Tolle Causam

Decker Weiss, NMD, FASA

It is debatable whether dementia is on the rise. According to the Alzheimer’s Association, brain disease and dementia are on the rise across all 50 US states, with an estimated 5.5 million Americans living with Alzheimer’s.¹ Statistically, “someone in the United States develops Alzheimer’s dementia every 66 seconds.”¹ However, recent data also shows that while the chances of avoiding dementia may have increased,² the overall prevalence of adults with dementia in the United States may have dropped by 24% between 2000 and 2012.³ One statistic that is not debated is that deaths from dementia have more than doubled between 2000 and 2107.⁴ While common inflammatory conditions such as sports injuries and autoimmune disease provide practitioners information via pain and dysfunction, dementia tends to have an “unsure” onset of symptoms over time, creating a potential delay in treatment. Regularly, spouses and loved ones of people with dementia make comments in my clinic like these: I didn’t notice it at first… I just thought it was normal at their age… Is there a screening test we could have performed earlier on?

According to an NIH-supported article published in the Expert Review of Neurotherapeutics, “Accurate diagnosis of dementia is important for prognosis and to guide therapy.”⁵ Although it is the minority of dementias that are considered reversible (maybe upwards of 11%), any case of dementia may respond to appropriate treatment once identified.⁵ When surveyed, naturopathic and holistic practitioners generally feel that early identification of common neurotransmitters and cortisol may be a more efficient way to screen, diagnose, monitor, and guide treatment (aimed at reversal) for patients with dementia, for 2 reasons:

1. Dysregulation of neurotransmitter and cortisol levels can be linked to chronic inflammation^6,7
2. Neurotransmitter dysfunction links inflammation directly to the brain⁸

Let’s take a deeper look at this.

Key Players

Serotonin

Findings from a new Johns Hopkins University study supported those of several other studies in finding a link between serotonin and dementia.⁹ According to researchers, lower serotonin levels may play a key role in memory decline and drive the progression of Alzheimer’s. Additional results suggest serotonin loss may be a key player in cognitive decline, not just be a side-effect of Alzheimer’s disease.⁹

Dopamine

Two ancillary details of importance arise from a couple of interesting findings: 1) Dopamine levels may drop 10% per decade in adults¹⁰ (if untreated); and 2) dopamine-boosting drugs appear to improve learning abilities in seniors.¹¹ In the brain, dopamine is sent from the ventral tegmental area to the hippocampus, where it supports healthy functioning of the hippocampus.¹² However, if the hippocampus – which is responsible, in part, for forming new memories – doesn’t receive enough dopamine, the ability to learn new information suffers. This in turn has been shown in a small study to likely increase the risk of dementia, and specifically Alzheimer’s.¹²

Norepinephrine

The locus coeruleus (LC) is the major subcortical site for the synthesis of norepinephrine.¹³

Extensive LC degeneration is nearly universal in Alzheimer’s disease and is^14,15 among the earliest detectable pathologies¹⁶, as early as 10 years before clinical dementia can be recognized and diagnosed.¹⁷ The locus coeruleus is deemed by most neurobiologists to be quite a large influencer in the brain due to its innervation to the thalamus, hippocampus, the frontal and entorhinal cortices and, to a minor extent, most other brain regions.^18,19 As the LC declines, norepinephrine’s influence over the brain is reduced, which may be partly what makes the brain vulnerable to Alzheimer’s. Why? It may be because norepinephrine has an inverse relationship with reactive oxygen species (cell-line study)²⁰ and because it positively influences cytokines to control inflammation.²¹

Glutamate

Glutamate is the principal excitatory neurotransmitter in the brain.²² Glutamate may also act as an endogenous neurotoxin.²³ Glutamate can cause chronic excitotoxicity, which may play a key role in neurodegenerative diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and Huntington’s disease.²⁴ A normal glutamatergic system supports healthy brain activity via the N-methyl-d-aspartate receptor (NMDAR), which is critical for the survival of neurons and synaptic plasticity. However, excessive activity of this receptor promotes excitotoxicity and cell death – possibly an underlying mechanism for the neurodegeneration that occurs in Alzheimer’s disease.²⁵

