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(Re)Searching for Neuroprotective Therapies in PD

Researchers continue to unravel the complexities of Parkinson’s Disease (PD), identifying new candidates and molecular pathways, which allow new drugs to be developed that may bring greater relief from PD symptoms, slow disease progression or even reverse it. Unfortunately, many agents that held promise in animal studies have not demonstrated an impact on disease progression in recent clinical trials (neurturin, coenzyme Q10, mitoquinone, creatine, pramipexole, pioglitazone).

Nevertheless, research into neuroprotective agents (which aim to reduce neurological damage) continues to be energized with several compounds being investigated in clinical trials. In PD, neurodegeneration involves multiple pathways and experts believe that targeting specific pathways may impact disease progression. According to experts, the therapies that hold the greatest promise include:

• Therapies that reduce oxidative stress
• Therapies that promote survival of dopaminergic neurons
• Therapies to block calcium channels
• Therapies that prevent neuroinflammation
• Immunization against α-synuclein
• Other pharmacological agents

These agents are being investigated in clinical trials taking place across the globe. Clinical trials are conducted in a series of steps called phases with each phase (1 through 4) answering a specific research question. According to the National Institute of Health:

• In phase I, researchers test a new drug in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify any side effects.
• In phase II, the drug is given to a larger group of people to see if it is effective and to further evaluate its safety.
• In phase III, the drug is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments and collect information that will allow the drug to be used safely.
• In phase IV, studies are done after the drug has been marketed to gather information on the drug’s effect in various populations and any side effects associated with long-term use.

Many of the drugs described below are being investigated in early phases, meaning that their safety and clinical efficacy have not been conclusively established. Therefore, the information contained in this article is for informational purposes only and should not be construed as medical advice. No recipient should act or refrain from acting on the basis of any content included in the article without seeking appropriate medical advice. The content of this article contains general information and may not reflect current developments or may not be relevant to any specific person. The University of Miami expressly disclaims all liability with respect to actions taken or not taken based on any or all of the contents of this article.
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Therapies to Reduce Oxidative Stress

What is oxidative stress?

Our bodies produce energy through metabolic processes that rely on the oxygen we inhale. Unfortunately, highly reactive molecules known as free radicals are generated as byproducts of the process that can damage other cells. Oxidative stress is the total burden placed on our bodies by the constant production of free radicals through metabolism plus any environmental factors we are exposed to such as pollution or alcohol. Oxidative stress is implicated in many diseases, including PD.

Inosine

Urate is a chemical that circulates at high concentrations in the blood defending our bodies from damage caused by harmful free radicals. A large study of 18,000 men demonstrated that higher serum urate levels are associated with a decreased risk of PD, with those in the top 25% of urate concentration having 55% lower odds of PD than men in the bottom 25%. Furthermore, early PD patients who initially have higher urate concentrations are associated with slower rates of decline. In a rat model of PD, urate treatment was shown to reduce the loss of dopaminergic neurons in the part of the brain primarily affected in PD, the substantia nigra, as well as improve motor performance, rendering urate an attractive candidate for PD researchers.

Inosine is a nutritional supplement that is converted into urate by the body. A phase 2 clinical trial (SURE-PD) of 75 early PD patients not yet requiring treatment demonstrated that long-term (i.e., 8-24 months) oral inosine treatment is clinically safe and tolerable. Higher dosing produced a moderate increase in blood and cerebrospinal urate concentrations to levels that are consistent with slower disease progression. Although insignificant, there were indications that higher inosine doses impacted clinical progression, and this effect was more evident in female vs. male patients.

The SURE-PD investigators are now recruiting early PD patients into a large phase 3 clinical trial to determine whether 24 months of oral inosine administration dosed to moderately elevate serum urate levels can slow motor decline, as well as cognitive decline and the time to disability warranting treatment.

The SURE-PD trial excluded patients with starting serum urate levels higher than the population median or with increased risk of gout or kidney stones. Although investigators did not observe an increase in risk in these serious adverse events over the treatment period of 8-24 months, it is important to note that increased serum urate may increase the risk of hypertension, coronary heart disease and stroke over the long-term. Although no patient developed gout, three patients receiving inosine developed kidney stones. Therefore, long-term usage of inosine would have to be weighed against these potential adverse events.

