fz [t(53); p < 0.05] and decreased amplitude of the P300 at Pz [t(53); p < 0.05] for the incongruent trials. CONCLUSIONS: Parkinson's disease patients with isolated minor hallucinations were more susceptible to interference mediated by irrelevant stimuli and had less cognitive control for suppressing these interferences. The failure of these systems could precipitate the intrusion and overrepresentation of peripheral irrelevant stimuli perceived as minor hallucinations. The Ericksen flanker task could be used as a sensitive clinical marker of the attentional defects leading to hallucinations in Parkinson's disease.
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Doença de Parkinson , Atenção/fisiologia , Alucinações/diagnóstico , Humanos , Testes Neuropsicológicos , Doença de Parkinson/diagnóstico , Tempo de Reação/fisiologiaRESUMO
Background: Apathy is highly prevalent and disabling in Parkinson's disease (PD). Pharmacological options for its management lack sufficient evidence. Objective: We studied the effects of safinamide on apathy in PD. Methods: Prospective, 24-week, two-site, randomized, double-blind, placebo-controlled, parallel-group exploratory study in non-demented PD on stable dopaminergic therapy randomized 1:1 to adjunct safinamide (50 mg/day for 2 weeks and 100 mg/day for 22 weeks) or placebo. The primary endpoint was the mean change from baseline to week 24 on the Apathy Scale (AS) total score. Secondary endpoints included changes in cognition, activities of daily living, motor scores, the impression of change, and safety and tolerability measures. Results: In total, 30 participants (active treatment = 15; placebo = 15; 80% showing clinically significant apathetic symptoms according to the AS) were enrolled, and included in the intention-to-treat analysis. Change in AS (ANOVA) showed a trend to significance [p = 0.059] mediated by a more marked decrease in AS score with safinamide (-7.5 ± 6.9) than with placebo (-2.8 ± 5.7). Post-hoc analysis (paired t-test) showed a significant positive change in the AS score between 12-week and 24-week [p = 0.001] only in the active group. No significant or trend changes were found for any of the secondary outcome variables. Adverse events were few and only mild in both treatment groups. Conclusions: Safinamide was safe and well-tolerated, but failed to provide evidence of improved apathy. The positive trend observed in the post-hoc analyses deserves to be studied in depth in larger studies. Trial Registration: EudraCT 2017-003254-17.
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BACKGROUND: Cognitive dysfunction is a disabling complication in Parkinson's disease (PD). Accuracy of diagnosis of mild cognitive impairment in PD (PD-MCI) depends on the tests performed, which limits results generalization. Blood-based biomarkers could provide additional objective information for PD-MCI diagnosis and progression. Blood neurofilament light chain (NfL), a marker of neuronal injury, has shown good performance for PD disease stratification and progression. While NfL is not disease-specific, phosphorylated-tau at threonine-181 (p-tau181) in blood is a highly specific marker of concomitant brain amyloid-ß and tau pathology. METHODS: We investigated the potential of plasma NfL and p-tau181 levels as markers of cognitive impairment in a prospective cohort of 109 PD patients with and without PD-MCI (age 68.1 ± 7 years, education 12.2± 5 years), and 40 comparable healthy controls. After a follow-up of 4 years, we evaluated their predictive value for progression to dementia. RESULTS: Although NfL and p-tau181 levels were significantly increased in PD compared with healthy controls, only NfL levels were significantly higher in PD-MCI compared with PD with normal cognition (PD-NC) at baseline. After a follow-up of 4 years, only NfL predicted progression to dementia (HR 1.23, 95% CI 1.02-1.53; pâ¯=â¯0.038). Significant correlations between fluid biomarkers and neuropsychological examination were only found with NfL levels. CONCLUSIONS: Plasma NfL levels objectively differentiates PD-MCI from PD-NC patients, and may serve as a plasma biomarker for predicting progression to dementia in PD. Plasma levels of p-tau181 does not seem to help in differentiating PD-MCI or to predict future cognitive deterioration.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Parkinson , Humanos , Pessoa de Meia-Idade , Idoso , Doença de Parkinson/complicações , Treonina , Estudos Prospectivos , Doença de Alzheimer/diagnóstico , Proteínas tau , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , BiomarcadoresRESUMO
Mild cognitive impairment in Parkinson's disease (PD-MCI) is associated with consistent structural and functional brain changes. Whether different approaches for diagnosing PD-MCI are equivalent in their neural correlates is presently unknown. We aimed to profile the neuroimaging changes associated with the two endorsed methods of diagnosing PD-MCI. We recruited 53 consecutive non-demented PD patients and classified them as PD-MCI according to comprehensive neuropsychological examination as operationalized by the Movement Disorders Task Force. Voxel-based morphometry, cortical thickness, functional connectivity and graph theoretical measures were obtained on a 3-Tesla MRI scanner. 18 patients (32%) were classified as PD-MCI with Level-II criteria, 19 (33%) with the Parkinson's disease Cognitive Rating Scale (PD-CRS) and 32 (60%) with the Montreal Cognitive Assessment (MoCA) scale. Though regions of atrophy differed across classifications, reduced gray matter in the precuneus was found using both Level-II and PD-CRS classifications in PD-MCI patients. Patients diagnosed with the PD-CRS also showed extensive changes in cortical thickness, concurring with the MoCA in regions of the cingulate cortex, and again with Level-II regarding cortical thinning in the precuneus. Functional connectivity analysis found higher coherence within salience network regions of interest, and decreased anticorrelations between salience/central executive and default-mode networks in the PD-CRS classification for PD-MCI patients. Graph theoretical metrics showed a widespread decrease in node degree for the three classifications in PD-MCI, whereas betweenness centrality was increased in select nodes of the default mode network (DMN). Clinical and neuroimaging commonalities between the endorsed methods of cognitive assessment suggest a corresponding set of neural correlates in PD-MCI: loss of structural integrity in DMN structures, mainly the precuneus, and a loss of weighted connections in the salience network that might be counterbalanced by increased centrality in the DMN. Furthermore, the similarity of the results between exhaustive Level-II and screening Level-I tools might have practical implications in the search for neuroimaging biomarkers of cognitive impairment in Parkinson's disease.