•Neurons in the subthalamic nucleus (STN) switch from spike to burst firing during dopamine deficiency in Parkinsonism.•STN burst firing is formed by intrinsic neuronal membrane properties and is ...regulated by afferent neurotransmitters.•STN burst firing is directly correlated with motor symptoms in Parkinsonism, including tremor, rigidity and bradykinesia.•Treatments targeting at membrane properties or associated receptors can reduce burst firing in STN and improve Parkinsonism.•STN burst firing is a pathophysiological target in the treatment of Parkinson’s disease, especially in the context of DBS.
Understanding the pathophysiological mechanism of Parkinson’s disease (PD) in the subthalamic nucleus (STN) has become a critical issue since deep brain stimulation (DBS) in this region has been proven as an effective treatment for this disease. The STN possesses a special ability to switch from the spike to the burst firing mode in response to dopamine deficiency in parkinsonism, and this STN burst is considered an electrophysiological signature of the cortico–basal ganglia circuit in the brains of PD patients. This review focuses on the role of STN burst firing in the pathophysiology of PD and during DBS. Here, we review existing literature on how STN bursts originate and the specific factors affecting their formation; how STN burst firing causes motor symptoms in PD and how interventions can rescue these symptoms. Finally, the similarities and differences between the two electrophysiological hallmarks of PD, STN burst firing and beta-oscillation, are discussed. STN burst firing should be considered as a pathophysiological target in PD during treatment with DBS.
Deep brain stimulation (DBS) conventionally target at basal ganglia or thalamic structures, modulating nodal points in the cortico-basal ganglia circuit, in order to effectively treat various ...movement disorders, including Parkinson's disease, tremor and dystonia (especially mobile type dystonia). However, there are still some other movement disorders, such as dystonia (especially fixed type dystonia), ataxia and freezing of gait, which are not responding well to the current DBS therapy. Cerebellum, similar to basal ganglia, also plays a critical role in the pathophysiology of movement disorders. Deep cerebellar structures, such as dentate nucleus or superior cerebellar peduncle, are noticed for their potential role as treatment targets in movement disorders in recent years. With increasing evidences of animal DBS experiments, recent clinical human subject studies reported that some movement disorders patients not responding to DBS with conventional targets, may benefit significantly from cerebellar DBS. These pioneer study results are invaluable for understanding the clinical use of cerebellar DBS for treatment of movement disorders. We review the recent data of cerebellar DBS performed by different groups and summarize the indications, surgical targets, programming details and outcomes in these clinical reports. We then synthesize the current pathophysiological study of cerebellum on different movement disorders and discuss the potential mechanism of action of cerebellar DBS. In addition to basal ganglia, it is important to study new DBS targets in the cerebellum for more comprehensive treatment of movement disorders.
•Cerebellum plays a critical role in movement disorders, such as dystonia, tremor and ataxia.•Deep brain stimulation (DBS) targeting at cerebellum can be an effective tool to treat these movement disorders.•Key targets for cerebellar DBS include dentate nucleus (DN) and superior cerebellar peduncle (SCP).•Further exploration into the pathophysiology and the mechanisms of action are necessary for future development.
Background and purpose
Levodopa‐induced dyskinesia (LID) is a common motor complication in patients with Parkinson's disease (PD). Although amantadine is indicated for LID treatment, it is uncertain ...whether early treatment with amantadine reduces the risk of LID in patients with PD. We aimed to evaluate the association between amantadine treatment and LID onset in patients with early‐stage PD.
Methods
This was a hospital‐based retrospective cohort study that used electronic medical records from January 1, 2009 to October 31, 2016. The effect of amantadine on LID onset was compared with those of anticholinergics and monoamine oxidase type B inhibitors in patients with PD. Propensity‐score weighting and landmark analysis were used to reduce potential confounding. The time to LID onset was analyzed using Cox models. Sensitivity analyses were performed to determine the robustness of the results.
Results
The analyses included 807, 661, and 518 patients at 6‐, 12‐, and 18‐month landmark points, respectively. Amantadine use was associated with delayed LID onset in the 6‐ and 12‐month landmark analyses, with adjusted hazard ratios of 0.65 (95% confidence interval CI = 0.49–0.86) and 0.64 (95% CI = 0.47–0.88), respectively. Sensitivity analysis findings were comparable to those of the main analysis.
Conclusions
Early treatment with amantadine may delay LID onset more than treatment with other symptomatic agents. Further studies are needed to elucidate the mechanism of amantadine in LID onset delay and to validate our findings.
This hospital‐based retrospective cohort study revealed that early treatment with amantadine is associated with delay onset of levodopa‐induced dyskinesia in patients with early Parkinson's disease. In addition, a potential heterogeneous treatment effect was found by predominant motor features. Longer use of amantadine appears to have greater beneficial effect in patients with akinetic‐rigid motor subtype, but not in patients with tremor predominant motor subtype.
Abstract
Normal hemostatic function is important for reduction of the risk of intracranial hemorrhage during stereotactic neurosurgery including deep brain stimulation (DBS) surgery. This study ...investigates the hemostatic function in patients with Parkinson’s disease (PD) undergoing preoperative evaluation for DBS, with emphasis on the number and function of platelets. In 107 PD patients, only one had abnormal activated partial prothrombin time and normal prothrombin time. Among the other 106 patients, six (5.7%) had only thrombocytopenia, seven (6.6%) only prolonged bleeding time (BT), and 14 (13.2%) only prolonged closure time (CT) of platelet function analyzer 100 (PFA-100). Totally, 34 of the 106 patients (32.1%) had at least one of three kinds of platelet abnormalities. No factor was found to be associated with the occurrence of platelet abnormalities except that abnormal platelet group and prolonged BT subgroup had more patients using selegiline and lower UPDRS-III motor subscore with medication off than normal platelet group (
p
< 0.05). The use of selegiline was significantly correlated with prolonged BT (
p
= 0.0041) and platelet abnormality (
p
= 0.0197). Therefore, it is important to have detailed evaluation of the hemostatic function for PD patients undergoing preoperative evaluation for DBS, especially the platelet number and function.