Deferiprone

PD patients have higher levels of iron in the substantia nigra of their brain and MRI studies have shown that higher nigral iron levels are associated with increased severity of motor symptoms. High iron concentrations may promote the formation of toxic molecules and aggregation of α-synuclein proteins (the protein implicated in PD pathogenesis), thus increasing the risk of neuronal cell death. Although it is still debated whether iron changes in PD are a cause or effect of neuronal cell death, iron’s role in oxidative stress is well supported. Therefore, its reduction may be potentially beneficial in modifying PD progression.

Deferiprone is an FDA-approved drug that reduces excess local iron buildup without causing systemic iron loss. The FAIR-PARK-I clinical trial led by the University Hospital in Lille demonstrated that orally administered deferiprone was well-tolerated by 40 early PD patients on stable dopaminergic treatment with only three cases of reversible neutropenia (low levels of white blood cells) recorded. Importantly, those assigned to deferiprone earlier showed greater improvement in motor function as compared to those who started the intervention later. The improvement was maintained throughout 12 months of intervention, although it decreased after 18 months of continuous treatment.

These results have prompted the development of the FAIR-PARK-II trial, a five-year clinical trial that will include 338 early PD patients not yet on antiparkinsonian treatment to assess the effect of nine months of deferiprone treatment on PD motor and non-motor symptoms and the ability of deferiprone to slow disease progression over time. Patients are currently being recruited across France, the U.K., Austria and the Czech Republic.

Similarly, Canadian ApoPharma is conducting a phase 2 clinical trial in 140 early PD patients on stable dopaminergic treatment to evaluate the effectiveness of nine months of various dosages of deferiprone on motor symptoms, as well as a range of secondary outcomes, including changes in inflammation, oxidative stress, cognitive function and antiparkinsonian medications. The investigators are currently recruiting patients across France, the U.K. and Canada.

Glutathione (GSH)

Glutathione is the brain’s central antioxidant protects neurons from the harmful effects of free radicals. Its depletion in the substantia nigra is one of the earliest biochemical changes seen in PD and the greater the glutathione loss, the greater the PD severity. Because glutathione cannot pass the blood-brain-barrier directly, intranasal delivery may provide a unique entry point to the brain that circumvents this obstacle.

Researchers from Bastyr University conducted a phase 1/2a clinical trial of 30 mild-to-moderate PD patients on stable medication that demonstrated that three months of intranasal glutathione delivery is safe and well-tolerated, causing only one adverse event (exacerbation of a preexisting ringing sensation). Since a positive effect of treatment on motor symptoms was observed, the researchers conducted a phase 2b clinical trial in 45 mild-to-moderate PD patients to determine whether three months of intranasally-delivered glutathione improves PD symptoms as compared to placebo. The results are not yet available, but if positive, a phase 3 trial with a delayed-start design testing neuroprotective effects will be employed.

Because GSH cannot be taken up by neurons directly, researchers from Cornell University, University of California at San Francisco and the University of Minnesota are each investigating whether N- acetylcysteine (NAC), that penetrates cells and converts to glutathione, can increase GSH levels in the brain. A pilot clinical trial of 12 patients on stable medication showed that two days of orally administered NAC was well-tolerated and raised levels of GSH in cerebrospinal fluid. Similarly, Cornell University is conducting a phase 1/2 clinical trial to investigate whether there are any associations between orally administered NAC, brain glutathione levels, oxidative stress markers and clinical presentation. If successful, these studies will pave the way for investigating the neuroprotective effects of NAC in larger clinical trials.

*Therapies that promote survival of dopaminergic neurons *

Neurotrophic factors are molecules that support the growth, survival, and differentiation of neurons from less specialized to a more specialized cell types. Glial cell-line derived neurotrophic factor (GDNF) is a type of neurotrophic factor that promotes the survival of dopaminergic neurons. It has been found that the levels of various neurotrophic factors, and particularly those of GDNF, are reduced in the substantia nigra of PD patients. Following success in several animal models of PD, clinical trials assessing different GDNF delivery approaches reported no clinical benefits. It is likely that the absence of clinical benefit is due to inefficient delivery methods that were unable to adequately distribute the trophic factors to the targeted brain region.

