Background. Context-dependent behavior is a phenomenon in which people demonstrate superior performance in the context where a motor task was originally learned, but show poorer performance in an ...unfamiliar context. Previous studies found that people with Parkinson’s disease (PD) demonstrated greater context-dependency than nondisabled adults. Moreover, the frontostriatal circuit appeared to play a role in mediating context-dependent behavior. Neuroimaging studies showed that people with PD and freezing of gait (FoG) had difficulty recruiting the frontostriatal circuit when performing a set-shifting task, known to be mediated by this neural network. Objective. This study aimed to investigate whether individuals with PD and FoG (PD + FoG) would be more context-dependent than those without FoG (PD − FoG). Furthermore, the association between context-dependent behavior and set-shifting ability would be determined. Methods. Sixteen individuals with PD + FoG, 15 participants with PD − FoG, and 15 nondisabled adults (Control) were recruited. The participants practiced 3 numerical sequences, each associated with a specific context. One day following practice, the participants were tested under 2 conditions: the sequence-context associations remained the same as practice or were changed. Set-shifting ability was measured by the Trail Making Test (TMT). Results. Compared to the PD − FoG group, the PD + FoG group showed a greater decrement in normalized motor performance when the sequence-context associations were changed. Context-dependency correlated with the TMT in the PD − FoG group but not in the PD + FoG or Control groups. Conclusion. While people with PD + FoG appeared to be more context-dependent than individuals without FoG, a relationship between context-dependent behavior and set-shifting existed only in those without FoG.
Aromatic L-amino acid decarboxylase (AADC) is required for the synthesis of the neurotransmitters dopamine and serotonin. Children with defects in the AADC gene show compromised development, ...particularly in motor function. Drug therapy has only marginal effects on some of the symptoms and does not change early childhood mortality. Here, we performed adeno-associated viral vector-mediated gene transfer of the human AADC gene bilaterally into the putamen of four patients 4 to 6 years of age. All of the patients showed improvements in motor performance: One patient was able to stand 16 months after gene transfer, and the other three patients achieved supported sitting 6 to 15 months after gene transfer. Choreic dyskinesia was observed in all patients, but this resolved after several months. Positron emission tomography revealed increased uptake by the putamen of 6-(18)Ffluorodopa, a tracer for AADC. Cerebrospinal fluid analysis showed increased dopamine and serotonin levels after gene transfer. Thus, gene therapy targeting primary AADC deficiency is well tolerated and leads to improved motor function.
Background
People with Parkinson’s disease (PD) are known to have motor learning difficulties. Although numerous studies have demonstrated that a single bout of aerobic exercise (AEX) can facilitate ...motor learning in non-disabled adults, the same beneficial effect in PD is unknown. Furthermore, associated neuroplastic changes have not been investigated.
Objectives
This study aimed to determine whether a single bout of aerobic exercise (AEX) can facilitate motor sequence learning in people with PD and to investigate the associated neurophysiological changes.
Methods
Thirty individuals with PD were recruited and randomized into the exercise group (PD + AEX) and non-exercise group (PD − AEX). At the first visit, corticomotor excitability was assessed using transcranial magnetic stimulation (TMS). All participants then performed a serial reaction time task (SRTT) followed by 20 minutes of moderately-high intensity aerobic exercise (AEX) for the PD + AEX group or rest for the PD − AEX group. The SRTT and TMS were reevaluated at 3 time points: immediately after aerobic exercise (AEX) or rest, on the second day after practice (D2), and a week after practice (D7).
Results
Both groups showed improvement throughout practice. At retention, the PD + AEX group showed improved SRTT performance on D7 compared to D2 (P = .001), while the PD − AEX group showed no change in performance. TMS results showed that the PD + AEX group had significantly higher corticomotor excitability than the PD − AEX group on D7.
Conclusion
A single session of aerobic exercise (AEX) could enhance motor sequence learning and induce neuroplastic changes. Clinicians can consider providing aerobic exercise (AEX) after motor task training for people with PD.
