Dear Dr. Dean,
My wife was diagnosed with Progressive Supranuclear Palsy (PSP) about six months ago. She began to have symptoms about two years ago, and was originally diagnosed with Parkinson’s disease. At that time, she was prescribed Sinemet (Carbidopa/Levodopa) 25/100 mg, which she is still taking today. At first, she took 3 per day; then the dosage was increased to 4 per day; and later was increased to 6 per day.
At first the medicine seemed to help her walking and freezing. However, as she increased the dosage, her side effects got much worse, which included:
Since the side effects got worse as the dosage was increased, I reduced the medicine from six capsules a day to two capsules a day. Her choking and speech got better, but she was still tired all the time.
My research indicates that PSP is related to Amyotrophic Lateral Sclerosis (AML) and Parkinson’s disease, and may be caused by misfolded proteins. About a week ago I started giving my wife six PropeLs a day (2 @ breakfast, 2 @ lunch, and 2 @ supper). I’ve noticed an improvement when she is drinking liquids, not choking as much, and a slight improvement in her speech, but no energy improvement so far. I also just ordered your FoldRight mix to see if it will help her.
Over the past year I’ve purchased many supplements and medications to try to help my wife. If she took all of them, it would be over 100 pills per day.
Do you have any suggestions for this condition?
DeVan and Vince, CO & FL
Dear DeVan and Vince:
First, the bad news: Progressive Supranuclear Palsy (PSP) has no known cause, and no known effective treatment. It is a rare progressive neurodegenerative disorder which affects the brainstem, basal ganglia, and cerebral cortex where it is characterized by the accumulation of neurofibrillary tangles comprised of “four-repeat (4R)” hyperphosphorylated misfolded tau protein aggregates. In addition to the extensive and multifocal neuropathological changes, there are multiple neurotransmitter abnormalities, including dopamine, acetylcholine, and gamma-aminobutyric acid systems.1
Classically, PSP is diagnosed by symptoms that include progressive gait disturbances, postural instability (inability to stand unassisted, early falls), personality changes, vertical ophthalmoparesis (weakness or paralysis of one or more extraocular muscles which are responsible for eye movements), and cognitive decline. Swallowing liquids and solids often becomes difficult as the disease progresses, leading to aspiration pneumonias, which is the main cause of death in advanced PSP. The loss of independent gait usually occurs less than 3 years after disease onset, with patients often wheelchair-bound by this time.2
PSP is considered a variant of Parkinson’s disease (PD) (and is frequently misdiagnosed as PD because of the similarity of early symptoms). Therefore, drug treatment usually starts with levodopa (L-DOPA) at doses as high as 1500 mg, which may initially alleviate some of the bradykinesia or rigidity, but rarely in a meaningful way. Levodopa treatment may be accompanied by other therapies that are used for symptomatic improvement in PD.3 However, none of these therapies provide effective control of symptoms, particularly in the early phase of the illness. PSP rapidly progresses over time and worsens dramatically within 1 – 3 years after symptom onset.
Although the specific cause of PSP has not been identified, it is known to share pathological characteristics of other neurodegenerative diseases such as Alzheimer’s disease (AD), PD, Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS) and Multi-System Atrophy (MSA). PSP, AD and MSA are known as tauopathies, due to accumulation of abnormal tau protein within neurons.
Figure 1. Stabilization of microtubules by tau protein (normal function of tau). Abnormal hyperphosphorylation of tau proteins causes catastrophic microtubule fibrillization and formation of insoluble tau oligomers, which aggregate to form protomers, which twist around each other to form paired helical filaments (PHFs), which assemble to produce neurofibrillary tangles (NFTs).9
Until recently, therapeutic approaches for PSP have been primarily symptomatic — directed at the PD-like first manifestations of the disease. However, as knowledge of the pathogenesis of PSP is acquired, physicians and scientists are developing treatments based on the underlying mechanisms of the disease. These approaches include attempts to prevent or reduce the formation of the abnormal tau proteins, facilitate their removal, and restore impaired mitochondrial function.
Based on what is known or speculated about PSP, here are some recommendations that may help to delay the progression of the disease:
I’ve mentioned Methylene Blue (MB) (aka methylthioninium chloride) several times previously. MB is the oldest synthetic drug (synthesized in 1886) and has been used to treat a variety of conditions including schizophrenia, mania, anxiety, emesis, cancer, high blood pressure, allergies and parasitic infections.10 Recently, MB has been found to be of benefit in a number of neurodegenerative diseases, and may help those with PSP.
