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Background: The goal of this study was to relate diffusion MR measures of white matter integrity of the retinofugal visual pathway with prolactin levels in a patient with downward herniation of the optic chiasm secondary to medical treatment of a prolactinoma. Methods: A 36-year-old woman with a prolactinoma presented with progressive bilateral visual field defects 9 years after initial diagnosis and medical treatment. She was diagnosed with empty-sella syndrome and instructed to stop cabergoline. Hormone testing was conducted in tandem with routine clinical evaluations over 1 year and the patient was followed with diffusion magnetic resonance imaging (dMRI), optical coherence tomography (OCT), and automated perimetry at three time points. Five healthy controls underwent a complementary battery of clinical and neuroimaging tests at a single time point. Results: Shortly after discontinuing cabergoline, diffusion metrics in the optic tracts were within the range of values observed in healthy controls. However, following a brief period where the patient resumed cabergoline (of her own volition), there was a decrease in serum prolactin with a corresponding decrease in visual ability and increase in radial diffusivity (p < 0.001). Those measures again returned to their baseline ranges after discontinuing cabergoline a second time. Conclusions: These results demonstrate the sensitivity of dMRI to detect rapid and functionally significant microstructural changes in white matter tracts secondary to alterations in serum prolactin levels. The inverse relations between prolactin and measures of white matter integrity and visual function are consistent with the hypothesis that prolactin can play a neuroprotective role in the injured nervous system.

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Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder primarily characterized by selective degeneration of both the upper motor neurons in the brain and lower motor neurons in the brain stem and the spinal cord. The exact mechanism for the selective death of neurons is unknown. A growing body of evidence demonstrates abnormalities in energy metabolism at the cellular and whole-body level in animal models and in people living with ALS. Many patients with ALS exhibit metabolic changes such as hypermetabolism and body weight loss. Despite these whole-body metabolic changes being observed in patients with ALS, the origin of metabolic dysregulation remains to be fully elucidated. A number of pre-clinical studies indicate that underlying bioenergetic impairments at the cellular level may contribute to metabolic dysfunctions in ALS. In particular, defects in CNS glucose transport and metabolism appear to lead to reduced mitochondrial energy generation and increased oxidative stress, which seem to contribute to disease progression in ALS. Here, we review the current knowledge and understanding regarding dysfunctions in CNS glucose metabolism in ALS focusing on metabolic impairments in glucose transport, glycolysis, pentose phosphate pathway, TCA cycle and oxidative phosphorylation. We also summarize disturbances found in glycogen metabolism and neuroglial metabolic interactions. Finally, we discuss options for future investigations into how metabolic impairments can be modified to slow disease progression in ALS. These investigations are imperative for understanding the underlying causes of metabolic dysfunction and subsequent neurodegeneration, and to also reveal new therapeutic strategies in ALS.

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Although alterations in energy metabolism are known in ALS, the specific mechanisms leading to energy deficit are not understood. We measured metabolite levels derived from injected [1-13C]glucose and [1,2-13C]acetate (i.p.) in cerebral cortex and spinal cord extracts of wild type and hSOD1G93A mice at onset and mid disease stages using high-pressure liquid chromatography, 1H and 13C nuclear magnetic resonance spectroscopy. Levels of spinal and cortical CNS total lactate, [3-13C]lactate, total alanine and [3-13C]alanine, but not cortical glucose and [1-13C]glucose, were reduced mostly at mid stage indicating impaired glycolysis. The [1-13C]glucose-derived [4-13C]glutamate, [4-13C]glutamine and [2-13C]GABA amounts were diminished at mid stage in cortex and both time points in spinal cord, suggesting decreased [3-13C]pyruvate entry into the TCA cycle. Lack of changes in [1,2-13C]acetate-derived [4,5-13C]glutamate, [4,5-13C]glutamine and [1,2-13C]GABA levels indicate unchanged astrocytic 13C-acetate metabolism. Reduced levels of leucine, isoleucine and valine in CNS suggest compensatory breakdown to refill TCA cycle intermediate levels. Unlabelled, [2-13C] and [4-13C]GABA concentrations were decreased in spinal cord indicating that impaired glucose metabolism contributes to hyperexcitability and supporting the use of treatments which increase GABA amounts. In conclusion, CNS glucose metabolism is compromised, while astrocytic TCA cycling appears to be normal in the hSOD1G93A mouse model at symptomatic disease stages.

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The Neuron Doctrine, the cornerstone of research on normal and abnormal brain functions for over a century, has failed to discern the basis of complex cognitive functions. The location and mechanisms of memory storage and recall, consciousness, and learning, remain enigmatic. The purpose of this article is to critically review the Neuron Doctrine in light of empirical data over the past three decades. Similarly, the central role of the synapse and associated neural networks, as well as ancillary hypotheses, such as gamma synchrony and cortical minicolumns, are critically examined. It is concluded that each is fundamentally flawed and that, over the past three decades, the study of non-neuronal cells, particularly astrocytes, has shown that virtually all functions ascribed to neurons are largely the result of direct or indirect actions of glia continuously interacting with neurons and neural networks. Recognition of non-neural cells in higher brain functions is extremely important. The strict adherence of purely neurocentric ideas, deeply ingrained in the great majority of neuroscientists, remains a detriment to understanding normal and abnormal brain functions. By broadening brain information processing beyond neurons, progress in understanding higher level brain functions, as well as neurodegenerative and neurodevelopmental disorders, will progress beyond the impasse that has been evident for decades.

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