Gene transfer is a process where viruses insert genes into the patient’s cells long-term. These genes encode therapeutic proteins, such as neurotrophic factors, that the patient will begin to produce, theoretically slowing or even counteracting dopaminergic cell loss. Although a recent clinical trial of viral delivery of another neurotrophic factor (neurturin) reported no efficacy, the study established the safety of this method. Currently, the National Institute of Neurological Disorders and Stroke is recruiting 100 advanced PD patients who are not well-controlled by medications into an open label study to assess the safety and tolerability of an enhanced gene transfer delivery system that provides precise GDNF delivery to the targeted brain region, as well as to collect preliminary data of clinical responses over five-years.

However, some caution that trophic therapies may be effective only when applied to those in earlier PD stages when there still remains a substantial neuronal population, which can still be protected from further damage by the neurotrophic factors.

Therapies to Block Calcium Channels

Dopaminergic neurons in the substantia nigra use L-type calcium channels to maintain steady levels of dopamine in their target neurons. However, this causes toxic calcium entry into the cell, which predisposes them to cell death. In fact, patients with early-stage PD have increased expression of L-type calcium channels in the brain as compared to healthy individuals, suggesting that a disrupted calcium equilibrium is an early event contributing to PD. Cohort studies have shown that the use of calcium channel blockers is associated with reduced PD risk of approximately 30%, particularly in patients in 65 years and older.

Isradipine is a calcium channel blocker with high affinity for L-type calcium channels that is FDA-approved for treating high blood pressure. A phase 2 clinical trial (STEADY-PD) of 99 early-stage PD patients not currently on dopaminergic treatment established that 10mg dose was the maximum tolerable dosage, a dosage, which achieves blood concentrations found to be neuroprotective in animal models of PD. Although this study did not find statistically significant differences between treatment and placebo groups, this study was not designed to test efficacy; nonetheless, a general positive trend was noted at higher doses. The most common adverse event associated with isradipine usage was leg swelling and dizziness. Although three people experienced this side effect, isradipine had no significant impact on blood pressure.

Following these results, a 36-month long NIH-sponsored phase 3 clinical trial of 336 early stage PD patients not currently receiving dopaminergic treatment is currently underway assessing the disease-modifying effects of isradipine 10mg vs. placebo on motor symptoms, as well as secondary measures of disease progression, including time to initiation or dopaminergic treatment, time to onset of motor complications and change in cognitive function.

Therapies that prevent neuroinflammation

Statins like simvastatin, which are used to lower cholesterol, have been shown to reduce α-synuclein aggregation and prevent inflammation and neurodegeneration in the laboratory. Epidemiological data regarding statin use and PD risk is contradictory, with some studies reporting reduced risk, others increased risk, and still others showing no effect.

Although epidemiological studies provide contradictory findings, the University of Plymouth has initiated a phase 2 clinical trial (PD-STAT) to determine whether simvastatin has the potential to affect disease progression in moderate severity PD patients over a two-year time frame. Investigators will assess motor scores, as well as changes in medication, depression, cognition and quality of life. The study is currently recruiting patients across the U.K.

Immunization against α-synuclein

Why immunize?

Recent research suggests that α-synuclein aggregates “infect” other neuronal cells, spreading the neurodegenerative process from neuron to neuron. Immunotherapy aims to reduce the amount of α-synuclein aggregates, thereby preventing their spread across the nervous system.

Active Immunization

Austrian biotech AFFIRIS AG has developed two vaccine candidates (PD01A and PD03A), which contain molecules that can trigger the body to produce antibodies that will clear pathogenic α-synuclein from the brain. The phase 1 clinical trial of 24 early PD patients demonstrated that PD01A administration was safe and well-tolerated over the 12-month study period, and elicited an immune response against α-synuclein in 50% of vaccinated patients with antibodies observed in blood and cerebrospinal fluid. These patients underwent an additional 52 weeks of follow-up to assess long-term safety, tolerability and clinical responses. It was found that the levels of alpha-synuclein antibodies declined after one year.

In September 2016, AFFIRIS AG announced the results of their phase I clinical trial of a single booster immunization in 28 PD patients previously vaccinated with PD01A. The trial showed that the booster immunization increased the responder rate, inducing a sustained immune response in 86% of vaccinated patients, of which 63% generated α-synuclein-specific antibodies. In fact, all those who responded in the first trial responded again, and even some who did not respond in the first trial, produced antibodies with the boost vaccine.