Clinical registration:
NCT04189887 (ClinicalTrials.gov).
Investigating DYT1 in a Taiwanese dystonia cohort Wu, Meng-Chen; Chang, Yung-Yee; Chen, Ying-Fa ...
Journal of the Formosan Medical Association,
January 2022, 2022-Jan, 2022-01-00, 20220101, 2022-01-01, Letnik:
121, Številka:
1
Journal Article
Recenzirano
Odprti dostop
A heterozygous three-nucleotide (GAG) in-frame deletion in the TOR1A gene causes the rare disease, dystonia (DYT1), which typically presents as focal limb dystonia during adolescence, then spreads to ...other limbs. This study investigated the frequency and clinical features of DYT1 in a Taiwanese dystonia cohort.
We performed targeted next generation sequencing in 318 patients with primary dystonia. We identified one DYT1 family with various types of dystonia, and we described the clinical presentations observed in this family during a 30-year follow-up. We compared the clinical characteristics to those reported in previous studies on DYT1 from 2000 to 2020.
Among 318 patients, we identified only one DYT1 patient (0.3%) with an autosomal dominant family history of dystonia. The proband was a 43-year-old man that experienced progressive onset of focal lower limb dystonia from age 11 years. The disease spread caudal-rostrally to the upper limbs and cervical muscles. Prominent cervical dystonia was noted during follow-up, which was an atypical presentation of DYT1. Clinical assessments of other family members showed intrafamily variability. The proband's father and an affected sibling demonstrated only mild right-hand writer's cramp. A systematic review of previously reported DTY1 cases showed that Asian patients had a higher frequency of cervical dystonia (44.8%) than groups of Ashkenazi Jews (35%) and Non-Jewish Caucasians (30.5%) (P = 0.04).
Our findings revealed that DYT1 is rare in a Taiwanese dystonia cohort. The presentation of marked cervical dystonia could be the main feature of Asian patients with DYT1.
•Some neurological disorders share common pathophysiological features.•Glutamatergic hyperactivity-related excitotoxicity is involved in neurodegeneration.•Ceftriaxone increases glutamate ...transporter-1 expression and glutamate reuptake and suppresses excitotoxicity.•Ceftriaxone may have potential for treating neuronal disorders.
Several neurodegenerative disorders, namely Parkinson’s disease dementia, dementia with Lewy bodies, and Alzheimer’s disease, share common pathophysiological features, such as (1) cognitive deficits, (2) glutamatergic hyperactivity-related excitotoxicity, and (3) deposition of α-synuclein (α-syn) and β-amyloid (Aβ). Ceftriaxone (CEF) is a well-tested and safe drug that has been used as an antibiotic for several decades. Recent studies have demonstrated the following effects of CEF: (1) increasing glutamate transporter-1 expression and glutamate reuptake and suppressing excitotoxicity, (2) binding well with α-syn and inhibition of α-syn polymerization, (3) modulating expression of genes related to Aβ metabolism, and (4) enhancing neurogenesis and recovery of neuronal density. In addition, our data revealed that CEF ameliorates seizure and abnormal neuronal firing in the brain. These results suggest the potential of CEF in treating neuronal disorders. This paper addresses the effects and pharmacology of CEF.
Objective:
We have reported that intrinsic membrane properties, especially T‐type Ca2+ channels, play a key role in the genesis of burst discharges in the subthalamic nucleus (STN) and parkinsonian ...locomotor symptoms. Whether deep brain stimulation (DBS) exerts its clinical benefits on Parkinson disease (PD) with changes in T currents or other conductances, however, remains elusive.
Methods:
Different stimulation protocols, including constant currents of opposite polarity, were applied to STN in vivo or in vitro, and the electrophysiological and behavioral effects were documented in normal and parkinsonian rodents. The effect of correlatively adjusted DBS protocols was also explored in 3 PD patients.
