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Molecular Therapy : the Journal of the... Jul 2024Neuroglobin, a member of the globin superfamily, is abundant in the brain, retina, and cerebellum of mammals and localizes to mitochondria. The protein exhibits...
Neuroglobin, a member of the globin superfamily, is abundant in the brain, retina, and cerebellum of mammals and localizes to mitochondria. The protein exhibits neuroprotective capacities by participating in electron transfer, oxygen supply, and protecting against oxidative stress. Our objective was to determine whether neuroglobin overexpression can be used to treat neurological disorders. We chose Harlequin mice, which harbor a retroviral insertion in the first intron of the apoptosis-inducing factor gene resulting in the depletion of the corresponding protein essential for mitochondrial biogenesis. Consequently, Harlequin mice display degeneration of the cerebellum and suffer from progressive blindness and ataxia. Cerebellar ataxia begins in Harlequin mice at the age of 4 months and is characterized by neuronal cell disappearance, bioenergetics failure, and motor and cognitive impairments, which aggravated with aging. Mice aged 2 months received adeno-associated viral vectors harboring the coding sequence of neuroglobin or apoptosis-inducing factor in both cerebellar hemispheres. Six months later, Harlequin mice exhibited substantial improvements in motor and cognitive skills; probably linked to the preservation of respiratory chain function, Purkinje cell numbers and connectivity. Thus, without sharing functional properties with apoptosis-inducing factor, neuroglobin was efficient in reducing ataxia in Harlequin mice.
Topics: Animals; Neuroglobin; Mitochondria; Mice; Nerve Tissue Proteins; Globins; Cerebellum; Cerebellar Ataxia; Neurons; Genetic Vectors; Homeostasis; Apoptosis Inducing Factor; Dependovirus; Disease Models, Animal; Genetic Therapy; Gene Expression
PubMed: 38796706
DOI: 10.1016/j.ymthe.2024.05.030 -
Cortex; a Journal Devoted To the Study... Jul 2024Huntington's Disease (HD) is an inherited neurodegenerative disease caused by the mutation of the Htt gene, impacting all aspects of living and functioning. Among...
OBJECTIVE
Huntington's Disease (HD) is an inherited neurodegenerative disease caused by the mutation of the Htt gene, impacting all aspects of living and functioning. Among cognitive disabilities, spatial capacities are impaired, but their monitoring remains scarce as limited by lengthy experts' assessments. Language offers an alternative medium to evaluate patients' performance in HD. Yet, its capacities to assess HD's spatial abilities are unknown. Here, we aimed to bring proof-of-concept that HD's spatial deficits can be assessed through speech.
METHODS
We developed the Spatial Description Model to graphically represent spatial relations described during the Cookie Theft Picture (CTP) task. We increased the sensitivity of our model by using only sentences with spatial terms, unlike previous studies in Alzheimer's disease. 78 carriers of the mutant Htt, including 56 manifest and 22 premanifest individuals, as well as 25 healthy controls were included from the BIOHD & (NCT01412125) & Repair-HD (NCT03119246) cohorts. The convergence and divergence of the model were validated using the SelfCog battery.
RESULTS
Our Spatial Description Model was the only one among the four assessed approaches, revealing that individuals with manifest HD expressed fewer spatial relations and engaged in less spatial exploration compared to healthy controls. Their graphs correlated with both visuospatial and language SelfCog performances, but not with motor, executive nor memory functions.
CONCLUSIONS
We provide the proof-of-concept using our Spatial Description Model that language can grasp HD patient's spatial disturbances. By adding spatial capabilities to the panel of functions tested by the language, it paves the way for eventual remote clinical application.
