Parkinson’s disease (PD) is one of the most prevalent movement disorder caused by degeneration of the dopaminergic neurons in substantia nigra pars compacta. Deep brain stimulation (DBS) at the ...subthalamic nucleus (STN) has been a new and effective treatment of PD. It is interesting how a neurological disorder caused by the deficiency of a specific chemical substance (i.e., dopamine) from one site could be so successfully treated by a pure physical maneuver (i.e., DBS) at another site. STN neurons could discharge in the single-spike or the burst modes. A significant increase in STN burst discharges has been unequivocally observed in dopamine-deprived conditions such as PD, and was recently shown to have a direct causal relation with parkinsonian symptoms. The occurrence of burst discharges in STN requires enough available T-type Ca
2+
currents, which could bring the relatively negative membrane potential to the threshold of firing Na
+
spikes. DBS, by injection of negative currents into the extracellular space, most likely would depolarize the STN neuron and then inactivate the T-type Ca
2+
channel. Burst discharges are thus decreased and parkinsonian locomotor deficits ameliorated. Conversely, injection of positive currents into STN itself could induce parkinsonian locomotor deficits in animals without dopaminergic lesions. Local application of T-type Ca
2+
channel blockers into STN would also dramatically decrease the burst discharges and improve parkinsonian locomotor symptoms. Notably, zonisamide, which could inhibit T-type Ca
2+
currents in STN, has been shown to benefit PD patients in a clinical trial. From the pathophysiological perspectives, PD can be viewed as a prototypical disorder of “brain arrhythmias”. Modulation of relevant ion channels by physical or chemical maneuvers may be important therapeutic considerations for PD and other diseases related to deranged neural rhythms.
Purpose
There is currently no diagnostic test specific to Parkinson’s disease, which means that a positive diagnosis, assessments of severity, and evaluations of treatment efficacy rely heavily on ...evaluation scales. But obtaining scale data is time-consuming and limited in time and place. Gait is the core target in evaluation scales. Because of the inertia instrument has widely been used in healthcare institutes for gait assessment. Since the inertial device is as well embedded in every smartphone. Our objective was to explore the feasibility of using the ubiquitous smartphone to assist in the assessment of gait.
Methods
Twenty subjects were recruited in the clinical trial, which included a general gait analysis and detecting freezing of gait episodes. The gait analysis results obtained using the smartphone were compared with those obtained using an off-the-shelf inertia instrument, and the detecting freezing of gait episodes were compared with the evaluations of clinical professionals.
Results
The degree of consistency between the gait analysis results obtained using the smartphone and those obtained using the inertia instrument are
ICC
= 0.835,
r
= 0.858, and
ρ
= 0.846. In the detecting freezing of gait episodes, in comparing the detections by the clinical evaluators and the smartphone, the sensitivity is 90.6 ± 7.71% and specificity is 94.3 ± 8.36%.
Conclusion
The overall analyses revealed high degree of consistency between the two analysis schemes. The convenience of the ubiquitous smartphone has a great potential to enhance the frequency of gait assessment, thereby providing more data by which to assess treatment efficacy.
Neurodegeneration with brain iron accumulation (NBIA) is a genetically and phenotypically heterogeneous group of inherited neurodegenerative disorder characterized by basal ganglia iron deposition. ...Mutations in Pantothenate Kinase 2 (PANK2) are major genetic causes for patients with NBIA. The location of PANK2 in the mitochondria suggests mutant PANK2 causing mitochondrial dysfunction in the pathogenesis of NBIA. Here, we used the Sendai virus delivery system to generate induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells of a female patient having compound heterozygous mutations in PANK2. This cellular model could provide a platform for pathophysiological studies of NBIA in the future.
Parkinson's disease (PD) is the most prevalent hypokinetic movement disorder, and symptomatic PD pathogenesis has been ascribed to imbalances between the direct and indirect pathways in the basal ...ganglia circuitry. Here, we applied glutamate receptor blockers to the subthalamic nucleus (STN) of parkinsonian rats and evaluated locomotor behaviors via single-unit and local-field recordings. Using this model, we found that inhibition of NMDAergic cortico-subthalamic transmission ameliorates parkinsonian motor deficits without eliciting any vivid turning behavior and abolishes electrophysiological abnormalities, including excessive subthalamic bursts, cortico-subthalamic synchronization, and in situ beta synchronization in both the motor cortex and STN. Premotor cortex stimulation revealed that cortico-subthalamic transmission is deranged in PD and directly responsible for the excessive stimulation-dependent bursts and time-locked spikes in the STN, explaining the genesis of PD-associated pathological bursts and synchronization, respectively. Moreover, application of a dopaminergic agent via a microinfusion cannula localized the therapeutic effect to the STN, without correcting striatal dopamine deficiency. Finally, optogenetic overactivation and synchronization of cortico-subthalamic transmission alone sufficiently and instantaneously induced parkinsonian-associated locomotor dysfunction in normal mice. In addition to the classic theory emphasizing the direct-indirect pathways, our data suggest that deranged cortico-subthalamic transmission via the NMDA receptor also plays a central role in the pathophysiology of parkinsonian motor deficits.
