Inflammation and Cognitive Decline: A Practical Guide to Reducing Neuroinflammation

 

Mild, self-limited inflammation is good; chronic inflammation is bad

Under normal circumstances, a little targeted inflammation is a good thing. Inflammation indicates an immune system response to insult or infection. Inflammatory cells and cytokines work in a coordinated fashion to wall off infection and eliminate pathogenic microorganisms. This immune response is particularly important for normal bodily processes, such as proper wound healing. On the other hand, prolonged inflammation is damaging to tissues of the body. Chronic inflammation, seen in rheumatoid arthritis, for example, can ultimately damage joints leading to pain, dysfunction, and deformity.

 

Neuroinflammation, cognition, and dementia

We are now learning that chronic inflammation also takes a toll on the brain. A growing body of scientific evidence has shown that prolonged inflammation is associated with cognitive decline and an increased risk of dementia.1 Just like chronic inflammation in the body, chronic inflammation in the brain (i.e. neuroinflammation) can be damaging. The brain’s immune cells, called microglia, release reactive oxygen species and damaging enzymes.2,3 While these substances would be helpful in killing bacteria, they are decidedly unhelpful when they encounter healthy nerve cells in the brain.

Brain structures responsible for attention, learning, and memory of prior experiences and facts, such as the hippocampi, and structures such as the basal ganglia responsible for remembering how to carry out a task, adjusting voluntary movements, and aspects of cognition and emotion,  contain more inflammatory enzymes than other brain regions, such as those that process vision or sound, for example. Consequently, chronic inflammation leads to cognitive problems and slowed movements more readily than it would lead to other neurological problems.

Microglia also release several pro-inflammatory cytokines including interleukin -1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFα). These cytokines are known to fan the flames of chronic inflammation. For example, the higher the levels of the inflammatory cytokine IL-6 found in someone's brain, the worse they score on the Mini Mental Status Exam, a test commonly used to detect cognitive impairment.4 In summary, lifestyle factors, inflammation, and cognitive decline are linked.

 

What causes chronic neuroinflammation?

Most clinical studies examining the role of inflammation and cognitive decline have looked at associations between these two characteristics. Researchers have noted that people who have neuroinflammation are more likely to have cognitive impairment than people without neural inflammation.3 Likewise, people with higher degrees of neuroinflammation have more severe cognitive disturbances than people with lesser amounts of neuroinflammation.3 As the wise scientific principle goes, however, association does not necessarily imply causation. Thus, it is difficult to determine if inflammation causes cognitive decline, if cognitive decline causes inflammation, or if hidden variables not being examined are seemingly linking the two in a noncausal way. Nonetheless, researchers have identified several factors associated with neuroinflammation and cognitive decline3,5 including:

·       Increasing age

·       Depression

·       Chronic stress

·       Poor lifestyle choices, such as smoking and unhealthy diet

·       Certain medical conditions, such as diabetes

·       Obesity

 

Focusing on neuroinflammation to slow cognitive decline

While the brain is what makes us uniquely human, inflammation in the brain is not fundamentally different than inflammation in other parts of the body.  The factors that contribute to inflammation in the body (systemic inflammation) overlap with inflammation in the brain (neuroinflammation).  We know a great deal about what causes systemic inflammation and, by extension, how to quell that inflammation.

Losing weight

If you look at the factors associated with neuroinflammation you can see that many of them are controllable or modifiable. Obesity is strongly correlated with systemic inflammation, neuroinflammation, and cognitive decline.5 Thus for people who are obese or overweight, weight loss is one intervention that can help reduce inflammation throughout the body and potentially slow cognitive decline.

Heathy diet

Going hand-in-hand with obesity is diet. Dietary choices can influence inflammation and cognitive decline.6,7 People who consumed diets processed food, peas, legumes, and fried food with a relative lack of whole grains had higher levels of inflammatory cytokines (e.g. IL-6) and accelerated rates of cognitive decline as they aged.7 On the other hand, people who consumed diets rich in healthy fats, fruits, and vegetables, including the Mediterranean diet, had lower levels of oxidative stress and neuroinflammation and slower cognitive decline.6  A diet rich in antioxidants and monounsaturated fatty acids is associated with reduced levels of systemic inflammation and, by extension, brain inflammation.6

Exercise

Aerobic activity is not only important for maintaining a healthy weight, but it may directly reduce inflammation. Moderate physical activity can decrease cognitive losses and help maintain cognitive function.8,9 This effect seems to be related to reductions in pro-inflammatory cytokines such as IL-6.10 It is not clear what level of aerobic activity is necessary to stave off cognitive decline. One strategy suggests performing 150 minutes of moderately vigorous activity spread throughout the week, for a minimum of 10 minutes in each episode.11 If you are interested in starting or increasing your exercise routine, consult with your physician to make sure it is safe to do so.