Results:
Delivery of negative constant current into STN dramatically ameliorated locomotor deficits in parkinsonian rats. It also depolarized STN neurons and decreased T‐channel availability as well as burst discharges. In contrast, delivery of positive constant currents to STN induced PD‐like locomotor deficits and increased STN burst discharges in normal rats. In addition, the therapeutic effect of DBS was greatly improved in 3 PD patients simply by increasing the pulse width from 60 to 240 microseconds, even at a lower stimulation frequency of 60Hz.
Interpretation:
The increased tendency of STN burst discharges may by itself serve as a direct cause of parkinsonian locomotor deficits, even in the absence of deranged dopaminergic innervation. Effective DBS therapy in PD very likely relies on adequate depolarization, and consequent modification of the relevant ionic currents and discharge patterns, of STN neurons. ANN NEUROL 2012;72:464–476.
Neuronal oscillations at beta frequencies (20-50 Hz) in the cortico-basal ganglia circuits have long been the leading theory for bradykinesia, the slow movements that are cardinal symptoms in ...Parkinson's disease (PD). The beta oscillation theory helped to drive a frequency-based design in the development of deep brain stimulation therapy for PD. However, in contrast to this theory, here we have found that bradykinesia can be completely dissociated from beta oscillations in rodent models. Instead, we observed that bradykinesia is causatively regulated by the burst-firing pattern of the subthalamic nucleus (STN) in a feed-forward, or efferent-only, mechanism. Furthermore, STN burst-firing and beta oscillations are two independent mechanisms that are regulated by different NMDA receptors in STN. Our results shift the understanding of bradykinesia pathophysiology from an interactive oscillatory theory toward a feed-forward mechanism that is coded by firing patterns. This distinct mechanism may improve understanding of the fundamental concepts of motor control and enable more selective targeting of bradykinesia-specific mechanisms to improve PD therapy.
Among dystonia patients receiving globus pallidus internus (GPi) deep brain stimulation (DBS), long-term outcomes remain to be established. To report the long-term outcomes of GPi DBS in a patient ...cohort with idiopathic and acquired dystonia.
In this long-term follow-up cohort, there were 4 patients with idiopathic dystonia and 2 patients with acquired dystonia. The Burke-Fahn-Marsden Dystonia Rating Scale was used to evaluate 6 consecutive patients preoperatively and at 6 months, 12 months, and the last follow-up. The relationship between etiology and clinical improvement was analyzed. Stimulation parameters were evaluated for similarities and differences among these patients.
The mean follow-up of our cohort was 65.3 months (median 40.5 months). The average improvement in the Burke-Fahn-Marsden Dystonia Rating Scale (mean ± SEM) were 56% ± 7.6, 67% ± 6.8 and 66% ± 9.7 at 6 months, 12 months, and the last follow-up, respectively. There was greater improvement during the long-term follow-up in the 4 patients with idiopathic dystonia than in the 2 patients with acquired dystonia. The 2 most ventral electrodes (contact 0 and 1) were activated in all 11 leads in this cohort. The average stimulation intensity, pulse width and frequency were 2.0 ± 0.24 mA, 252 ± 43 μs, and 99 ± 6.0 Hz, respectively.
Isolated dystonia, either monogenic or idiopathic, usually responds better to GPi DBS than to acquired dystonia. Selection of patients by dystonia etiology, accurate placement of DBS leads in GPi targets, and proper stimulation programming are crucial to achieve better long-term outcomes.