Mutations in the gene encoding the mitochondrial protein high temperature requirement A2 (HTRA2) are inconsistently associated with a risk of Parkinson’s disease (PD). We assessed the presence of
...HTRA2
mutations among patients with PD and performed functional assay of identified mutations or variants. Among the total 1,373 subjects, the entire
HTRA2
coding region was sequenced in 113 early-onset PD (EOPD), 20 familial PD patients and 150 control subjects. An additional 390 sporadic late-onset PD patients and 700 controls were subsequently screened to validate possible mutations found in the first set. We identified two novel heterozygous variants, c.427C > G (Pro143Ala) and c.906 +3 G > A, in 2 (1.5%) EOPD patients. The missense variant, Pro143Ala, was also observed in one late-onset PD patient but was absent in total 850 control subjects (relative risk 2.3, 95% CI 1.5–2.8,
P
= 0.04). Expressing Pro143Ala variant of HTRA2 in primary dopaminergic neurons causes neurite degeneration. Following exposure to rotenone, the ultra-structural mitochondrial abnormality, the percentage of mitochondrial dysfunction and apoptosis in cells carrying the HTRA2 Pro143Ala variant was significantly higher than wild-type cells. Mechanistically, protein level of phosphorylated HTRA2 was increased in cells carrying the Pro143Ala variant, suggesting Pro143Ala variant promotes HTRA2 phosphorylation with resultant mitochondrial dysfunction. Our results support a biologically relevant role of
HTRA2
in PD susceptibility in Taiwanese. Further large-scale association studies are warranted to confirm the role of
HTRA2
Pro143Ala variant in the risk of PD.
The inosine monophosphate dehydrogenase gene (IMPDH2) was recently reported as a novel gene associated with autosomal dominantly inherited dystonia. We investigated 245 Taiwanese patients with ...molecularly unassigned isolated or combined dystonia without features of neurodevelopmental disorders and found none had pathogenic variants. Our findings suggest that IMPDH2 may not play a major role in dystonia.
•No pathogenic variants of IMPDH2 were identified in Taiwanese dystonia patients.•The IMPDH2 gene may not play a major role in dystonia in our population.•Future IMPDH2 screening in dystonia with neurodevelopmental disorders is needed.
Patients with Parkinson's disease and cognitive impairment (PD-CI) deteriorate faster than those without cognitive impairment (PD-NCI), suggesting an underlying difference in the neurodegeneration ...process. We aimed to verify brain age differences in PD-CI and PD-NCI and their clinical significance. A total of 94 participants (PD-CI, n = 27; PD-NCI, n = 34; controls, n = 33) were recruited. Predicted age difference (PAD) based on gray matter (GM) and white matter (WM) features were estimated to represent the degree of brain aging. Patients with PD-CI showed greater GM-PAD (7.08 ± 6.64 years) and WM-PAD (8.82 ± 7.69 years) than those with PD-NCI (GM: 1.97 ± 7.13, P
= 0.011; WM: 4.87 ± 7.88, P
= 0.049) and controls (GM: -0.58 ± 7.04, P
= 0.004; WM: 0.88 ± 7.45, P
= 0.002) after adjusting demographic factors. In patients with PD, GM-PAD was negatively correlated with MMSE (P
= 0.011) and MoCA (P
= 0.013) and positively correlated with UPDRS Part II (P
= 0.036). WM-PAD was negatively correlated with logical memory of immediate and delayed recalls (P
= 0.003 and P
< 0.001). Also, altered brain regions in PD-CI were identified and significantly correlated with brain age measures, implicating the neuroanatomical underpinning of neurodegeneration in PD-CI. Moreover, the brain age metrics can improve the classification between PD-CI and PD-NCI. The findings suggest that patients with PD-CI had advanced brain aging that was associated with poor cognitive functions. The identified neuroimaging features and brain age measures can serve as potential biomarkers of PD-CI.
Erythropoietin has been used to treat brain injuries and increase preoperative hemoglobin levels. A seven-year-old boy presented with aromatic l-amino acid decarboxylase deficiency, an enzyme ...responsible for producing dopamine and serotonin. He received gene therapy through an injection of adeno-associated viral vectors to the bilateral putamen, but not to the brain stem where serotoninergic neurons reside. An erythropoiesis-stimulating agent was given before surgery to increase his preoperative hemoglobin level. Unexpectedly, in preoperative planning, prominent cerebral vasculatures were visualized on magnetic resonance imaging. One month later, symptoms of serotonin overproduction, including vomiting, diarrhea, and high fever presented, which lead to dehydration and shock. We speculated that the viral vector spread from the putamen through the proliferating vasculature to the brain stem, causing the complication.
An increase in neuronal burst activities in the subthalamic nucleus (STN) is a well-documented electrophysiological feature of Parkinson disease (PD). However, the causal relationship between ...subthalamic bursts and PD symptoms and the ionic mechanisms underlying the bursts remain to be established. Here, we have shown that T-type Ca(2+) channels are necessary for subthalamic burst firing and that pharmacological blockade of T-type Ca(2+) channels reduces motor deficits in a rat model of PD. Ni(2+), mibefradil, NNC 55-0396, and efonidipine, which inhibited T-type Ca(2+) currents in acutely dissociated STN neurons, but not Cd(2+) and nifedipine, which preferentially inhibited L-type or the other non–T-type Ca(2+) currents, effectively diminished burst activity in STN slices. Topical administration of inhibitors of T-type Ca(2+) channels decreased in vivo STN burst activity and dramatically reduced the locomotor deficits in a rat model of PD. Cd(2+) and nifedipine showed no such electrophysiological and behavioral effects. While low-frequency deep brain stimulation (DBS) has been considered ineffective in PD, we found that lengthening the duration of the low-frequency depolarizing pulse effectively improved behavioral measures of locomotion in the rat model of PD, presumably by decreasing the availability of T-type Ca(2+) channels. We therefore conclude that modulation of subthalamic T-type Ca(2+) currents and consequent burst discharges may provide new strategies for the treatment of PD.
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