By Ralph Sanchez, L.Ac.,CNS,D.Hom.

The role of chronic inflammation in degenerative disease associated with aging is considered to be a primary vector for the progression of neurodegenative disorders and a powerful factor that underlies their etiology. One needs only to look at the leading causes of mortality, heart disease and stroke, and the research models of inflammation that clearly link it to the pathogenesis and the pathology of these disease processes to understand that inflammation and chronic degenerative disease are inseparable.

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Since inflammation is central to aging-associated disease processes, it has been heavily investigated in models of neurodegeneration. In Alzheimer’s disease  (AD), the investigation has sought to clarify whether inflammation is a causative stimulus, or a concomitant feature of the disease. Regardless of the etiological focus, the role of chronic inflammation in AD is a well established and the continuing illumination of that knowledge base is vital to the emerging paradigm that seeks to emphasize prevention over a pharmaceutical solution.

Pro-inflammatory molecules—The Message of Inflammation

Several research models have sought to establish the association between quantifiable levels of inflammation in the body and the increased risk it confers in the development of late-onset Alzheimer’s disease (LOAD). Other models looking to define the pro-inflammatory processes in the Alzheimer brain have sought to examine how inflammation arises and perpetuates the characteristic pathology of AD. Since genetics rule the propensity for the onset of LOAD (associated risk factors notwithstanding), the identification of “Pro-inflammatory” genes in AD have also been heavily studied, and identified.(1) In addition, the APOe4 variant, a genetic risk factor for cardiovascular and LOAD, is associated with a pronounced pro-inflammatory profile, while the APOe3 variant is protective.(2)

Many studies have established that measurable biomarkers (biological markers )* of inflammation is strongly associated with an increased risk for LOAD. In a subset of the larger Framingham Heart Study, that included 691 healthy people with an average age of 79, circulating cytokines (proinflammatory molecules), were tracked for 7 years. The individuals with highest levels of cytokines, incurred more than  double the risk to develop Alzheimer’s disease, as those with the lowest amount of cytokines.(3)

Similarly, in a study of 300 of  subjects with with mild to severe LOAD, the proinflammatory cytokine tumor necrosis factor α (TNF-α),  was assessed in both patient, and caregiver over a 6 month period. Blood levels of  TNF-α  were measured at two, four and six months. In approximately half of all subjects, increases in the serum levels of TNF-α during the study, were linked to twofold increase in the rate of cognitive decline over a six month period. Subjects that had high baseline levels of TNF-α were associated with a fourfold increase in the rate of cognitive decline. Those that had low serum levels of TNF-α did demonstrate any cognitive decline during the six month study timeline.(4)

These examples of systemic inflammatory pathways that elevate the risk for LOAD and it’s progression demonstrates how aberrant physiological processes related to inflammation, can profoundly impact the brain. What drives these pro-inflammatory pathways? Systemic inflammation patterns that are primary to the disease process inherent in obesity, heart disease, and type 2 diabetes have been established as principle mechanisms that underlie neuroinflammatory pathways in AD.(5)

Once the cascade of systemic inflammation permeates the central nervous system (CNS), it activates immune cells (microglia) that ramp up pro-inflammatory pathways. The phenomena of brain inflammation is complex, and I will only briefly describe some pivotal points.

The Brain Microglia & Inflammation

In the CNS, a collection of specialized cells referred to as the microglia cells,** are the resident immune cells of the CNS. Microglia perform immunoprotective and modulating roles, and essential CNS maintenance functions, including the removal of debris, and pathogens, and the “pruning” of synapses. The latter is an important sculpting process (remodeling) that ‘weeds” out neural connections in a developing brain.(6,7) Ultimately, their role in surveying, protecting, and remodeling the neurological terrain is vital in a healthy CNS, and prototypical immune proinflammatory responses are part and parcel of their activation.

Microglial inflammatory responses are driven by a host of factors. In dementia disorders associated with Alzheimer’s, or vascular disease, typical inflammation driven insults to the CNS include trauma (TIAs/stroke), beta-amyloid aggregation, infections, toxins, or a convergent pro-inflammatory cascade originating in the body (e.g. type 2 diabetes/vascular disease). Once the microglia are “activated”, a neuroinflammatory cascade ensues that may induce, or exacerbate the neurodegenerative mechanisms associated with dementia patterns.

There is sufficient evidence to assert that inflammation pathways are a significant component to the genesis, and exacerbation of AD pathology.The pro-inflammatory vicious cycle may originate from cardiometabolic disease mechanisms, or are prompted via neurological trauma, and epigenetic factors that stimulate the expression of genetic variants associated with higher risk of AD.(9)

Microglial activation is an essential component in the repair process following trauma, and in the attempt to contain proliferation of aggregates of beta-amyloid protein. However, activation of the microglia  induces a variety of pro-inflammatory cytokines and neurotoxic factors that are believed to induce and/or exacerbate neurodegeneration (1). Without the optimal buffering mechanisms, or an outright inhibition of the insult, the initial inflammatory response morphs into a chronic stage that overrides counter regulatory systems, and molecules (antioxidants), and permeates the microglial activation that escalates into a neuropathological pattern.

The neuroinflammatory response in AD has been shown to precede the prototypical lesions, plague and neurofribrillary tangles (NFTs), that are characteristic of advanced pathology. The early beta-amyloid aggregates are a primary stimulus in the activation of microglia, and the cascade of inflammation begins early in the time spectrum of AD neuropathology.(8) This is potentially the most advantageous time to intervene with anti-inflammatory protocols that may assuage the progression of characteristic pathology inherent in AD.(2)

Anti-inflammatory Drug Interventions

To date, there is not medical silver bullet that delivers any effective long term therapeutic intervention into the myriad of neuropathological cascades that are part and parcel of the neurodegenerative pattern of AD. Anti-inflammatory Drug Interventions have yielded less than stellar results.