Figure 2. Proposed model for the interaction of methylene blue with specific mitochondrial and cellular components:The four complexes are: complex I (ETC I), complex II (ETC II), complex III (ETC III), and complex IV (ETC IV) in addition to ATP synthase (i.e., complex V). The electron transfer through each one of the ETC starts at ETC I, which catalyzes two electrons oxidation of NADH and continues until water is formed on ETC IV. Coenzyme Q serves as low-molecular weight electron carrier from ETCs I and II to III. Cytochrome c (cyt c) serves as electron carrier from ETC III to ETC IV.
Production of superoxide radical from complex I is prevented by MB, which serves as electron carrier that competes with molecular oxygen on the electrons “leaking” from complex I. During this process, MB is converted to MBH2. Then MBH2, a reduce MB, carries the electrons to cytochrome c, which is then oxidized by ETC.5
ETC followed by roman number refers to the specific components of the electron transport chain (ETC) of the mitochondria.
MIM, MOM, and IMS refers to the mitochondrial inner membrane, mitochondrial outer membrane, and intermembrane space, respectively.
MB and MBH2 refer to oxidized and reduced forms of methylene blue, respectively.
MB and related compounds have been proposed as the proverbial “magic bullet” because they not only are neuroprotective, but are also able to facilitate soluble tau clearance.14
Mouse doses of MB that have been shown to be effective in “tauopathic” transgenic mice are in the range of 10 mg/kg/day. FDA conversion tables show that a 10 mg/kg dose in a mouse is equivalent to about 1 mg/kg in humans.14 For my patients, I recommend a daily dose of 200 mg MB/day. MB is available by prescription from a compounding pharmacy, or one can use “reagent grade” MB, available over the counter or on the internet (very inexpensive), without a prescription. Use a “micro spoon” (15 – 20 mg) to fill empty gelatin capsules by hand (easier with an inexpensive manual encapsulating machine). MB will turn one’s urine blue or green, so be prepared for this shocking (until you get used to it) but harmless sign.
Another innovative approach to preventing the Tau protein-induced neurofibrillary tangles is to use naturally-occurring osmolytes (such as trehalose, glycine, taurine, proline, inositol, betaine, and creatine).5 Osmolytes are important nutrients that offer an important new approach to prevent amyloid aggregation and to prevent the formation of PSP-promoting misfolded tau protein aggregates. Durk & Sandy’s FoldRight formula provides this combination of nutrients, designed to maintain proteins in a correctly folded state and delay the progression of Alzheimer’s disease and Progressive Supranuclear Palsy.15
CoQ10 and other Mitochondrial Resuscitators
In 2008, in an attempt to restore mitochondrial function, scientists performed a placebo-controlled Phase II trial of 21 patients with “probable” PSP. Half of the group received 5 mg/kg (about 350 mg) CoQ10 per day for six weeks. During this relatively short period, CoQ10 appeared to improve cerebral energy metabolism, and slightly improved the PSP rating scale and the Frontal Assessment Battery. The authors concluded that “Since CoQ10 appears to improve cerebral energy metabolism in PSP, long-term treatment might have a disease-modifying neuroprotective effect.”16 On the basis of this study, a one-year Phase III study was initiated (NCT 00382824), with a proposed completion date of 2013.17 In this study, the doses of CoQ10 reportedly ranged from 1200 – 2400 mg/day. Unfortunately, no results from this study have yet been released.
Other mitochondrial enhancers that could be considered include creatine (an Osmolyte, remember?), niacinamide and pyruvate. Based on the mitochondrial hypothesis of PSP, a randomized, double blind Phase I study to examine safety and tolerability of a cocktail of these nutrients has recently been completed (NCT 00605930).6 Results are still pending. The doses used in the study were a bar of 2 g of pyruvate and 1 g of creatine, and a pill of 1 g of niacinamide each day. This formula should be easy to copy from a health food store or online.
