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Brain and Behavior May 2024Sequential working memory is the ability to maintain and manipulate sequential information at a second time scale. Patients with progressive supranuclear palsy (PSP) or...
PURPOSE
Sequential working memory is the ability to maintain and manipulate sequential information at a second time scale. Patients with progressive supranuclear palsy (PSP) or Parkinson's disease (PD) perform poorly in tests that require the flexible arrangement of thoughts or actions. This study investigated whether sequential working memory is differently impaired in patients with PSP versus PD.
METHOD
Twenty-nine patients with PSP Richardson's syndrome (PSP-RS), 36 patients with PD, and 36 healthy controls (HC) completed 3 well-established neuropsychological tests, including digit span forward (DST-F), digit span backward (DST-B), and adaptive digit ordering tests (DOT-A). The DST-F required maintaining digit sequences, and the DST-B and DOT-A required maintaining and manipulating digit sequences.
FINDING
The PSP-RS group scored lower than the PD and HC groups in the DST-B and DOT-A but not in the DST-F, indicating that the ability to manipulate sequences was impaired, but the maintenance ability was preserved in PSP-RS patients. Moreover, in PSP-RS, the DST-B score negatively correlated with the severity of motor symptoms. The actual levodopa dose positively correlated with the DST-B ordering cost (DST-F score vs. DST-B score). The PSP patients who took a greater dose of levodopa tended to have higher DST-B ordering cost. There was no effect of levodopa on DST-B or DOT-A in PD.
CONCLUSION
These results suggested that the ability to manipulate sequence was already reduced in patients with PSP-RS and was worse than in patients with PD.
Topics: Humans; Supranuclear Palsy, Progressive; Male; Female; Aged; Parkinson Disease; Middle Aged; Memory, Short-Term; Neuropsychological Tests; Levodopa
PubMed: 38702898
DOI: 10.1002/brb3.3527 -
Clinical Neurology and Neurosurgery Jun 2024Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disease mostly associated with severe lactic acidosis, rapid progression of neurological...
Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disease mostly associated with severe lactic acidosis, rapid progression of neurological symptoms and death during childhood. We present a 33-year-old male with PDC deficiency caused by a Val262Leu mutation in PDHA1gene. He demonstrated generalized dystonia affecting trunk and upper extremities and paraparesis as the most significant features, with onset of symptoms at age 8. Brain MRI showed bilaterally increased signal within the globus pallidus, typical of Leigh syndrome. A periodic lactate increase in serum and cerebrospinal fluid was detected. We describe a case of pyruvate dehydrogenase deficiency being diagnosed only 25 years after the onset of symptoms and highlight PDHC deficiency as a possible cause of treatable dystonia in childhood, which may respond well to thiamine and levodopa treatment.
Topics: Humans; Male; Adult; Pyruvate Dehydrogenase Complex Deficiency Disease; Pyruvate Dehydrogenase (Lipoamide); Dystonia; Levodopa; Dystonic Disorders; Magnetic Resonance Imaging; Mutation
PubMed: 38701546
DOI: 10.1016/j.clineuro.2024.108307 -
Movement Disorders Clinical Practice Jun 2024Blood pressure control in Parkinson's disease (PD) under subthalamic deep brain stimulation (STN-DBS) is influenced by several intertwined aspects, including autonomic...
BACKGROUND
Blood pressure control in Parkinson's disease (PD) under subthalamic deep brain stimulation (STN-DBS) is influenced by several intertwined aspects, including autonomic failure and levodopa treatment.
OBJECTIVE
To evaluate the effect of chronic STN-DBS, levodopa, and their combination on cardiovascular autonomic functions in PD.
METHODS
We performed cardiovascular reflex tests (CRTs) before and 6-months after STN-DBS surgery in 20 PD patients (pre-DBS vs. post-DBS). CRTs were executed without and with medication (med-OFF vs. med-ON).
RESULTS
CRT results and occurrence of neurogenic orthostatic hypotension (OH) did not differ between pre- and post-DBS studies in med-OFF condition. After levodopa intake, the BP decrease during HUTT was significantly greater compared to med-OFF, both at pre-DBS and post-DBS evaluation. Levodopa-induced OH was documented in 25% and 5% of patients in pre-DBS/med-ON and post-DBS/med-ON study.
CONCLUSION
Chronic stimulation did not influence cardiovascular responses, while levodopa exerts a relevant hypotensive effect. The proportion of patients presenting levodopa-induced OH decreases after STN-DBS surgery.
Topics: Humans; Parkinson Disease; Deep Brain Stimulation; Male; Female; Middle Aged; Aged; Levodopa; Autonomic Nervous System; Antiparkinson Agents; Blood Pressure; Subthalamic Nucleus; Hypotension, Orthostatic
PubMed: 38698586
DOI: 10.1002/mdc3.14060 -
Global Health & Medicine Apr 2024This study aimed to explore the brain network characteristics in elderly patients with Parkinson's disease (PD) with depressive symptoms. Thirty elderly PD patients with...
