INTRODUCTION

Cognitive function declines with aging, and cognitive impairment in elderly is a major problem that can affect activities of daily living (ADL) and quality of life. Cognitive decline is correlated with brain atrophy associated with synaptic loss. For instance, alteration of synaptic efficacy in the hippocampus is an initial event in cognitive disorders such as Alzheimer's disease (AD). Functional synapses are the elemental unit of synaptic computation in the neural network, and the density of functional synapses determines the capacity for information transmission. The structural and functional loss of synapses are associated with impaired cognition. Even under physiological conditions, a considerable number of synapses are nonfunctional (i.e. silent/dormant), and the ratio of functional/nonfunctional synapses fluctuates over time.

Neural activity in brain is the means for brain computation. Orderly neural activity is essential for normal brain functions. Excessive or sustained neuronal activity in brain disrupts brain computation, resulting in the reduction of cognitive ability and behavior abnormality.

SUMMARY

Methods for improving synaptic transmission among neurons and/or improving cognitive function by using agents that raise neuronal intracellular concentration of magnesium are disclosed. Also provided herein are methods of determining the amenability of an individual to treatment for neurological disorder, e.g., cognitive impairment, by measuring changes in intracellular magnesium concentration.

Embodiments of the present disclosure include a method of modifying a functional property of neurons, the method including contacting one or more neurons containing a presynaptic terminal, with a composition containing an effective amount of an intracellular magnesium concentration ([Mg2+]i)-elevating agent, to modify one or more functional properties of the neurons, wherein the functional property includes one or more of: a functional presynaptic terminal density; a mitochondrial function per unit dendritic area; a terminal abundance of one or more presynaptic Ca2+sensitivity-related proteins; and a probability of synaptic release in response to background activity, e.g., low frequency single action potential input. In certain embodiments, the contacting is effective to: increase the functional presynaptic terminal density; increase the mitochondrial function per unit dendritic area; increase the abundance of one or more presynaptic Ca2+sensitivity-related proteins; and/or reduce the probability of synaptic release in response to low frequency single action potential input.

In certain embodiments, the agent includes a magnesium-containing compound or an inhibitor of intracellular magnesium efflux or a magnesium influx promoter. In certain embodiments, the effective amount of the [Mg2+]i-elevating agent raises an intracellular concentration of magnesium in the one or more neurons by 1.1 fold or more. In certain embodiments, the effective amount of the [Mg2+]i-elevating agent provides for an average extracellular concentration of magnesium from 0.6 mM to 1.4 mM. In certain embodiments, the effective amount of the [Mg2+]i-elevating agent provides for an average extracellular concentration of magnesium from 0.6 mM to 1.2 mM.

In certain embodiments, the contacting includes administering an effective amount of the [Mg2+]i-elevating agent, or a precursor thereof, to an individual. In certain embodiments, the agent, or a precursor thereof, is administered orally.

In certain embodiments, the method is for treating a neurological disorder, or a symptom thereof, in the individual. In certain embodiments, the neurological disorder is associated with insufficient synaptic density, or is associated with sustained and/or elevated spontaneous activity of neurons in the individual. In certain embodiments, the neurological disorder is selected from Alzheimer's disease, mild cognitive impairment (MCI), Parkinson's disease, dementia, Huntington's disease, autism, schizophrenia, cognitive decline as secondary effect of disease or medical treatment such as chemotherapy-related cognitive impairment or cognitive dysfunction (chemo brain), depression, sleep disorder, anxiety, attention deficit hyperactivity disorder (ADHD), migraine, headache, stroke, neuropathy, epilepsy, cerebral palsy, chronic pain, involuntary muscular contractions and convulsive twitches, spasm, wrinkling, dystonia and tremor, anxiety and depression associated with sustained neural activity in prefrontal cortex (PFC) and amygdala, and insomnia.

Also provided herein is a method that includes: administering a [Mg2+]i-elevating agent to an individual having or suspected of having a neurological disorder; determining a first level of magnesium in blood cells of a first blood sample obtained from the individual before the administering; and evaluating a change in cognitive competency of the individual from before to after the administering. In certain embodiments, the method further includes measuring the level of magnesium in the blood cells, before the administering, to determine the first level of magnesium. In certain embodiments, the method further includes determining a second level of magnesium in blood cells of a second blood sample obtained from the individual after the administering. In certain embodiments, the method further includes measuring the level of magnesium in the blood cells, after the administering, to determine the second level of magnesium. In certain embodiments, the method further includes continuing administration of the [Mg2+]i-elevating agent to the individual when the second level of magnesium is greater than the first level of magnesium.

In certain embodiments, the cognitive competency includes executive function, working memory, attention and/or short-term episodic memory. In certain embodiments, the method further includes administering a cognitive test for evaluating the cognitive competency of the individual before and/or after administering the [Mg2+]i-elevating agent. In certain embodiments, the method further includes continuing administration of the [Mg2+]i-elevating agent to the individual when the cognitive competency is not improved or is substantially the same as from before compared to after administering the [Mg2+]i-elevating agent, and when the second level of magnesium is greater than the first level of magnesium.

In certain embodiments, the neurological disorder includes cognitive impairment and/or a magnesium deficiency-caused neurological disorder. In certain embodiments, the cognitive impairment includes age-related cognitive decline, mild cognitive impairment, Alzheimer's disease, or cognitive fluctuation.

In any embodiment, the blood cells may include red blood cells.

In any embodiment, the [Mg2+]i-elevating agent may include a magnesium-containing compound, e.g., magnesium threonate.

Also provided herein is a method of reducing a cognitive impairment in an individual, the method including: administering an effective amount of magnesium threonate to a human individual having or suspected of having a cognitive impairment, wherein the effective amount reduces a functional age of a brain of the human individual. In certain embodiments, the effective amount includes an amount from 20 mg/kg/day to 50 mg/kg/day. In certain embodiments, the amount is from 20 mg/kg/day to 30 mg/kg/day. In certain embodiments, the magnesium threonate is administered for 6 days or more. In certain embodiments, the cognitive impairment includes cognitive fluctuation, age-related cognitive decline, mild cognitive impairment and/or a magnesium deficiency-caused neurological disorder.

In any embodiment, the magnesium threonate may be administered orally.

In any embodiment, the human individual may have an age of from 45 years to 80 years.

Also provided herein is a method of identifying an active agent that modifies a functional property of a neuron, the method including: contacting a first population of neurons in vitro with a first medium containing a candidate agent, wherein the neurons comprise a magnesium indicator dye; and measuring a level of intracellular magnesium ([Mg2+]i) in one or more subcellular regions of the neurons after the contacting, wherein the candidate agent is determined to be an active agent that modifies a [Mg2+]i-dependent functional property of a neuron when the measured level is higher than a reference level of intracellular magnesium, and wherein the [Mg2+]i-dependent functional property includes one or more of: a functional presynaptic terminal density; a mitochondrial function per unit dendritic area; an abundance of one or more presynaptic Ca2+sensitivity-related proteins; and an average probability of synaptic release in response to background activity, e.g., low frequency single action potential input. In certain embodiments, the one or more subcellular regions includes neuronal branches, and wherein measuring the level of intracellular magnesium includes: measuring for each neuronal branch: an average fluorescence level from the magnesium indicator dye; and a diameter of the branch; and calculating the level of intracellular magnesium based on the diameter and the average fluorescence level in each branch.

