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Imaging Neurochemistry and Brain Structure Tracks Clinical Decline and Mechanisms of ALS in Patients.

ABSTRACT: Background: Oxidative stress and protein aggregation are key mechanisms in amyotrophic lateral sclerosis (ALS) disease. Reduced glutathione (GSH) is the most important intracellular antioxidant that protects neurons from reactive oxygen species. We hypothesized that levels of GSH measured by MR spectroscopic imaging (MRSI) in the motor cortex and corticospinal tract are linked to clinical trajectory of ALS patients. Objectives: Investigate the value of GSH imaging to probe clinical decline of ALS patients in combination with other neurochemical and structural parameters. Methods: Twenty-four ALS patients were imaged at 3 T with an advanced MR protocol. Mapping GSH levels in the brain is challenging, and for this purpose, we used an optimized spectral-edited 3D MRSI sequence with real-time motion and field correction to image glutathione and other brain metabolites. In addition, our imaging protocol included (i) an adiabatic T1ρ sequence to image macromolecular fraction of brain parenchyma, (ii) diffusion tensor imaging (DTI) for white matter tractography, and (iii) high-resolution anatomical imaging. Results: We found GSH in motor cortex (r = -0.431, p = 0.04) and corticospinal tract (r = -0.497, p = 0.016) inversely correlated with time between diagnosis and imaging. N-Acetyl-aspartate (NAA) in motor cortex inversely correlated (r = -0.416, p = 0.049), while mean water diffusivity (r = 0.437, p = 0.033) and T1ρ (r = 0.482, p = 0.019) positively correlated with disease progression measured by imputed change in revised ALS Functional Rating Scale. There is more decrease in the motor cortex than in the white matter for GSH compared to NAA, glutamate, and glutamine. Conclusions: Our study suggests that a panel of biochemical and structural imaging biomarkers defines a brain endophenotype, which can be used to time biological events and clinical progression in ALS patients. Such a quantitative brain endophenotype may stratify ALS patients into more homogeneous groups for therapeutic interventions compared to clinical criteria.

SUBMITTER: Andronesi OC

PROVIDER: S-EPMC7744722 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The aim of the study was to verify whether neuromuscular magnetic stimulation (NMMS) improves muscle function in spinal-onset amyotrophic lateral sclerosis (ALS) patients. Twenty-two ALS patients were randomized in two groups to receive, daily for two weeks, NMMS in right or left arm (referred to as real-NMMS, rNMMS), and sham NMMS (sNMMS) in the opposite arm. All the patients underwent a median nerve conduction (compound muscle action potential, CMAP) study and a clinical examination that included a handgrip strength test and an evaluation of upper limb muscle strength by means of the Medical Research Council Muscle Scale (MRC). Muscle biopsy was then performed bilaterally on the flexor carpi radialis muscle to monitor morpho-functional parameters and molecular changes. Patients and physicians who performed examinations were blinded to the side of real intervention. The primary outcome was the change in the muscle strength in upper arms. The secondary outcomes were the change from baseline in the CMAP amplitudes, in the nicotinic ACh currents, in the expression levels of a selected panel of genes involved in muscle growth and atrophy, and in histomorphometric parameters of ALS muscle fibers. The Repeated Measures (RM) ANOVA with a Greenhouse-Geisser correction (sphericity not assumed) showed a significant effect [F(3, 63)?=?5.907, p?<?0.01] of rNMMS on MRC scale at the flexor carpi radialis muscle, thus demonstrating that the rNMMS significantly improves muscle strength in flexor muscles in the forearm. Secondary outcomes showed that the improvement observed in rNMMS-treated muscles was associated to counteracting muscle atrophy, down-modulating the proteolysis, and increasing the efficacy of nicotinic ACh receptors (AChRs). We did not observe any significant difference in pre- and post-stimulation CMAP amplitudes, evoked by median nerve stimulation. This suggests that the improvement in muscle strength observed in the stimulated arm is unlikely related to reinnervation. The real and sham treatments were well tolerated without evident side effects. Although promising, this is a proof of concept study, without an immediate clinical translation, that requires further clinical validation.

