105 research outputs found
Oxidative stress-induced apoptosis in neurons correlates with mitochondrial DNA base excision repair pathway imbalance
Neurodegeneration can occur as a result of endogenous oxidative stress. Primary cerebellar granule cells were used in this study to determine if mitochondrial DNA (mtDNA) repair deficiencies correlate with oxidative stress-induced apoptosis in neuronal cells. Granule cells exhibited a significantly higher intracellular oxidative state compared with primary astrocytes as well as increases in reductants, such as glutathione, and redox sensitive signaling molecules, such as AP endonuclease/redox effector factor-1. Cerebellar granule cultures also exhibited an increased susceptibility to exogenous oxidative stress. Menadione (50 μM) produced twice as many lesions in granule cell mtDNA compared with astrocytes, and granule cell mtDNA repair was significantly less efficient. A decreased capacity to repair oxidative mtDNA damage correlates strongly with mitochondrial initiated apoptosis in these neuronal cultures. Interestingly, the mitochondrial activities of initiators for base excision repair (BER), the bifunctional glycosylase/AP lyases as well as AP endonuclease, were significantly higher in cerebellar granule cells compared with astrocytes. The increased mitochondrial AP endonuclease activity in combination with decreased polymerase γ activity may cause an imbalance in oxidative BER leading to an increased production and persistence of mtDNA damage in neurons when treated with menadione. This study provides evidence linking neuronal mtDNA repair capacity with oxidative stress-related neurodegeneration
Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study
OBJECTIVE: To determine the efficacy and safety of deutetrabenazine as a treatment for tardive dyskinesia (TD).
METHODS: One hundred seventeen patients with moderate to severe TD received deutetrabenazine or placebo in this randomized, double-blind, multicenter trial. Eligibility criteria included an Abnormal Involuntary Movement Scale (AIMS) score of ≥6 assessed by blinded central video rating, stable psychiatric illness, and stable psychoactive medication treatment. Primary endpoint was the change in AIMS score from baseline to week 12. Secondary endpoints included treatment success at week 12 on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change.
RESULTS: For the primary endpoint, deutetrabenazine significantly reduced AIMS scores from baseline to week 12 vs placebo (least-squares mean [standard error] -3.0 [0.45] vs -1.6 [0.46], p = 0.019). Treatment success on CGIC (48.2% vs 40.4%) favored deutetrabenazine but was not significant. Deutetrabenazine and placebo groups showed low rates of psychiatric adverse events: anxiety (3.4% vs 6.8%), depressed mood/depression (1.7% vs 1.7%), and suicidal ideation (0% vs 1.7%, respectively). In addition, no worsening in parkinsonism, as measured by the Unified Parkinson's Disease Rating Scale motor subscale, was noted from baseline to week 12 in either group.
CONCLUSIONS: In patients with TD, deutetrabenazine was well tolerated and significantly reduced abnormal movements.
CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with TD, deutetrabenazine reduces AIMS scores
Neural representations of the sense of self
The brain constructs representations of what is sensed and thought about in the
form of nerve impulses that propagate in circuits and network assemblies
(Circuit Impulse Patterns, CIPs). CIP representations of which humans are
consciously aware occur in the context of a sense of self. Thus, research on
mechanisms of consciousness might benefit from a focus on how a conscious sense
of self is represented in brain. Like all senses, the sense of self must be
contained in patterns of nerve impulses. Unlike the traditional senses that are
registered by impulse flow in relatively simple, pauci-synaptic projection
pathways, the sense of self is a system- level phenomenon that may be generated
by impulse patterns in widely distributed complex and interacting circuits. The
problem for researchers then is to identify the CIPs that are unique to
conscious experience. Also likely to be of great relevance to constructing the
representation of self are the coherence shifts in activity timing relations
among the circuits. Consider that an embodied sense of self is generated and
contained as unique combinatorial temporal patterns across multiple neurons in
each circuit that contributes to constructing the sense of self. As with other
kinds of CIPs, those representing the sense of self can be learned from
experience, stored in memory, modified by subsequent experiences, and expressed
in the form of decisions, choices, and commands. These CIPs are proposed here to
be the actual physical basis for conscious thought and the sense of self. When
active in wakefulness or dream states, the CIP representations of self act as an
agent of the brain, metaphorically as an avatar. Because the selfhood CIP
patterns may only have to represent the self and not directly represent the
inner and outer worlds of embodied brain, the self representation should have
more degrees of freedom than subconscious mind and may therefore have some
capacity for a free-will mind of its own. S everal lines of evidence for this
theory are reviewed. Suggested new research includes identifying distinct
combinatorially coded impulse patterns and their temporal coherence shifts in
defined circuitry, such as neocortical microcolumns. This task might be
facilitated by identifying the micro-topography of field-potential oscillatory
coherences among various regions and between different frequencies associated
with specific conscious mentation. Other approaches can include identifying the
changes in discrete conscious operations produced by focal trans-cranial
magnetic stimulation
A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease
Objective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD.
Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach.
Results: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study.
Conclusions: These data do not justify use of CoQ as a treatment to slow functional decline in HD
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