Topics: Humans; Huntington Disease; Male; Female; Middle Aged; Adult; Speech; Neuropsychological Tests; Space Perception; Aged
PubMed: 38795650
DOI: 10.1016/j.cortex.2024.04.014 -
Medicina (Kaunas, Lithuania) Apr 2024This study delves into the multifaceted approaches to treating Parkinson's disease (PD), a neurodegenerative disorder primarily affecting motor function but also... (Review)
Review
This study delves into the multifaceted approaches to treating Parkinson's disease (PD), a neurodegenerative disorder primarily affecting motor function but also manifesting in a variety of symptoms that vary greatly among individuals. The complexity of PD symptoms necessitates a comprehensive treatment strategy that integrates surgical interventions, pharmacotherapy, and physical therapy to tailor to the unique needs of each patient. Surgical options, such as deep brain stimulation (DBS), have been pivotal for patients not responding adequately to medication, offering significant symptom relief. Pharmacotherapy remains a cornerstone of PD management, utilizing drugs like levodopa, dopamine agonists, and others to manage symptoms and, in some cases, slow down disease progression. However, these treatments often lead to complications over time, such as motor fluctuations and dyskinesias, highlighting the need for precise dosage adjustments and sometimes combination therapies to optimize patient outcomes. Physical therapy plays a critical role in addressing the motor symptoms of PD, including bradykinesia, muscle rigidity, tremors, postural instability, and akinesia. PT techniques are tailored to improve mobility, balance, strength, and overall quality of life. Strategies such as gait and balance training, strengthening exercises, stretching, and functional training are employed to mitigate symptoms and enhance functional independence. Specialized approaches like proprioceptive neuromuscular facilitation (PNF), the Bobath concept, and the use of assistive devices are also integral to the rehabilitation process, aimed at improving patients' ability to perform daily activities and reducing the risk of falls. Innovations in technology have introduced robotic-assisted gait training (RAGT) and other assistive devices, offering new possibilities for patient care. These tools provide targeted support and feedback, allowing for more intensive and personalized rehabilitation sessions. Despite these advancements, high costs and accessibility issues remain challenges that need addressing. The inclusion of exercise and activity beyond structured PT sessions is encouraged, with evidence suggesting that regular physical activity can have neuroprotective effects, potentially slowing disease progression. Activities such as treadmill walking, cycling, and aquatic exercises not only improve physical symptoms but also contribute to emotional well-being and social interactions. In conclusion, treating PD requires a holistic approach that combines medical, surgical, and therapeutic strategies. While there is no cure, the goal is to maximize patients' functional abilities and quality of life through personalized treatment plans. This integrated approach, along with ongoing research and development of new therapies, offers hope for improving the management of PD and the lives of those affected by this challenging disease.
Topics: Humans; Parkinson Disease; Physical Therapy Modalities; Independent Living; Gait; Deep Brain Stimulation; Quality of Life; Exercise Therapy
PubMed: 38792894
DOI: 10.3390/medicina60050711 -
International Journal of Molecular... May 2024Parkinson's disease (PD) is a progressive disorder characterized by the apoptosis of dopaminergic neurons in the basal ganglia. This study explored the potential effects...
Parkinson's disease (PD) is a progressive disorder characterized by the apoptosis of dopaminergic neurons in the basal ganglia. This study explored the potential effects of aminophylline, a non-selective adenosine A and A receptor antagonist, on catalepsy and gait in a haloperidol-induced PD model. Sixty adult male Swiss mice were surgically implanted with guide cannulas that targeted the basal ganglia. After seven days, the mice received intraperitoneal injections of either haloperidol (experimental group, PD-induced model) or saline solution (control group, non-PD-induced model), followed by intracerebral infusions of aminophylline. The assessments included catalepsy testing on the bar and gait analysis using the Open Field Maze. A two-way repeated-measures analysis of variance (ANOVA), followed by Tukey's post hoc tests, was employed to evaluate the impact of groups (experimental × control), aminophylline (60 nM × 120 nM × saline/placebo), and interactions. Significance was set at 5%. The results revealed that the systemic administration of haloperidol in the experimental group increased catalepsy and dysfunction of gait that paralleled the observations in PD. Co-treatment with aminophylline at 60 nM and 120 nM reversed catalepsy in the experimental group but did not restore the normal gait pattern of the animals. In the non-PD induced group, which did not present any signs of catalepsy or motor dysfunctions, the intracerebral dose of aminophylline did not exert any interference on reaction time for catalepsy but increased walking distance in the Open Field Maze. Considering the results, this study highlights important adenosine interactions in the basal ganglia of animals with and without signs comparable to those of PD. These findings offer valuable insights into the neurobiology of PD and emphasize the importance of exploring novel therapeutic strategies to improve patient's catalepsy and gait.
Topics: Animals; Catalepsy; Mice; Male; Aminophylline; Disease Models, Animal; Gait; Haloperidol; Parkinson Disease
PubMed: 38791229
DOI: 10.3390/ijms25105191 -
International Journal of Molecular... May 2024Movement disorders such as bradykinesia, tremor, dystonia, chorea, and myoclonus most often arise in several neurodegenerative diseases with basal ganglia and white...