Project description:Binge drinking is common in human adolescents. The adolescent brain is undergoing structural maturation and has a unique sensitivity to alcohol neurotoxicity. Therefore, adolescent binge ethanol may have long-term effects on the adult brain that alter brain structure and behaviors that are relevant to alcohol-use disorders.To determine whether adolescent ethanol (AE) binge drinking alters the adult brain, male C57BL/6 mice were treated with either water or ethanol during adolescence (5 g/kg/d, i.g., postnatal days P28 to P37) and assessed during adulthood (P60 to P88). An array of neurotransmitter-specific genes, behavioral tests (i.e., reversal learning, prepulse inhibition, and open field), and postmortem brain structure using magnetic resonance imaging (MRI) and immunohistochemistry, were employed to assess persistent alterations in adult brain.At P38, 24 hours after AE binge, many neurotransmitter genes, particularly cholinergic and dopaminergic, were reduced by ethanol treatment. Interestingly, dopamine receptor type 4 mRNA was reduced and confirmed using immunohistochemistry. Normal control maturation (P38 to P88) resulted in decreased neurotransmitter mRNA, e.g., an average decrease of 56%. Following AE treatment, adults showed greater gene expression reductions than controls, averaging 73%. Adult spatial learning assessed in the Morris water maze was not changed by AE treatment, but reversal learning experiments revealed deficits. Assessment of adult brain region volumes using MRI indicated that the olfactory bulb and basal forebrain were smaller in adults following AE. Immunohistochemical analyses found reduced basal forebrain area and fewer basal forebrain cholinergic neurons.Adolescent binge ethanol treatment reduces adult neurotransmitter gene expression, particularly cholinergic genes, reduces basal forebrain and olfactory bulb volumes, and causes a reduction in the density of basal forebrain acetylcholine neurons. Loss of cholinergic neurons and forebrain structure could underlie adult reversal learning deficits following adolescent binge drinking.

Project description:The predictable rhythmic structure is important to most ecologically relevant sounds for humans, such as is found in the rhythm of speech or music. This study addressed the question of how rhythmic predictions are maintained in the auditory system when there are multiple perceptual interpretations occurring simultaneously and emanating from the same sound source. We recorded the electroencephalogram (EEG) while presenting participants with a tone sequence that had two different tone feature patterns, one based on the sequential rhythmic variation in tone duration and the other on sequential rhythmic variation in tone intensity. Participants were presented with the same sound sequences and were instructed to listen for the intensity pattern (ignore fluctuations in duration) and press a response key to detected pattern deviants (attend intensity pattern task); to listen to the duration pattern (ignore fluctuations in intensity) and make a button press to duration pattern deviants (attend duration pattern task), and to watch a movie and ignore the sounds presented to their ears (attend visual task). Both intensity and duration patterns occurred predictably 85% of the time, thus the key question involved evaluating how the brain treated the irrelevant feature patterns (standards and deviants) while performing an auditory or visual task. We expected that task-based feature patterns would have a more robust brain response to attended standards and deviants than the unattended feature patterns. Instead, we found that the neural entrainment to the rhythm of the standard attended patterns had similar power to the standard of the unattended feature patterns. In addition, the infrequent pattern deviants elicited the event-related brain potential called the mismatch negativity component (MMN). The MMN elicited by task-based feature pattern deviants had a similar amplitude to MMNs elicited by unattended pattern deviants that were unattended because they were not the target pattern or because the participant ignored the sounds and watched a movie. Thus, these results demonstrate that the brain tracks multiple predictions about the complexities in sound streams and can automatically track and detect deviations with respect to these predictions. This capability would be useful for switching attention rapidly among multiple objects in a busy auditory scene.

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Imaging Neurochemistry and Brain Structure Tracks Clinical Decline and Mechanisms of ALS in Patients.

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