Dystonia is a clinically and genetically heterogeneous movement disorder. However, genetic causes of dystonia remain largely unknown in Asian subjects. To address this, we applied an integrated ...two-step approach that included gene dosage analysis and a next-generation sequencing panel containing 72 known genes causative for dystonia and related movement disorders to 318 Taiwanese patients with isolated or combined dystonia. Whole-genome sequencing was performed for one multiplex family with no known causative variant. The panel confirmed the genetic diagnosis in 40 probands (12.6%). A genetic diagnosis was more likely with juvenile onset compared with adult onset (24.2% vs 10.8%; P = 0.03) and those with combined features, especially with myoclonus, compared with isolated dystonia (35.3% vs 10.5%; P = 0.004). The most common causative genes were SGCE followed by GCH1, TH, CACNA1B, PRRT2, MR1, CIZ1, PLA2G6, and PRKN. Genetic causes were identified from single cases in TOR1A, TUBB4A, THAP1, ATP1A3, ANO3, GNAL, KMT2B, SLC6A3, ADCY5, CYP27A1, PANK2, C19orf12, and SPG11. The whole-genome sequencing analysis identified a novel intragenic deletion in OPHN1 in a multiplex family with X-linked dystonia and intellectual delay. Our findings delineate the genetic architecture and clinical spectrum of dystonia-causing pathogenic variants in an Asian population.
Aromatic l-amino acid decarboxylase (AADC) deficiency is an inherited disease that causes depletion of neurotransmitters and severe motor dysfunction in infants and children. We previously reported ...compassionate use of an adeno-associated virus (AAV) vector containing the human AADC gene (AAV2-hAADC) in four children with AADC deficiency (aged 4–6 years). In this study, we aimed to establish the efficacy and safety of this treatment.
We did an open-label, phase 1/2 trial at the National Taiwan University Hospital (Taipei, Taiwan). We included patients who had a definitive diagnosis and clinical symptoms of AADC deficiency (hypotonia, dystonia, and oculogyric crisis), who were older than 24 months or had skull bones suitable for stereotactic surgery, and who had an anti-AAV2 antibody titre lower than 1·0 optical density. All patients received bilateral intraputaminal injections of AAV2-hAADC (1·81 × 1011 vg in total) through stereotactic brain surgery. Primary efficacy outcomes were an increase in the Peabody Developmental Motor Scales (second edition; PDMS-2) score of greater than 10 points and an increase in homovanillic acid (HVA) or 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the cerebrospinal fluid 12 months after gene therapy. We assessed patients at baseline and at 3, 6, 9, and 12 months after gene therapy, and every 6 months thereafter for one further year; all patients who received the treatment were included in the analysis. We assessed for surgical complications (cerebrospinal fluid leakage and intracerebral haemorrhage) at days 3–7 after AAV2 gene therapy, and we assessed adverse events during the follow-up evaluations for 12 months. This study is registered with ClinicalTrials.gov, number NCT01395641.
Ten patients (median age 2·71 years, IQR 2·46–6·35) were enrolled from Oct 1, 2014, to Dec 2, 2015. All patients tolerated the surgeries and vector injections. One patient died from influenza B encephalitis during an endemic outbreak 10 months after treatment; therefore, 9 months of data were included in the analyses for this patient. All patients met the primary efficacy endpoint: 12 months after gene therapy, PDMS-2 scores were increased by a median of 62 points (IQR 39–93; p=0·005) and HVA concentrations by a median of 25 nmol/L (IQR 11–48; p=0·012); however, there was no significant change in 5-HIAA concentrations (median difference 0, IQR 0–5; p=0·20). In total, 101 adverse events were reported, with the most common being pyrexia (16 16% of 101 events) and orofacial dyskinesia (ten 10%). 12 serious adverse events occurred in six patients, including one death (treatment-unrelated encephalitis due to influenza B infection), one life-threatening pyrexia, and ten events that led to hospital admission. Transient post-gene therapy dyskinesia occurred in all patients but was resolved with risperidone. Of 31 treatment-related adverse events, only one (patient 1) was severe in intensity, and none led to hospital admission or death.
Our findings suggest that intraputaminal injection of AAV2-hAADC is well tolerated and might improve motor development in children with AADC deficiency.
AADC Research Fund at National Taiwan University Hospital and the National Research Programme for Biopharmaceuticals.
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