Decreased resting-state functional connectivity and brain network abnormalities in the prefrontal cortex of elderly patients with Parkinson's disease accompanied by depressive symptoms.
This study aimed to explore the brain network characteristics in elderly patients with Parkinson's disease (PD) with depressive symptoms. Thirty elderly PD patients with depressive symptoms (PD-D) and 26 matched PD patients without depressive symptoms (PD-NOD) were recruited based on HAMD-24 with a cut-off of 7. The resting-state functional connectivity (RSFC) was conducted by 53-channel functional near-infrared spectroscopy (fNIRS). There were no statistically significant differences in MMSE scores, disease duration, Hoehn-Yahr stage, daily levodopa equivalent dose, and MDS-UPDRS III between the two groups. However, compared to the PD-NOD group, the PD-D group showed significantly higher MDS-UPDRS II, HAMA-14, and HAMD-24. The interhemispheric FC strength and the FC strength between the left dorsolateral prefrontal cortex (DLPFC-L) and the left frontal polar area (FPA-L) was significantly lower in the PD-D group (FDR < 0.05). As for graph theoretic metrics, the PD-D group had significantly lower degree centrality (aDc) and node efficiency (aNe) in the DLPFC-L and the FPA-L (FDR, < 0.05), as well as decreased global efficiency (aEg). Pearson correlation analysis indicated moderate negative correlations between HAMD-24 scores and the interhemispheric FC strength, FC between DLPFC-L and FPA-L, aEg, aDc in FPA-L, aNe in DLPFC-L and FPA-L. In conclusion, PD-D patients show decreased integration and efficiency in their brain networks. Furthermore, RSFC between DLPFC-L and FPA-L regions is negatively correlated with depressive symptoms. These findings propose that targeting DLPFC-L and FPA-L regions non-invasive brain stimulation may be a potential intervention for alleviating depressive symptoms in elderly PD patients.
PubMed: 38690130
DOI: 10.35772/ghm.2023.01043 -
BMC Public Health Apr 2024Adherence to antiparkinsonian drugs (APDs) is critical for patients with Parkinson's disease (PD), for which medication is the main therapeutic strategy. Previous... (Observational Study)
Observational Study
BACKGROUND
Adherence to antiparkinsonian drugs (APDs) is critical for patients with Parkinson's disease (PD), for which medication is the main therapeutic strategy. Previous studies have focused on specific disorders in a single system when assessing clinical factors affecting adherence to PD treatment, and no international comparative data are available on the medical costs for Chinese patients with PD. The present study aimed to evaluate medication adherence and its associated factors among Chinese patients with PD using a systematic approach and to explore the impact of adequate medication adherence on direct medical costs.
METHODS
A retrospective analysis was conducted using the electronic medical records of patients with PD from a medical center in China. Patients with a minimum of two APD prescriptions from January 1, 2016 to August 15, 2018 were included. Medication possession ratio (MPR) and proportion of days covered were used to measure APD adherence. Multiple linear regression analysis was used to identify factors affecting APD adherence. Gamma regression analysis was used to explore the impact of APD adherence on direct medical costs.
RESULTS
In total, 1,712 patients were included in the study, and the mean MPR was 0.68 (± 0.25). Increased number of APDs and all medications, and higher daily levodopa-equivalent doses resulted in higher MPR (mean difference [MD] = 0.04 [0.03-0.05]; MD = 0.02 [0.01-0.03]; MD = 0.03 [0.01-0.04], respectively); combined digestive system diseases, epilepsy, or older age resulted in lower MPR (MD = -0.06 [-0.09 to -0.03]; MD = -0.07 [-0.14 to -0.01]; MD = -0.02 [-0.03 to -0.01], respectively). Higher APD adherence resulted in higher direct medical costs, including APD and other outpatient costs. For a 0.3 increase in MPR, the two costs increased by $34.42 ($25.43-$43.41) and $14.63 ($4.86-$24.39) per year, respectively.
CONCLUSIONS
APD adherence rate among Chinese patients with PD was moderate and related primarily to age, comorbidities, and healthcare costs. The factors should be considered when prescribing APDs.
Topics: Humans; Parkinson Disease; Medication Adherence; Male; Female; Retrospective Studies; Middle Aged; Aged; Electronic Health Records; China; Antiparkinson Agents; Health Care Costs
PubMed: 38689223
DOI: 10.1186/s12889-024-18431-y -
MSphere May 2024Mitochondrial functions are critical for the ability of the fungal pathogen to cause disease. However, mechanistic connections between key functions such as the...