Cortisol

Clinical studies have shown that elevated cortisol is linked with reduced cognitive functioning as well as impairments in language, episodic memory, processing speed, spatial memory, and social cognition. In healthier subjects (in terms of brain and cognition), higher cortisol levels have been linked with cognitive decline and increased risk of AD.²⁶

Screening Guidelines

In a literature review, as well as my informal polling of clinicians actively diagnosing and treating dementia, a reliable way to measure and monitor neurotransmitters was determined to be via urine,²⁷ and an accurate way to measure the levels of cortisol, as well as to examine the cortisol curve, is via saliva in 4 time-point cortisol test.²⁸

The New 4-Point Protocol

However, despite the evidence, acceptance of screening and monitoring for dementia using these methods has still not become standard. So, for the first time in print, based on interviews with over 40 leading dementia scientists and practitioners, here are my current recommendations:

1. Initial screening for men should begin in an asymptomatic male at age 50 if there is no family history, and at age 45 if there is.
2. Initial screening for asymptomatic women with no family history should start at menopause. If a hysterectomy was performed, then screening for neurotransmitters and cortisol should start 90 days post-surgery.
3. In either sex, if symptoms arise, testing should be initiated immediately.
4. Always test for methylation defects and homocysteine as a part of the diagnostic process.

Monitoring

For patients undergoing therapy such as amino acids or methylation support, the initial follow-up testing should be performed at 90 days, and a second test 90 days later; a third test should be performed 6 months after the second test. If the patient has recovered, then yearly screening should still be performed, as dementia is caused by multiple factors, including new physiologic stressors that can emerge in the course of people’s lives.

Reversal

Earlier in the article I mentioned that rates of recovery, when AD is caught early, are at around 11%; however, this does not include amino acid therapy, methylation correction, breakthroughs in botanical treatments (such as curcumin), or stress, wellness, and nutrition modification. In the unofficial poll of scientists and clinicians performed by the author, the general consensus is that with modern intervention, reversal rates of AD can be as high as 80% when caught early. But the key, as with colon cancer or heart disease, is to catch it early on a screening test, not later as the disease activates and destroys. The conclusion of this article passes a simple message to the reader: screen, screen, screen!

References:

1. Bond-Nelms C. Alzheimer’s Is Accelerating Across the U.S. November 17, 2017. AARP Web site. https://www.aarp.org/health/conditions-treatments/info-2017/alzheimers-rates-rise-fd.html. Accessed May 14, 2019.
2. Graham J. Chances of Avoiding Dementia on Rise in U.S. May 24, 2018. Scientific American Web site. https://www.scientificamerican.com/article/chances-of-avoiding-dementia-on-rise-in-u-s/. Accessed May 14, 2019.
3. Alzheimer’s Association. Dementia Prevalence Is Falling, So Why Is the Alzheimer’s Death Rate Rising? August 14, 2017. Available at: https://www.alzheimers.net/dementia-prevalence-falling-alzheimers-death-rate-rising/. Accessed May 14, 2019.
4. Kramarow EA, Tejada-Vera B. Dementia Mortality in the United States, 2000–2017. National Vital Statistics Reports. 2019;68(2). CDC Web site.https://www.cdc.gov/nchs/data/nvsr/nvsr68/nvsr68_02-508.pdf. Accessed May 14, 2019.
5. Scott KR, Barrett AM. Dementia syndromes: evaluation and treatment. Expert Rev Neurother. 2007;7(4):407-422.
6. Miller AH, Haroon E, Raison CL, Felger JC. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety. 2013;30(4):297-306.
7. Ennis GE, An Y, Resnick SM, et al. Long-term cortisol measures predict Alzheimer disease risk. Neurology. 2017;88(4):371-378.
8. Xu Y, Yan J, Zhou P, et al. Neurotransmitter receptors and cognitive dysfunction in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol. 2012;97(1):1-13.
9. Smith GS, Barrett FS, Joo JH, et al. Molecular imaging of serotonin degeneration in mild cognitive impairment. Neurobiol Dis. 2017;105:33-41.
10. Rutledge RB, Smittenaar P, Zeidman P, et al. Risk Taking for Potential Reward Decreases across the Lifespan. Curr Biol. 2016;26(12):1634-1639.
11. Shohamy D, Wimmer GE. Dopamine and the cost of aging. Nat Neurosci. 2013;16(5):519-521.
12. De Marco M, Venneri A. Volume and Connectivity of the Ventral Tegmental Area are Linked to Neurocognitive Signatures of Alzheimer’s Disease in Humans. J Alzheimers Dis. 2018;63(1):167-180.
13. Freedman R, Foote SL, Bloom FE. Histochemical characterization of a neocortical projection of the nucleus locus coeruleus in the squirrel monkey. J Comp Neurol. 1975;164(2):209-231.
14. Bondareff W, Mountjoy CQ, Roth M, et al. Neuronal degeneration in locus ceruleus and cortical correlates of Alzheimer disease. Alzheimer Dis Assoc Disord. 1987;1(4):256-262. 
15. Haglund M, Sjobeck M, Englund E. Locus ceruleus degeneration is ubiquitous in Alzheimer’s disease: possible implications for diagnosis and treatment. Neuropathology. 2006;26(6):528-532.
16. Mann DM, Lincoln J, Yates PO, et al. Changes in the monoamine containing neurones of the human CNS in senile dementia. Br J Psychiatry. 1980;136:533-541. 
17. Grudzien A, Shaw P, Weintraub S, et al. Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging. 2007;28(3):327-335. 
18. Counts SE, Mufson EJ. Locus Coeruleus. In: Mai JK, Paxinos G, eds. The Human Nervous System. 3rd edition. New York, NY: Elsevier; 2012.
19. Sara SJ. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci. 2009;10(3):211-223.
20. Patel PR, Hegde ML, Theruvathu J, et al. Norepinephrine Reduces Reactive Oxygen Species (ROS) and DNA Damage in Ovarian Surface Epithelial Cells. J Bioanal Biomed. 2015;7(3):75-80.
21. Rommelfanger KS, Weinshenker D. Norepinephrine: The redheaded stepchild of Parkinson’s disease. Biochem Pharmacol. 2007;74(2):177-190.
22. Meldrum BS. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr.2000;130(4S Suppl):1007S-1015S.
23. Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch.2010;460(2):525-542.
24. Lewerenz J, Maher P. Chronic Glutamate Toxicity in Neurodegenerative Diseases—What is the Evidence? Front Neurosci. 2015;9:469. 
25. Wang R, Reddy PH. Role of Glutamate and NMDA Receptors in Alzheimer’s Disease. J Alzheimer’s Dis. 2017;57(4):1041-1048.
26. Ouanes S, Popp J. High Cortisol and the Risk of Dementia and Alzheimer’s Disease: A Review of the Literature. Front Aging Neurosci. 2019;11:43.
27. Siu WK. Genetics of monoamine neurotransmitter disorders. Transl Pediatr. 2015;4(2):175-180.
28. Fisher RN, McLellan CP, Sinclair WH. The Validity and Reliability for a Salivary Cortisol Point of Care Test. J Athl Enhancement. 2015;4:4. Available at: https://www.scitechnol.com/the-validity-and-reliability-for-a-salivary-cortisol-point-of-care-test-mDRz.php?article_id=3740. Accessed May 15, 2019.

Decker Weiss, NMD, FASA, became the first naturopathic cardiologist, completing cardiovascular hospital-based training in the Columbia Hospital system, the AZ Heart Institute, and the AZ Heart Hospital. Dr Weiss kept privileges at the AZ Heart Hospital while opening the Scottsdale Heart Institute. There he helped thousands of patients prevent surgery and reverse heart disease naturally. In 2018, Dr Weiss shifted to focused research on inflammation and radicalization, as well as how the brain and spirit can recovery from PTSD, and sex slavery/sex work as he launched Peace Possible™, a 501C3 non-profit with ongoing projects in Iraq, Syrian border areas, Thailand Viet Nam, Senegal, Rwanda, and more.