The minimal detectable change (MDC) is the smallest amount of difference in individual scores that represents true change (beyond random measurement error). The MDCs of the Timed "Up & Go" Test (TUG) ...and the Dynamic Gait Index (DGI) in people with Parkinson disease (PD) are largely unknown, limiting the interpretability of the change scores of both measures.
The purpose of this study was to estimate the MDCs of the TUG and the DGI in people with PD.
This investigation was a prospective cohort study.
Seventy-two participants were recruited from special clinics for movement disorders at a university hospital. Their mean age was 67.5 years, and 61% were men. All participants completed the TUG and the DGI assessments twice, about 14 days apart. The MDC was calculated from the standard error of measurement. The percentage MDC (MDC%) was calculated as the MDC divided by the mean of all scores for the sample. Furthermore, the intraclass correlation coefficient was used to examine the reproducibility between testing sessions (test-retest reliability).
The respective MDC and MDC% of the TUG were 3.5 seconds and 29.8, and those of the DGI were 2.9 points and 13.3. The test-retest reliability values for the TUG and the DGI were high; the intraclass correlation coefficients were .80 and .84, respectively.
The study sample was a convenience sample, and the participants had mild to moderately severe PD.
The results showed that the TUG and the DGI have generally acceptable random measurement error and test-retest reliability. These findings should help clinicians and researchers determine whether a change in an individual patient with PD is a true change.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Dystonia is a heterogeneous movement disorder, and it remains unclear whether neurodegeneration is involved. Neurofilament light chain (NfL) is a biosignature of neurodegeneration. We aimed to ...investigate whether plasma NfL levels were elevated and associated with disease severity in patients with dystonia.
We enrolled 231 unrelated dystonia patients (isolated dystonia n = 203; combined dystonia n = 28) and 54 healthy controls from movement disorder clinics. Clinical severity was evaluated using the Fahn Marsden Dystonia Rating Scale, the Unified Dystonia Rating Scale, and the Global Dystonia Rating Scale. Blood NfL levels were measured by single-molecule array.
Plasma NfL levels were significantly higher in those with generalized dystonia compared to those with focal dystonia (20.1 ± 8.8 vs. 11.7 ± 7.2 pg/mL; p = 0.01) or controls (p < 0.01), while the level was comparable between the focal dystonia group and controls (p = 0.08). Furthermore, the dystonia combined with parkinsonism group had higher NfL levels than the isolated dystonia group (17.4 ± 6.2 vs. 13.5 ± 7.5 pg/mL; p = 0.04). Notably, whole-exome sequencing was performed in 79 patients and two patients were identified as having likely pathogenic variants: one had a heterozygous c.122G>A (p.R41H) variant in THAP1 (DYT6) and the other carried a c.1825G>A (p.D609N) substitution in ATP1A3 (DYT12). No significant correlation was found between plasma NfL levels and dystonia rating scores.
Plasma NfL levels are elevated in patients with generalized dystonia and dystonia combined with parkinsonism, suggesting that neurodegeneration is involved in the disease process of this subgroup of patients.
Background and purpose
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited disorder that manifests as a mixture of cerebellar ataxia, parkinsonism, and polyneuropathy; in type IV ...SCA3, pure parkinsonism is the only symptom. Currently, no disease‐modifying treatment is available, but variable responses to antiparkinsonism agents have been reported. However, the benefits of deep brain stimulation (DBS) for treating parkinsonism in this subtype of SCA3 remain unclear.
Methods
A 39‐year‐old male patient with a rare disorder of type IV SCA3 presented with pure parkinsonism including unilateral resting tremor, rigidity, and bradykinesia at the age of 30 years. Young‐onset Parkinson disease was diagnosed at the age of 32 years. His family history revealed a mild ataxia in his father since the age of 55 years. Genetic testing confirmed an expanded CAG repeated number, with 66 in this case and 63 in his father for SCA3 mutation. Excellent response to levodopa and dopamine agonists in the first 3 years was noted, but wearing‐off phenomena, levodopa‐induced dyskinesia, and severe impulse control disorders later developed. To alleviate drug‐induced complications, he received bilateral subthalamic nucleus deep brain stimulation (STN‐DBS) in the absence of cerebellar signs, depression, and cognitive impairment.
Results
As of 2019, no impulsive control disorders, motor fluctuations, or DBS‐related complications were observed during a 4‐year follow‐up, with 66% Unified Parkinson's Disease Rating Scale Part III reduction at medication OFF state noted, whereas levodopa equivalent daily dosage decreased by almost half.
Conclusions
STN‐DBS may be considered as adjunct treatment for severe dopa‐related motor/nonmotor complications in patients with parkinsonian phenotype of SCA 3.
This study describes the use of bilateral subthalamic nucleus deep brain stimulation (STN‐DBS) in a 39‐year‐old male type IV spinocerebellar ataxia type 3 patient, with significant and lasting improvement in parkinsonism noted at 63 months after follow‐up, and with no deep brain stimulation (DBS)‐related complications noted. Further investigation of STN‐DBS in parkinsonism caused by non‐Parkinson disease–related genes is warranted.
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