Epidemiological studies*** have shown a reduced risk of AD in individuals taking Nonsteroidal anti-inflammatory drugs (NSAIDs)****. Juxtaposed to these findings, are the trials that revealed no benefits in reducing cognitive decline in patients with AD. The contrasted outcomes highlights the growing consensus that anti-inflammatory interventions are more wisely applied in the early stages of AD.(2)

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Are NSAIDs a viable solution to prevention of AD? The modulation of inflammation is central to the risk reduction for the onset of AD, and for the management of the disease process. However, prolonged use of NSAIDs is not advisable or recommended. Long term NSAID therapy is associated with severe side effects (SEs). SEs from chronic NSAID use include gastrointestinal damage, heart failure, liver and kidney damage.

Microglial activation, and the role of related pro-inflammatory pathways associated with the pathomechanisms of cognitive decline, and it’s progression into AD, or vascular dementia, begins in the early stages of the disease process.  Once the damage is evidenced by the pathological hallmark plaques and tangles that represent an advanced disease pattern, there may be little that is clinically achievable, albeit some stabilization, and slowing the progression of the disease process may be possible.

Rather than the disease centered model of pharmacological interventions, the real promise in the early intervention, and possible prevention of AD lies in the tried, and true interventions that are effective in all degenerative diseases associated with inflammation. Nutraceuticals that provide anti-inflammatory, anti-oxidative, and anti-nitrative protection are plausible options for possible prevention, or delay of AD in individuals that are at increased risk. It boils down to getting to the cause, rather than treating the effect.

 

* Biomarker—A measurable substance, biochemical, genetic, or molecular, in an organism that may be indicative of some disease state, or the risk for it.

** Microglia—Microglial cells are one of the three main types of central nervous system glia. The central nervous system (CNS) consists of neurons and glial cells. The three types of CNS Glial cells are Astrocytes, Oligodendrocytes, and Microglia. Glial are commonly described as the “supporting cells” of the nervous system.

*** Epidemiology: In medical science, epidemiological studies investigate the patterns and causes, and control of disease in human populations

**** NSAIDs (Nonsteroidal anti-inflammatory drugs) are a classification of prescription, and over-the-counter (OTCs) medications for the treatment of pain and inflammation related disorders. NSAIDs function by inhibiting both cyclooxygenase 1 and 2 (Cox-1 and Cox-2) enzyme pathways that form pro-inflammatory signaling molecules (prostaglandins). Examples of NSAIDs include: Ibuprofen, naproxen, Celebrex and aspirin.

*****Nutraceuticals: The term nutraceutical was first coined in the 1990’s by Dr. Stephen DeFelice, and was defined as: “A nutraceutical is any substance that is a food or a part of a food and provides medical or health benefits, including the prevention and treatment of disease”. Currently, the term is often used to describe a dietary supplement, Medical Food, or food product that provides health and medical benefits, including the prevention and treatment of disease.*

References:

1. Pro-inflammatory gene expression and neurotoxic effects of activated microglia are attenuated by absence of CCAAT/enhancer binding protein β

Marco Straccia, Núria Gresa-Arribas, Guido Dentesano, Aroa Ejarque-Ortiz, Josep M Tusell, Joan Serratosa, Carme Solà, and Josep Saura

Journal of Neuroinflammation 2011, 8:156

2. Neuroinflammation in Alzheimer’s disease wanes with age.

Hoozemans JJ1, Rozemuller AJ, van Haastert ES, Eikelenboom P, van Gool WA.

J Neuroinflammation. 2011 Dec 7;8:171.

3. “Inflammatory markers and the risk of Alzheimer disease: The Framingham Study.” 

Tan ZS et al.

Neurology 2007;68:1902-1908.

4. Systemic inflammation and disease progression in Alzheimer disease

C. Holmes, C. Cunningham, E. Zotova, J. Woolford, C. Dean, S. Kerr, D. Culliford, and V. H. Perry

Neurology September 8, 2009 vol. 73 no. 10 768-774

5. LINKING CARDIOMETABOLIC DISORDERS TO SPORADIC AD: A PERSPECTIVE ON POTENTIAL MECHANISMS AND MEDIATORS

Narayan R. Bhat

J Neurochem. Nov 2010; 115(3): 551–562.

6. Synaptic Pruning by Microglia Is Necessary for Normal Brain Development

Rosa C. Paolicelli, Giulia Bolasco, Francesca Pagani, et al.

Science 9 September 2011: Vol. 333 no. 6048 pp. 1391-1392

7. Microglia and synapse interactions: fine tuning neural circuits and candidate molecules.

Miyamoto A1, Wake H, Moorhouse AJ, Nabekura J.

Front Cell Neurosci. 2013 May 15;7:70.

8. The significance of neuroinflammation in understanding Alzheimer’s disease.                                               

Eikelenboom P1, Veerhuis R, Scheper W, Rozemuller AJ, van Gool WA, Hoozemans JJ.

J Neural Transm. 2006 Nov;113(11):1685-95. Epub 2006 Oct 13.

9. Neuroinflammation – an early event in both the history and pathogenesis of Alzheimer’s disease.                           

Eikelenboom P1, van Exel E, Hoozemans JJ, Veerhuis R, Rozemuller AJ, van Gool WA.

Neurodegener Dis. 2010;7(1-3):38-41.

 

* These statements have not been evaluated by the Food and Drug Administration.

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