Although the study was not designed to test efficacy, laboratory tests showed that PD01A-induced antibodies bind specifically to the α-synuclein fibrils. Preliminary observations indicate that some of the responder patients demonstrated stabilization in their motor symptoms and medication usage throughout the observation period (on average three years). The investigators are now assessing the effect of a second booster vaccination.

Additionally, AFFIRIS AG is investigating the safety and tolerability of two doses of the biotech’s second vaccine candidate PD03A in early PD in a randomized placebo-controlled patient-blinded study.

Passive Immunization

In passive immunization, patients are treated with antibody targeting α-synuclein that is created in the laboratory, rather than allowing the body to naturally generate antibodies. Irish biotech Prothena Corp and Swiss Roche Pharmaceuticals have partnered to develop a phase I clinical trial to assess the safety and tolerability of intravenous infusion of PRX002 antibody and its ability to produce an immune response against abnormal α-synuclein aggregates in 60 mild-to-moderate PD patients. According to their 2015 press release, intravenous administration of the antibody was safe, well-tolerated and associated with rapid and dose-dependent reduction of serum α-synuclein of up to 96% after a single dose in healthy volunteers.

It is important to note there is concern with both passive and active immunization therapies that the removal of α-synuclein may alter the normal functioning of other synucleins or trigger autoimmunity. These concerns follow the early termination of another immunization trial targeting amyloid plaques in Alzheimer’s Disease that resulted in an increased number of meningoencephalitis cases (inflammation of the meninges and brain). Additionally, it is yet to be determined whether the antibodies will cross the blood brain barrier and whether they will adequately target the toxic α-synuclein species (since it is known that normal forms of α-synuclein do have a physiological role in the brain).

Other Pharmacological Agents

Exenatide

Diabetes exists at a much higher prevalence in PD patients as compared to the non-PD population, and up to 80% of PD patients have abnormal blood sugar levels. Biological studies have uncovered molecular pathways that PD and type 2 diabetes share in common, suggesting that therapeutic agents for treating diabetes may have benefit in PD. In fact, animal studies have demonstrated that exenatide, an FDA-approved treatment for type 2 diabetes, may have neuroprotective and/or neurorestorative properties at doses comparable to those used to treat diabetes in humans. Its neuroprotective effect may be due to its anti-inflammatory properties, its ability to stimulate new nerve cells and/or to enhance neuronal function.

In an open-label study of 45 moderate stage PD patients on stable PD medication, researchers from the University College London demonstrated that 12 months of self-administered injections of exenatide was associated with clinically relevant improvement in motor and cognitive measures as compared to conventional PD treatment only controls (who deteriorated) that lasted up to 2 months following treatment completion. Although generally well-tolerated, patients receiving exenatide commonly experienced weight loss and nausea; furthermore, an increase in dyskinesia was noted, which required lowering levodopa dosage in some patients. Although imaging did not detect any significant changes in the number of dopaminergic neurons in the brains of exenatide-treated patients, the researchers did not include a comparison group, so it is difficult to draw conclusions.

Continued follow-up for an additional 12-months after stopping exenatide treatment showed that the increase in dyskinesias, although higher in treated patients, was no longer significantly different from controls at the 24-month mark. Importantly, many of the motor and cognitive benefits persisted at 24-months. Although there was no placebo arm in the trial, the benefit, which lasted a year after treatment cessation, is unlikely fully explained by the placebo effect, giving strength to the claim that exenatide may confer neuroprotective benefits.

Building upon these findings, the University College in London has conducted a phase 2 clinical trial (EXENATIDE-PD) examining the effect of 48-weeks of exenatide on improving motor and non-motor symptoms in 60 patients with moderate severity PD on dopaminergic treatment with wearing off symptoms. The results are expected in 2017 with initial observations suggesting good outcomes.

GM1 Ganglioside

GM1 ganglioside, a component of neuronal cell membranes, is reduced in PD patients’ brains. GM1 ganglioside may be involved in multiple pathways relevant to PD, including calcium equilibrium and α-synuclein aggregation. Animal studies have shown that GM1 treatment rescues damaged dopaminergic neurons and stimulates their repair, increases dopamine levels in the striatum and enhances dopamine synthesis in residual neurons, leading researchers to attempt to translate these findings into clinical trials.