Movement disorders such as bradykinesia, tremor, dystonia, chorea, and myoclonus most often arise in several neurodegenerative diseases with basal ganglia and white matter involvement. While the pathophysiology of these disorders remains incompletely understood, dysfunction of the basal ganglia and related brain regions is often implicated. The gene, part of the family, has emerged as a crucial player in neurological pathology, implicated in diverse phenotypes ranging from movement disorders to Leigh syndrome. We present a clinical case of -associated disease with two variants in the gene in an adult female. This case contributes to our evolving understanding of -related diseases and underscores the importance of genetic screening in diagnosing and managing such conditions.
Topics: Humans; Female; Spinocerebellar Ataxias; Vesicular Transport Proteins; Adult; Phenotype; Mutation; Genes, Recessive; Pedigree; Proteins
PubMed: 38791166
DOI: 10.3390/ijms25105127 -
Brain Sciences May 2024Levodopa (L-DOPA) treatment represents the gold standard therapy for Parkinson's disease (PD) patients. L-DOPA therapy shows many side effects, among them,... (Review)
Review
Levodopa (L-DOPA) treatment represents the gold standard therapy for Parkinson's disease (PD) patients. L-DOPA therapy shows many side effects, among them, L-DOPA-induced dyskinesias (LIDs) remain the most problematic. Several are the mechanisms underlying these processes: abnormal corticostriatal neurotransmission, pre- and post-synaptic neuronal events, changes in gene expression, and altered plasticity. In recent years, researchers have also suggested non-neuronal mechanisms as a possible cause for LIDs. We reviewed recent clinical and pre-clinical studies on neuroinflammation contribution to LIDs. Microglia and astrocytes seem to play a strategic role in LIDs phenomenon. In particular, their inflammatory response affects neuron-glia communication, synaptic activity and neuroplasticity, contributing to LIDs development. Finally, we describe possible new therapeutic interventions for dyskinesia prevention targeting glia cells.
PubMed: 38790492
DOI: 10.3390/brainsci14050514 -
Bioengineering (Basel, Switzerland) Apr 2024Dyskinesias and freezing of gait are episodic disorders in Parkinson's disease, characterized by a fluctuating and unpredictable nature. This cross-sectional study aims...
BACKGROUND
Dyskinesias and freezing of gait are episodic disorders in Parkinson's disease, characterized by a fluctuating and unpredictable nature. This cross-sectional study aims to objectively monitor Parkinsonian patients experiencing dyskinesias and/or freezing of gait during activities of daily living and assess possible changes in spatiotemporal gait parameters.
METHODS
Seventy-one patients with Parkinson's disease (40 with dyskinesias and 33 with freezing of gait) were continuously monitored at home for a minimum of 5 days using a single wearable sensor. Dedicated machine-learning algorithms were used to categorize patients based on the occurrence of dyskinesias and freezing of gait. Additionally, specific spatiotemporal gait parameters were compared among patients with and without dyskinesias and/or freezing of gait.
RESULTS
The wearable sensor algorithms accurately classified patients with and without dyskinesias as well as those with and without freezing of gait based on the recorded dyskinesias and freezing of gait episodes. Standard spatiotemporal gait parameters did not differ significantly between patients with and without dyskinesias or freezing of gait. Both the time spent with dyskinesias and the number of freezing of gait episodes positively correlated with the disease severity and medication dosage.
CONCLUSIONS
A single inertial wearable sensor shows promise in monitoring complex, episodic movement patterns, such as dyskinesias and freezing of gait, during daily activities. This approach may help implement targeted therapeutic and preventive strategies for Parkinson's disease.
PubMed: 38790307
DOI: 10.3390/bioengineering11050440 -
BMC Neurology May 2024The thalamus has a central role in the pathophysiology of idiopathic cervical dystonia (iCD); however, the nature of alterations occurring within this structure remain...
BACKGROUND
The thalamus has a central role in the pathophysiology of idiopathic cervical dystonia (iCD); however, the nature of alterations occurring within this structure remain largely elusive. Using a structural magnetic resonance imaging (MRI) approach, we examined whether abnormalities differ across thalamic subregions/nuclei in patients with iCD.
METHODS
Structural MRI data were collected from 37 patients with iCD and 37 healthy controls (HCs). Automatic parcellation of 25 thalamic nuclei in each hemisphere was performed based on the FreeSurfer program. Differences in thalamic nuclei volumes between groups and their relationships with clinical information were analysed in patients with iCD.