Mitochondrial functions are critical for the ability of the fungal pathogen to cause disease. However, mechanistic connections between key functions such as the mitochondrial electron transport chain (ETC) and virulence factor elaboration have yet to be thoroughly characterized. Here, we observed that inhibition of ETC complex III suppressed melanin formation, a major virulence factor. This inhibition was partially overcome by defects in Cir1 or HapX, two transcription factors that regulate iron acquisition and use. In this regard, loss of Cir1 derepresses the expression of laccase genes as a potential mechanism to restore melanin, while HapX may condition melanin formation by controlling oxidative stress. We hypothesize that ETC dysfunction alters redox homeostasis to influence melanin formation. Consistent with this idea, inhibition of growth by hydrogen peroxide was exacerbated in the presence of the melanin substrate L-DOPA. In addition, loss of the mitochondrial chaperone Mrj1, which influences the activity of ETC complex III and reduces ROS accumulation, also partially overcame antimycin A inhibition of melanin. The phenotypic impact of mitochondrial dysfunction was consistent with RNA-Seq analyses of WT cells treated with antimycin A or L-DOPA, or cells lacking Cir1 that revealed influences on transcripts encoding mitochondrial functions (e.g., ETC components and proteins for Fe-S cluster assembly). Overall, these findings reveal mitochondria-nuclear communication ROS and iron regulators to control virulence factor production in .IMPORTANCEThere is a growing appreciation of the importance of mitochondrial functions and iron homeostasis in the ability of fungal pathogens to sense the vertebrate host environment and cause disease. Many mitochondrial functions such as heme and iron-sulfur cluster biosynthesis, and the electron transport chain (ETC), are dependent on iron. Connections between factors that regulate iron homeostasis and mitochondrial activities are known in model yeasts and are emerging for fungal pathogens. In this study, we identified connections between iron regulatory transcription factors (e.g., Cir1 and HapX) and the activity of complex III of the ETC that influence the formation of melanin, a key virulence factor in the pathogenic fungus . This fungus causes meningoencephalitis in immunocompromised people and is a major threat to the HIV/AIDS population. Thus, understanding how mitochondrial functions influence virulence may support new therapeutic approaches to combat diseases caused by and other fungi.
Topics: Melanins; Cryptococcus neoformans; Iron; Electron Transport; Mitochondria; Iron-Regulatory Proteins; Fungal Proteins; Gene Expression Regulation, Fungal; Virulence Factors; Oxidative Stress; Transcription Factors; Electron Transport Chain Complex Proteins
PubMed: 38687055
DOI: 10.1128/msphere.00250-24 -
Molecular Brain Apr 2024Dopamine plays important roles in cognitive function and inflammation and therefore is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's...
Dopamine plays important roles in cognitive function and inflammation and therefore is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Drugs that increase or maintain dopamine levels in the brain could be a therapeutic strategy for AD. However, the effects of dopamine and its precursor levodopa (L-DOPA) on Aβ/tau pathology in vivo and the underlying molecular mechanisms have not been studied in detail. Here, we investigated whether L-DOPA treatment alters neuroinflammation, Aβ pathology, and tau phosphorylation in 5xFAD mice, a model of AD. We found that L-DOPA administration significantly reduced microgliosis and astrogliosis in 5xFAD mice. In addition, L-DOPA treatment significantly decreased Aβ plaque number by upregulating NEP and ADAM17 levels in 5xFAD mice. However, L-DOPA-treated 5xFAD mice did not exhibit changes in tau hyperphosphorylation or tau kinase levels. These data suggest that L-DOPA alleviates neuroinflammatory responses and Aβ pathology but not tau pathology in this mouse model of AD.
Topics: Animals; Levodopa; Alzheimer Disease; Disease Models, Animal; ADAM17 Protein; Amyloid beta-Peptides; tau Proteins; Neuroinflammatory Diseases; Phosphorylation; Mice, Transgenic; Plaque, Amyloid; Mice; Brain
PubMed: 38685105
DOI: 10.1186/s13041-024-01092-8 -
Case Reports in Ophthalmology 2024Oculogyric crisis (OGC) is a dystonic movement disorder of varying durations that manifests as bilateral paroxysmal upward eye deviation accompanied by involuntary...
INTRODUCTION
Oculogyric crisis (OGC) is a dystonic movement disorder of varying durations that manifests as bilateral paroxysmal upward eye deviation accompanied by involuntary blinking, tongue protrusion, and autonomic symptoms. Separately, septo-optic dysplasia (SOD) is a congenital disorder involving hypoplasia of the optic nerve as well as hypothalamic and pituitary abnormalities. In the presented case, we report a case of OGC in the setting of SOD with proposed pathogenesis.