DMAE (dimethylaminoethanol) or Centrophenoxine (meclophenoxate)
Figure 3. Proposed pathway leading to aggregation of abnormal tau proteins. Age-related mitochondrial dysfunction leads to formation of lipofuscin (aging pigment). Lipofuscin granules become seeds for triggering Tau aggregation. The resulting Tau oligomers add to congestion in the metabolic pathway, promoting further Tau aggregation—a “vicious cycle.” Abnormal amyloid processing (Amyloid Precursor Protein [APP]) adds to the endogenous load on the mitochondria and shortens the time to critical failure.13
The dietary supplement DMAE (and its pharmaceutical “cousin”, Centrophenoxine) have been demonstrated to reduce the neuronal load of lipofuscin.19–2122
Grape Seed Polyphenol Extracts
Grape seed polyphenolic extract (GSPE) (one well-tested brand, MegaNatural AZ, from Polyphenolics, Inc.) has been found to be capable of interfering with the abnormal assembly of tau.4,23,24 GSPE is from the seeds of grapes (Vitis vinifera) grown in California. The active ingredients in GSPE are reported to be catechins and epicatechins — similar to the active ingredients in Green Tea (EGCG — epigallocatechin-3 gallate), minus the gallate moiety.24 Long-term dietary supplementation with GSPE in the Tg2576 Alzheimer’s disease mouse model (200 mg/kg BW/day — equivalent to 1 g/day in humans) reduced the accumulation of misfolded tau aggregates. Anecdotal evidence from a human compassionate use phase study in PSP patients showed delayed progression of symptoms after 5 months treatment with 1200 mg GSPE/day.25 This strongly supports the use of GSPE as a potential treatment for PSP and possibly other tauopathies. I recommended those at risk of PSP or other neurodegenerative diseases take two 300 mg capsules of GSPE three times per day.
Green Tea (EGCG)
Figure 4. Proposed schematic model for EGCG neuroprotective/neurorescue action. For explanation see text.29
The authors28 concluded that “EGCG dietary supplementation [is] a potentially safe and effective prophylaxis for Alzheimer’s disease” [and presumably other tauopathies].
EGCG absorption and plasma levels can be enhanced by drinking green tea, on an empty stomach, together with 200 mg ascorbic acid and 1,000 mg omega-3 fatty acids. Omega-3 fatty acids enhance oral bioavailability of EGCG and also improve its efficacy.30
Figure 5. Schematic illustrating the ability of olive oil polyphenols to prevent Tau fibrillization in vitro. Oleuropein aglycone was found to be more active as a Tau aggregation inhibitor than methylene blue, inhibiting fibrillization at low concentrations. These findings provide further support for the beneficial nutritional properties of olives and olive oil against neurodegenerative tauopathies.33
Anhydrous Betaine (Trimethylglycine), Vitamins B6 and B12
In 2010, two separate studies nearly simultaneously reported that neurodegenerative diseases (PSP, ALS, and Parkinson’s disease) were all characterized by elevated levels of homocysteine.6,34 Each team confirmed that homocysteine is neurotoxic, and suggested that early intervention with nutritional therapy with methylcobalamin, pyridoxine and anhydrous betaine (trimethylglycine) be used to reduce the progression of these diseases. I recommend at least 1 mg of methylcobalamin, 200 – 500 mg of pyridoxine, and 5,000 mg of anhydrous betaine (trimethylglycine) be administered each day if homocysteine levels are elevated.
Figure 6. Model depicting the proposed mechanism of curcumin to provide neuroprotection. (Black arrows = stimulation; red symbol = inhibition).38
Proposed mechanisms for turmeric’s broad range of beneficial effects (Fig. 6) are that it acts as a natural free radical (ROS) scavenger; an activator of the neurotrophic factor κB (NF-κB) (by which it decreases the release of inflammatory interleukins); as a stress response mimetic that induces components of the protein homeostasis network; and directly acts to mitigate the protein misfolding cascade. Additionally, turmeric may act as a dietary restriction (DR) mimetic to activate the adenosine monophosphate kinase (AMPK) pathway.38
Figure 7. Optimized turmeric decreased phosphorylated Tau Protein by 80% in Tg2576 mice treated with optimized turmeric (HSS-888) or tetrahydrocurcumin (THC).40
Collectively, these data provide rationale for turmeric to be used for clinical use for the treatment of tauopathies, including AD and PSP.41 Block39 calculated that the human equivalent to the dose used in the mouse studies would range from 500 – 2500 mg/day. I would err on the high side.
Keeping in mind those with PSP suffer difficulty swallowing which limits how much medication/supplements they are able to consume, here are my recommendations for a daily “basic load” of tau inhibitors for anyone suffering from or at risk of neurodegenerative diseases, especially PSP:
Rather than try to swallow this many capsules, it would probably be easier and safer to use a blender or “Nutri-Bullet” to make drinks or “smoothies.”
I hope this information helps — please keep me posted of your progress,
Ward Dean, MD