An open-label study of 10 moderate-to-severe PD patients showed that intravenous infusion followed by 18-weeks of at-home injection of GM1 ganglioside was safe and well-tolerated, and resulted in a significant improvement in motor symptoms and function. Five patients who continued treatment for an additional six months maintained all functional benefits that were observed at 18 weeks. Subsequently, a clinical trial of 48 mild-to-moderate PD patients showed a significant improvement of motor symptoms, activities of daily living scores, as well as timed motor tests following 16-weeks of treatment as compared to placebo-treated patients. A five-year extension study involving 26 patients from the prior study showed that long-term use was safe, and generally improved motor scores over baseline and stabilized motor performance.

In a phase 2 clinical trial of 77 mild-to-moderate PD patients, researchers demonstrated that the group that received GM1 earlier improved their motor symptoms to a greater degree than did the late-start group, while the standard-of-care comparison group declined. However, motor scores declined in both treatment groups upon treatment cessation. Nonetheless, preliminary imaging results suggest that GM1 treatment slowed the loss of striatal dopamine terminals as compared to the standard-of-care comparison group, with a more pronounced effect in the early-start group. In some cases, an increase in dopamine terminals was observed in certain striatal regions of treated patients.

Long-term use of GM1 is not associated with any adverse events aside from injection-site specific reactions such as swelling. Although some researchers have expressed concern over the risk of Guillain-Barre Syndrome (GBS), the GM1-GBS link remains unproven.

Nicotine

Numerous population-based studies have demonstrated an inverse and dose-dependent relationship between smoking tobacco and PD risk with smoking reducing PD risk approximately 36%. Interestingly, a lower PD risk is even observed in former smokers and in those experiencing second-hand smoke. Several animal models of PD have shown that nicotine enhances dopaminergic neuronal integrity in the brain’s striatum. Nicotine may promote neuronal survival, inhibit the formation of α-synuclein aggregates, reduce oxidative stress, modulate inflammation and may be involved in calcium equilibrium. In animal models of PD, nicotine appears to reduce neuronal damage, rather than restore neurons, suggesting that therapeutic intervention using nicotine would likely be most effective in early stage PD.

Although earlier studies did not show any beneficial effect of short-term nicotine treatment, investigators from the Hôpital Henri Mondor in France demonstrated in an open-label study that high doses of transdermal nicotine over 17 weeks improved motor symptoms of all 6 moderate PD patients, allowing for a reduction of dopaminergic treatment in most, but also producing moderate yet frequent nausea.

A U.S./German team is conducting a phase 2 clinical trial (NIC-PD) to assess the effect of long-term (12 months) transdermal nicotine treatment vs. placebo on PD progression, measured through change in PD symptoms, as well as secondary outcomes such as time to initiation of symptomatic treatment, change in cognition, depression and quality of life in 160 patients with early PD who are not yet receiving dopaminergic treatment. Results are expected in 2017.

Because the link between smoking and many serious ailments, such as cancer, lung and heart diseases, is well established, the risks of smoking outweigh any potential protection smoking may offer against PD.

Caffeine

Caffeine consumption is associated with lowering PD risk by about 33%. The inverse association is strong in men but unclear in women, possibly due to the weakening effect of hormone replacement therapy. Caffeine’s neuroprotective properties are attributed to its blocking the adenosine-2A receptor, highly expressed in the brain’s striatum, which appears to alleviate PD motor symptoms.

A six-week clinical trial set to investigate the effect of caffeine on daytime sleepiness of PD patients demonstrated that caffeine intake had no significant effect on this primary endpoint; interestingly, caffeine did improve the severity of motor symptoms. To investigate further, McGill University is currently conducting a phase 3 clinical trial (TEDA) of 120 mild-to-moderate PD patients on stable treatment to assess the effect of caffeine on motor and non-motor symptoms. Investigators are interested to see if continued caffeine helps reduce the dose of PD medication and/or prevents their side effects, as well as determine whether early use of caffeine produces long-term benefits.

Epidemiological studies suggest that consumption of 3-4 cups of coffee daily can reduce the risk of PD. However, this must be weighed against potential adverse effects such as sleep disturbances and resting tremor. Furthermore, the beneficial effects of caffeine may not be observed in all individuals due to genetic differences, as those with variants in the CYP1A2 gene metabolize caffeine at a much slower rate than normal.

