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New Blood Biomarkers for Alzheimer's, Parkinson's, MS and Traumatic Brain Injury
- The evidence is now present allowing clinicians to aid in the diagnosis, treatment and monitoring of their patients dealing with suspected neurodegenerative conditions via routine blood testing.
- Once thought to be found only in cerebrospinal fluid (CSF), beta-amyloid and tau proteins can now be detected in the bloodstream.
- Just as important is the incorporation of nutritional supplementation to target and lessen oxidative stress factors, reduce the inflammatory process, decrease permeability of the BBB, and slow the hyperphosphorylation and aggregation of tau and beta amyloid proteins.
Until recently, the diagnosis of neurodegenerative diseases such as dementia, Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and traumatic brain injury (TBI) had been made by the combination of evaluating a patient’s clinical presentation of symptoms and detecting positive findings on imaging studies such as MRI and PET scan. In many cases, a true confirmation would only occur upon post-mortem brain evaluation.1
Glial Cells, Neuronal Proteins & the Precursors of Neurodegeneration
There are approximately 86–100 billion neurons that reside in the human brain, with an almost equal number of the three glial cell types referred to as astrocytes, oligodendrocytes and microglia.2 While neurons provide the most basic functions in brain cell communication, such as specific signaling protein and neurotransmitter production, glial cells play a role in regulating blood supply to the neurons and myelin production; and also act as the nerve system’s resident immune cells.3-4
Normally, upon production of a neuronal protein, a folding process takes place which establishes a number of roles to be performed by that particular protein. In the presence of neurodegenerative diseases such as dementia and AD, there is a misfolding process that takes place, leading to failure of the neuron’s cellular and chemical integrity.5
The two most notable proteins are referred to as beta-amyloid and tau. These proteins, when altered, begin to aggregate intracellularly as well as in the extracellular spaces, leading to the phenomena described as neurofibrillary tangles and/or plaque formation.5-6
As these damaged proteins continue to aggregate over time, neuronal cell communication is lost, leading to symptoms such as memory loss, forgetfulness, mood swings, and/or motor dysfunction.
The Power of Blood Testing
The evidence is now present allowing clinicians to aid in the diagnosis, treatment and monitoring of their patients dealing with suspected neurodegenerative conditions by the use of routine blood testing. Once thought to be found only in cerebrospinal fluid (CSF), beta-amyloid and tau proteins can now be detected in the bloodstream.
In addition to these specific protein markers being detected, some other more subtle markers can be used to evaluate the permeability of the blood-brain barrier (BBB). A faulty BBB can be caused by many factors including underlying pathologies from several different chronic inflammatory conditions.7 Other common causes may occur from oxidative stress and poor lifestyle choices, which often involves the overconsumption of alcohol, excessive tobacco use, poor diet, and lack of exercise.8
Key Lab Biomarkers
The following laboratory biomarkers are now available and have shown great promise in the early detection, diagnosis and management of neurodegenerative processes:
*Neurofilament Light Chain (NfL) – A neuron-specific intermediate filament protein that has recently emerged as a biomarker of neuronal injury with great clinical potential. NfL elevation was initially observed in the CSF of people with dementia, including AD, frontotemporal dementia (FTD), and ischemic vascular dementia (IVD). Now available as a blood biomarker, it can be used in cases related to traumatic brain injuries, as well as other progressive neurodegenerative diseases such as AD, ALS and MS.9
*Beta-Amyloid 42/40 Ratio – A plasma test now available to detect one of the hallmark proteins (amyloid) found in neurofibrillary tangles and plaque formation characteristic in the clinical diagnosis of AD.10
*Phosphorylated Tau 181 (pTau-181) – This plasma test is designed to measure the amount of phosphorylated tau proteins, another hallmark indicator related to the diagnosis of AD and other forms of dementia, in addition to PD.11
Apolipoprotein E4 Variant (Apo-E4) and Next Generation Sequencing (NGS) Early Alzheimer’s Detection Test – Two individual tests designed to detect the presence of a genetic predisposition to AD and amyloid protein precursors.12-13
Matrix Metalloproteinase 9 (MMP-9) – An enzyme vital in the physiological and pathological role of the CNS. MMPs regulate inflammation, microglial activation, blood-brain barrier (BBB) integrity, dopaminergic apoptosis, and alpha-synuclein modulation. MMP-9 prompts the rise in vascular wall permeability by targeting the extracellular matrix (ECM) and tight junctional properties.14
Interleukin 17A (IL-17A) – It is now generally accepted that IL-17A causes disease via the activation of microglial cells and can be used effectively in the diagnosis and treatment monitoring of human autoimmune diseases and neurodegenerative diseases such as AD, PD, MS, and ALS.15
*Indicates biotin elimination 72 hours prior to testing.
Treatment and Prevention – Including Supplementation
While no exact causes of neurodegeneration exist, practicing a healthy lifestyle, which includes a balanced diet, getting quality rest and regular exercise, is key in both treatment and prevention.
Just as important is the incorporation of nutritional supplementation designed specifically to target and lessen oxidative stress factors, reduce the inflammatory process, decrease permeability of the BBB, and slow the hyperphosphorylation and aggregation of tau and beta amyloid proteins.