CASE PRESENTATION
A 27-year-old female presented with a history of SOD (optic nerve hypoplasia and hypopituitarism) with acute, recurrent, painless, bilateral, intermittent, simultaneous tonic conjugate upward eye deviation (i.e., OGC) and dystonic body posturing. She experienced her first episode upon meeting her biological sister for the first time at a loud, crowded public restaurant with continued episodes of OGC increasing in frequency and duration over the subsequent months. She later responded well to treatment with carbidopa/levodopa.
CONCLUSION
Based on our current understanding of OGC, we hypothesize that acute stressful life events in the setting of prior hypothalamic-pituitary axis dysfunction secondary to SOD could lower the threshold for developing OGC. Although most cases of OGC are idiopathic, various etiologies including medications, stress, and hormonal imbalance have been postulated as possible pathogenic mechanisms. We describe a case of SOD with OGC, and based upon our review of the English language ophthalmic literature, we believe that our case is novel.
PubMed: 38682038
DOI: 10.1159/000534493 -
Neurobiology of Disease Jun 2024Resting tremor is the most common presenting motor symptom in Parkinson's disease (PD). The supplementary motor area (SMA) is a main target of the...
Resting tremor is the most common presenting motor symptom in Parkinson's disease (PD). The supplementary motor area (SMA) is a main target of the basal-ganglia-thalamo-cortical circuit and has direct, facilitatory connections with the primary motor cortex (M1), which is important for the execution of voluntary movement. Dopamine potentially modulates SMA and M1 activity, and both regions have been implicated in resting tremor. This study investigated SMA-M1 connectivity in individuals with PD ON and OFF dopamine medication, and whether SMA-M1 connectivity is implicated in resting tremor. Dual-site transcranial magnetic stimulation was used to measure SMA-M1 connectivity in PD participants ON and OFF levodopa. Resting tremor was measured using electromyography and accelerometry. Stimulating SMA inhibited M1 excitability OFF levodopa, and facilitated M1 excitability ON levodopa. ON medication, SMA-M1 facilitation was significantly associated with smaller tremor than SMA-M1 inhibition. The current findings contribute to our understanding of the neural networks involved in PD which are altered by levodopa medication and provide a neurophysiological basis for the development of interventions to treat resting tremor.
Topics: Humans; Levodopa; Parkinson Disease; Male; Motor Cortex; Female; Tremor; Aged; Middle Aged; Transcranial Magnetic Stimulation; Antiparkinson Agents; Electromyography; Neural Pathways; Evoked Potentials, Motor
PubMed: 38679112
DOI: 10.1016/j.nbd.2024.106518 -
Biomedicine & Pharmacotherapy =... Jun 2024Mitochondrial dysmorphology/dysfunction follow global cerebral ischemia-reperfusion (GCI/R) injury, leading to neuronal death. Our previous researches demonstrated that...
Mitochondrial dysmorphology/dysfunction follow global cerebral ischemia-reperfusion (GCI/R) injury, leading to neuronal death. Our previous researches demonstrated that Levodopa (L-DOPA) improves learning and memory impairment in GCI/R rats by increasing synaptic plasticity of hippocampal neurons. This study investigates if L-DOPA, used in Parkinson's disease treatment, alleviates GCI/R-induced cell death by enhancing mitochondrial quality. Metabolomics and transcriptomic results showed that GCI/R damage affected the Tricarboxylic acid (TCA) cycle in the hippocampus. The results of this study show that L-DOPA stabilized mitochondrial membrane potential and ultrastructure in hippocampus of GCI/R rats, increased dopamine level in hippocampus, decreased succinic acid level, and stabilized Ca level in CA1 subregion of hippocampus. As a precursor of dopamine, L-DOPA is presumed to improves mitochondrial function in hippocampus of GCI/R rats. However, dopamine cannot cross the blood-brain barrier, so L-DOPA is used in clinical therapy to supplement dopamine. In this investigation, OGD/R models were established in isolated mouse hippocampal neurons (HT22) and primary rat hippocampal neurons. Notably, dopamine exhibited a multifaceted impact, demonstrating inhibition of mitochondrial reactive oxygen species (mitoROS) production, stabilization of mitochondrial membrane potential and Ca level, facilitation of TCA circulation, promotion of aerobic respiratory metabolism, and downregulation of succinic acid-related gene expression. Consistency between in vitro and in vivo results underscores dopamine's significant neuroprotective role in mitigating mitochondrial dysfunction following global cerebral hypoxia and ischemia injury. Supplement dopamine may represent a promising therapy to the cognitive impairment caused by GCI/R injury.
Topics: Animals; Mitochondria; Levodopa; Hippocampus; Membrane Potential, Mitochondrial; Male; Mice; Reperfusion Injury; Rats; Rats, Sprague-Dawley; Neurons; Dopamine; Reactive Oxygen Species; Brain Ischemia; Cell Respiration; Citric Acid Cycle; Calcium; Neuroprotective Agents
PubMed: 38678966
DOI: 10.1016/j.biopha.2024.116664