Zonisamide

Zonisamide is a treatment that is FDA-approved for treating epilepsy and licensed in Japan as an adjunctive treatment for motor symptoms in PD. In animal models of PD, zonisamide reduces oxidative stress, toxicity caused by α-synuclein, dopaminergic neurodegeneration and enhances dopamine synthesis and release, rendering it an interesting candidate to explore in PD.

Two Japanese studies are currently recruiting patients that both assess the effects of combined levodopa/zonisamide treatment vs. levodopa treatment alone on dopaminergic cell death. The open-label trial, conducted by Hamamatsu University School of Medicine, will use PET imaging to assess dopaminergic cell loss and neuroinflammation following treatment, as well as record changes in PD symptoms, quality of life and behavioral disturbances in 20 early PD patients. The observational study of 30 mild-to-moderate PD patients, conducted by Toho University Omori Medical Center, will use DaTscan to assess dopaminergic cell loss after one year of treatment and determine any associations with changes in PD symptoms. A clinical trial (ZONIST) of zonisamide in 60 early Parkinson disease is registered, but its status is currently unknown.

Conclusions

Several drugs that have shown neuroprotective properties in animal models of PD have regrettably reported no efficacy in recent clinical trials. Still others, like the ADAGIO trial of rasagiline, have yielded results “consistent with a possible disease-modifying effect” although findings were overall inconclusive. This is likely due to our incomplete understanding of mechanisms contributing to PD, as well as the lack of appropriate “tools” to measure disease modification in clinical trials.

As researchers continue to identify genes involved in PD, it is likely that patients may benefit most from personalized/precision-based medicine, which target specific aspects of their PD pathophysiology. Characterizing patients based on their genetic profiles may allow the identification of specific subtypes of PD patients that would respond most to a specific drug. For instance, the FAIRPARK investigators found that PD patients with a certain DNA variations in the ceruloplasmin (CP)-feroxidase gene appear to respond better to iron removal in the brain by deferiprone. Furthermore, since biological pathways may act together to generate PD, combination of drugs with different mechanisms of action, similar to cocktails used in cancer treatment, may be necessary to successfully impact disease progression.

Researchers agree that neuroprotective therapies would likely work best on patients in the earliest stages of PD. Unfortunately, it is challenging to identify preclinical patients due to the lack of adequate biological markers that precede the onset of motor symptoms. Luckily, initiatives like the Parkinson’s Progression Marker Initiative (PPMI) are well underway to identify sensitive biomarkers by following PD patients and recording changes in clinical characteristics, imaging and key molecules over time.

Although researchers recognize the challenges involved, they remain optimistic about identifying therapies that slow or even reverse PD. Additional targets to the ones described above are being investigated, including sagramostim, adipose-derived stromal stem cells, kinase inhibitors, erythropoietin, granulocyte-stimulating factor, α-synuclein aggregation modulators, myeloperoxidase inhibitors, metformin, among many others. Development of a successful neuroprotective treatment would have a huge impact on PD patients, transforming PD from a continually progressive, disabling disease to a chronic but more manageable condition.

It might still be some time until a neuroprotective and/or neurorestorative agent is identified. In the meantime, all PD patients are encouraged to adopt healthy lifestyles, which may contribute to overall healthiness, reduce some of PD’s symptomatic burdens and secondary phenomena (e.g. depression). Studies have underscored the importance of a nutritious diet and physical activity as important strategies in the prevention of most age-related diseases, including neurodegenerative diseases.

Patients are encouraged to exercise regularly, as both animal and human studies continue to demonstrate how physical activity may trigger processes in the brain that induce neuroplasticity, allowing the brain to adapt and change in order to maximize its function. A Mediterranean diet may also offer some benefits, as it reduces odds for PD by 14% in those who consume it regularly. Although clinical trials have not demonstrated a clinical benefit from vitamin E, there is preliminary evidence that antioxidant vitamins such as C and E, as well as unsaturated fatty acids, polyphenols, stillbenes and phytoestrogens may also have therapeutic role. It is important to speak with your healthcare provider before taking any supplements. However, choosing foods that are rich in these nutrients may provide some benefit.

Complete List of Neuroprotection_References.docx