RESULTS
Compared to HCs, a significant reduction in thalamic nuclei volume primarily in central medial, centromedian, lateral geniculate, medial geniculate, medial ventral, paracentral, parafascicular, paratenial, and ventromedial nuclei was found in patients with iCD (P < 0.05, false discovery rate corrected). However, no statistically significant correlations were observed between altered thalamic nuclei volumes and clinical characteristics in iCD group.
CONCLUSION
This study highlights the neurobiological mechanisms of iCD related to thalamic volume changes.
Topics: Humans; Male; Female; Middle Aged; Torticollis; Magnetic Resonance Imaging; Thalamus; Adult; Aged; Thalamic Nuclei
PubMed: 38789945
DOI: 10.1186/s12883-024-03680-6 -
Journal of the Neurological Sciences Jun 2024Safinamide is an effective adjunctive therapy for wearing-off in Parkinson's disease (PD); however, evidence is lacking in older patients and those in the early stages... (Observational Study)
Observational Study
BACKGROUND
Safinamide is an effective adjunctive therapy for wearing-off in Parkinson's disease (PD); however, evidence is lacking in older patients and those in the early stages of wearing-off. This study evaluated the efficacy and safety of safinamide as adjunctive therapy in patients with PD treated with levodopa monotherapy in clinical practice.
METHODS
This multicentre, open-label observational study was conducted at five sites in Japan. Patients diagnosed with PD and wearing-off initiated safinamide as adjunctive therapy with levodopa monotherapy. Efficacy endpoints were mean changes in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I, III, and IV scores; daily ON-time without dyskinesia using 24-h patient symptom diaries; and 39-item Parkinson's Disease Questionnaire (PDQ-39) scores at 18 weeks of treatment.
RESULTS
In total, 24 patients initiated safinamide (66.7% were aged ≥75 years); the mean duration of wearing-off was 1.2 years. MDS-UPDRS Part III total score, Part IV total score, and PDQ-39 summary index decreased significantly from baseline (mean change -7.0 [p = 0.012], -2.4 [p = 0.007] and - 5.3 [p = 0.012], respectively). There was a non-statistically significant increase of 1.55 h in mean daily ON-time without dyskinesia. Numerical Rating Scale total score for pain (p = 0.015), and scores for OFF-period pain (p = 0.012) and nocturnal pain (p = 0.021) subdomains were significantly improved in the subgroup with pain. Most reported adverse events were classified as mild.
CONCLUSION
Safinamide improved motor and non-motor symptoms and quality of life-related measures in older patients with PD in the early stages of wearing-off without new safety concerns.
STUDY REGISTRATION
University Hospital Medical Information Network in Japan; study ID: UMIN000044341.
Topics: Humans; Parkinson Disease; Male; Benzylamines; Female; Aged; Levodopa; Alanine; Japan; Antiparkinson Agents; Middle Aged; Treatment Outcome; Drug Therapy, Combination; Aged, 80 and over; Severity of Illness Index; East Asian People
PubMed: 38788287
DOI: 10.1016/j.jns.2024.123051 -
Cells May 2024Huntington's disease (HD) arises from expanded CAG repeats in exon 1 of the () gene. The resultant misfolded HTT protein accumulates within neuronal cells, negatively...
Huntington's disease (HD) arises from expanded CAG repeats in exon 1 of the () gene. The resultant misfolded HTT protein accumulates within neuronal cells, negatively impacting their function and survival. Ultimately, HTT accumulation results in cell death, causing the development of HD. A nonhuman primate (NHP) HD model would provide important insight into disease development and the generation of novel therapies due to their genetic and physiological similarity to humans. For this purpose, we tested CRISPR/Cas9 and a single-stranded DNA (ssDNA) containing expanded CAG repeats in introducing an expanded CAG repeat into the gene in rhesus macaque embryos. Analyses were conducted on arrested embryos and trophectoderm (TE) cells biopsied from blastocysts to assess the insertion of the ssDNA into the gene. Genotyping results demonstrated that 15% of the embryos carried an expanded CAG repeat. The integration of an expanded CAG repeat region was successfully identified in five blastocysts, which were cryopreserved for NHP HD animal production. Some off-target events were observed in biopsies from the cryopreserved blastocysts. NHP embryos were successfully produced, which will help to establish an NHP HD model and, ultimately, may serve as a vital tool for better understanding HD's pathology and developing novel treatments.
Topics: Animals; Macaca mulatta; Huntingtin Protein; Huntington Disease; Blastocyst; Trinucleotide Repeat Expansion; Embryo, Mammalian; CRISPR-Cas Systems; Female; Disease Models, Animal
PubMed: 38786052
DOI: 10.3390/cells13100829