The following nutrients are recognized as necessary in the management and potential prevention of neurodegenerative processes:
- Omega 3 fatty acids (EPA/DHA), in their role as both anti-inflammatories and nerve tissue repair.16
- For oxidative stress reduction, glutathione (GSH), Co-Q10, and the lipid soluble vitamins A, D, E and K.16-19
- The B-complex vitamins share multiple roles in the production of specific nerve growth factors, while also reducing the production of destructive enzymes and inflammatory cytokines.16,19
- Cinnamon and ginko biloba appear to reduce the hyperphosphorylation process of tau proteins, in addition to eliminating the formation of neurofibrillary tangles and beta amyloid aggregation.20-22
- Choline and phosphatidylcholine (PC) play multiple roles in blocking amyloid beta plaque development, in addition to suppressing microglial cell activation and providing fuel for the short-term memory region of the hippocampus.23-24
- Alpha-lipoic acid has the ability to aid in the recycling of other antioxidants while also increasing production of GSH.25
- Melatonin has been used in the process of an individual reaching delta wave sleep, which is also known to activate the brain’s clearing of toxins (glymphatic system); in addition to reducing the MMP-9 enzyme known to degenerate the BBB, leading to increased permeability and toxic uptake into the brain cells.26
- Several other nutrients, including huperzine A and acetyl-L-carnitine, are also showing promise in their role of modulating the neurotransmitter acetylcholine at the hippocampal level.
References
- Young PNE, et al. Imaging biomarkers in neurodegeneration: current and future practices. Alzheimer’s Res Ther, 2020;12:49.
- von Bartheld CS, Bahney J, Herculano-Houzel S. The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J Comp Neurol, 2016 Dec 15; 524(18):3865-3895
- Kim Y, Park J, Choi YK. The role of astrocytes in the central nervous system focused on BK channel and heme oxygenase metabolites: a review. Antioxidants, 2019 May;8(5):121.
- Bradl M, Lassmann H. Oligodendrocytes: biology and pathology. Acta Neuropathol, 2010;119(1):37–53.
- Soto C, Estrada LD. Protein misfolding and neurodegeneration. Arch Neurol, 2008 Feb;65(2):184-9.
- Peng C, Trojanowski JQ, Lee VM-Y. Protein transmission in neurodegenerative disease. Nat Rev Neurol, 2020;16:199-212.
- Dotiwala AK, McCausland C, Samra NS. Anatomy, Head and Neck, Blood Brain Barrier. Treasure Island (FL): StatPearls Publishing, 2023.
- Fox LM, Yamamoto A. Macroautophagy of Aggregation-Prone Proteins in Neurodegenerative Disease. In: Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging. Volume 7: Role of Autophagy in Therapeutic Applications. Academic Press, 2015.
- Rojas JC. Neurofilament light as a dementia biomarker. Pract Neurol, Nov/Dec. 2020
- Li Y, Schindler SE, et al. Validation of plasma amyloid-ß 42/40 for detecting Alzheimer disease amyloid plaques. Neurol Res, Feb 2022;98(7).
- DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegeneration. 2019 Aug 2;14(1):32.
- Altmann A, Tian L, Henderson VW, Greicius MD; Alzheimer’s Disease Neuroimaging Initiative Investigators. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol, 2014 Apr;75(4):563-73.
- D’Argenio V, Sarnataro D. New insights into the molecular bases of familial Alzheimer’s disease. J Pers Med, 2020 Apr 19;10(2):26.
- Agrawal SM, Lau L, Yong VW. MMPs in the central nervous system: where the good guys go bad. Semin Cell Dev Biol, 2008,19:42-51.
- Chen J, Liu X, Zhong Y. Interleukin-17A: the key cytokine in neurodegenerative diseases. Front Aging Neurosci, 2020;12:566922.2.
- Rai SN, Singh P, Steinbusch HWM, et al. The role of vitamins in neurodegenerative disease: an update. Biomedicines, 2021 Oct;9(10):1284.
- Khan M, et al. S-Nitrosoglutathione reduces oxidative injury and promotes mechanisms of neurorepair following traumatic brain injury in rats. J Neuroinflammation, 2011;8:78.
- Chen JJ. Altered central and blood glutathione in Alzheimer’s disease and mild cognitive impairment: a meta-analysis. Alzheimer’s Res Ther, 2022;14:23.
- Yang X, Zhang Y, Xu H, et al. Neuroprotection of coenzyme Q10 in neurodegenerative diseases. Curr Topics Medicinal Chem, 2016;16(8).
- Yuan Q, Wang C-W, Shi J, Lin Z-X. Effects of ginkgo biloba on dementia: an overview of systematic reviews. J Enthnopharmacol, Jan 2017;195:1-9.
- Qubty D, Rubovitch V, Tali Benromano T, et al. Orally administered cinnamon extract attenuates cognitive and neuronal deficits following traumatic brain injury. J Mol Neurosci, 2021 Jan;71(1):178-186.
- Ciaramelli C, Palmioli A, et al. NMR-driven identification of cinnamon bud and bark components with anti-Aß activity. Front Chem, 2022;10:896253.
- Magaquian D, Delgado Ocaña S, Perez C, Banchio C. Phosphatidylcholine restores neuronal plasticity of neural stem cells under inflammatory stress. Sci Rep, 2021;11:22891
- “Common Nutrient Supplement Choline May Hold the Answers to Combating Alzheimer’s.” Neuroscience News, Sept. 27, 2019.
- Zaitone SA, Abo-Elmatty DM, Shaalan AA. Acetyl-L-carnitine and alpha-lipoic acid affect rotenone-induced damage in nigral dopaminergic neurons of rat brain, implication for Parkinson’s disease therapy. Pharmacol Biochem Behav, 2012;100:347-360.
- Rudra DS, Pal U, Maiti NC. Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site. J Pineal Res, 2013 May;54(4):398-405.