RESUMO
Importance: Mutations of the glucocerebrosidase gene, GBA1 (OMIM 606463), are the most important risk factor for Parkinson disease (PD). In vitro and in vivo studies have reported that ambroxol increases ß-glucocerebrosidase (GCase) enzyme activity and reduces α-synuclein levels. These observations support a potential role for ambroxol therapy in modifying a relevant pathogenetic pathway in PD. Objective: To assess safety, tolerability, cerebrospinal fluid (CSF) penetration, and target engagement of ambroxol therapy with GCase in patients with PD with and without GBA1 mutations. Interventions: An escalating dose of oral ambroxol to 1.26 g per day. Design, Setting, and Participants: This single-center open-label noncontrolled clinical trial was conducted between January 11, 2017, and April 25, 2018, at the Leonard Wolfson Experimental Neuroscience Centre, a dedicated clinical research facility and part of the University College London Queen Square Institute of Neurology in London, United Kingdom. Participants were recruited from established databases at the Royal Free London Hospital and National Hospital for Neurology and Neurosurgery in London. Twenty-four patients with moderate PD were evaluated for eligibility, and 23 entered the study. Of those, 18 patients completed the study; 1 patient was excluded (failed lumbar puncture), and 4 patients withdrew (predominantly lumbar puncture-related complications). All data analyses were performed from November 1 to December 14, 2018. Main Outcomes and Measures: Primary outcomes at 186 days were the detection of ambroxol in the CSF and a change in CSF GCase activity. Results: Of the 18 participants (15 men [83.3%]; mean [SD] age, 60.2 [9.7] years) who completed the study, 17 (8 with GBA1 mutations and 9 without GBA1 mutations) were included in the primary analysis. Between days 0 and 186, a 156-ng/mL increase in the level of ambroxol in CSF (lower 95% confidence limit, 129 ng/mL; P < .001) was observed. The CSF GCase activity decreased by 19% (0.059 nmol/mL per hour; 95% CI, -0.115 to -0.002; P = .04). The ambroxol therapy was well tolerated, with no serious adverse events. An increase of 50 pg/mL (13%) in the CSF α-synuclein concentration (95% CI, 14-87; P = .01) and an increase of 88 ng/mol (35%) in the CSF GCase protein levels (95% CI, 40-137; P = .002) were observed. Mean (SD) scores on part 3 of the Movement Disorders Society Unified Parkinson Disease Rating Scale decreased (ie, improved) by 6.8 (7.1) points (95% CI, -10.4 to -3.1; P = .001). These changes were observed in patients with and without GBA1 mutations. Conclusions and Relevance: The study results suggest that ambroxol therapy was safe and well tolerated; CSF penetration and target engagement of ambroxol were achieved, and CSF α-synuclein levels were increased. Placebo-controlled clinical trials are needed to examine whether ambroxol therapy is associated with changes in the natural progression of PD. Trial Registration: ClinicalTrials.gov identifier: NCT02941822; EudraCT identifier: 2015-002571-24.
Assuntos
Ambroxol/uso terapêutico , Glucosilceramidase/genética , Mutação , Doença de Parkinson/tratamento farmacológico , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/genética , Resultado do TratamentoRESUMO
OBJECTIVE: Neuropsychiatric symptoms are a major component of dementia irrespective of severity or subtype. We aimed to determine the feasibility of biographical films to reduce neuropsychiatric symptoms in people with moderate to severe dementia over a 32-week period. METHOD: A total of 11 people with dementia situated in a residential care home took part in this mixed-method feasibility study. Carers reported neuropsychiatric symptoms of residents at three time-points, and their experience of the study was obtained at a feedback session. RESULTS: There was a significant reduction in neuropsychiatric symptoms in residents with neuropsychiatric impairment from baseline to the end of study (p = .042; d = .98). Thematic analysis identified three major themes: Triggered memories, knowledge gained to support care, and perceived changes in the resident. CONCLUSION: The findings suggest that it is feasible to use biographical films long-term to reduce neuropsychiatric symptoms of dementia, alongside routine care.
Assuntos
Sintomas Comportamentais/terapia , Demência/complicações , Filmes Cinematográficos , Psicoterapia/métodos , Idoso , Sintomas Comportamentais/etiologia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Memória Episódica , Casas de SaúdeRESUMO
We present an extension of a neurobiologically inspired robotics model, termed CoRLEGO (Choice reaching with a LEGO arm robot). CoRLEGO models experimental evidence from choice reaching tasks (CRT). In a CRT participants are asked to rapidly reach and touch an item presented on the screen. These experiments show that non-target items can divert the reaching movement away from the ideal trajectory to the target item. This is seen as evidence attentional selection of reaching targets can leak into the motor system. Using competitive target selection and topological representations of motor parameters (dynamic neural fields) CoRLEGO is able to mimic this leakage effect. Furthermore if the reaching target is determined by its colour oddity (i.e. a green square among red squares or vice versa), the reaching trajectories become straighter with repetitions of the target colour (colour streaks). This colour priming effect can also be modelled with CoRLEGO. The paper also presents an extension of CoRLEGO. This extension mimics findings that transcranial direct current stimulation (tDCS) over the motor cortex modulates the colour priming effect (Woodgate et al., 2015). The results with the new CoRLEGO suggest that feedback connections from the motor system to the brain's attentional system (parietal cortex) guide visual attention to extract movement-relevant information (i.e. colour) from visual stimuli. This paper adds to growing evidence that there is a close interaction between the motor system and the attention system. This evidence contradicts the traditional conceptualization of the motor system as the endpoint of a serial chain of processing stages. At the end of the paper we discuss CoRLEGO's predictions and also lessons for neurobiologically inspired robotics emerging from this work.
Assuntos
Atenção/fisiologia , Comportamento de Escolha/fisiologia , Córtex Motor/fisiologia , Movimento/fisiologia , Desempenho Psicomotor/fisiologia , Robótica , Percepção Visual/fisiologia , Braço/fisiologia , Mapeamento Encefálico , Humanos , Lobo Parietal/fisiologiaRESUMO
The present paper asks whether the motor cortex contributes to prediction-based guidance of target selection. This question was inspired by recent evidence that suggests (i) recurrent connections from the motor system into the attentional system may extract movement-relevant perceptual information and (ii) that the motor cortex cannot only generate predictions of the sensory consequences of movements but may also operate as predictor of perceptual events in general. To test this idea we employed a choice reaching task requiring participants to rapidly reach and touch a predictable or unpredictable colour target. Motor cortex activity was modulated via transcranial direct current stimulation (tDCS). In Experiment 1 target colour repetitions were predictable. Under such conditions anodal tDCS facilitated selection versus sham and cathodal tDCS. This improvement was apparent for trajectory curvature but not movement initiation. Conversely, where no predictability of colour was embedded reach performance was unaffected by tDCS. Finally, the results of a key-press experiment suggested that motor cortex involvement is restricted to tasks where the predictable target colour is movement-relevant. The outcomes are interpreted as evidence that the motor system contributes to the top-down guidance of selective attention to movement targets.