Smoking cessation

Smoking is a highly pro-inflammatory activity. Preventing early cognitive decline is one of many reasons to stop smoking if you currently do so.

Chronic stress and depression

Chronic stress, chronic inflammation, and depression are intertwined. Poorer cognitive function is associated with an increased risk of depression, social withdrawal, and a decreased quality of life.12 Indeed, recent research suggests that depression may be caused by neuroinflammation, at least indirectly.13 Therefore, people who are concerned about cognitive decline should make an effort to effectively manage stress whether through psychotherapy, meditation and mindfulness, or other approaches. Likewise, people with depressive symptoms should treat those symptoms aggressively, utilizing both behavioral modification (e.g. diet, exercise, and social contact) and medication.

Diabetes

Diabetes is a chronic, proinflammatory state. Elevated levels of glucose not only “stick” to hemoglobin protein in red blood cells (which is what is measured with hemoglobin A1C), but it also sticks to other proteins and fats (a general process known as glycation) important to nerve cell function. Glycation can damage blood vessels vital to keeping brain cells alive by providing them with nutrition and oxygen leading to brain cell death and suboptimal function. Furthermore, glycation promotes the production of destructive reactive oxygen species that prematurely age brain cells.  Just as the goal in diabetes management is to keep blood glucose levels within a healthy range, the way to reduce the risk of neuroinflammation is to control blood sugar levels and keep hemoglobin A1C below the target you have worked out with your physician.

Increasing age

As you can see from the factors associated with inflammation, not all of them are modifiable. One nonmodifiable risk factor that stands out among this list is advanced age. As the brain ages, a certain amount of cognitive decline is to be expected. While scientists used to believe that moderate worsening in cognitive ability in elderly populations were within the realm of normal—this is no longer thought to be the case. Truly normal aging is only associated with only a small decrease in cognitive ability. More severe cognitive decline typically represents mild cognitive impairment or dementia. Fortunately, lifestyle changes that reduce neuroinflammation (such as moderate physical exercise) appear to reduce the risk of mild cognitive impairment and dementia.11

Steps you can make today to decrease neuroinflammation and slow cognitive decline

  • If you smoke, quit!
  • Treat chronic proinflammatory diseases that may promote neuroinflammation and cognitive decline, such as:
    • Diabetes
    • Chronic obstructive pulmonary disease (COPD)
    • Autoimmune diseases (rheumatoid arthritis, Crohn's disease, etc.)
    • Hyperlipidemia (high cholesterol)
    • Hypertension (high blood pressure)
  • If you are overweight or obese, lose weight
  • Start and maintain a healthy diet, which includes the following:
    • An abundance of antioxidants, fiber, whole grains, and monounsaturated fatty acids
    • Minimal intake of red meat and processed food
  • Get at least 150 minutes of moderate-intensity physical exercise per week
  • Aggressively treat depression
  • Take steps to reduce chronic stress

References

1.           Godbout JP, Johnson RW. Age and Neuroinflammation: A Lifetime of Psychoneuroimmune Consequences. Neurol Clin. 2006;24(3):521-538. doi:10.1016/j.ncl.2006.03.010

2.           Blasko I, Stampfer-Kountchev M, Robatscher P, Veerhuis R, Eikelenboom P, Grubeck-Loebenstein B. How Chronic Inflammation Can Affect the Brain and Support the Development of Alzheimer's Disease in Old Age: The Role of Microglia and Astrocytes. Aging Cell. 2004;3(4):169-176. doi:10.1111/j.1474-9728.2004.00101.x

3.           Sartori AC, Vance DE, Slater LZ, Crowe M. The Impact of Inflammation on Cognitive Function in Older Adults: Implications for Health Care Practice and Research. The Journal of Neuroscience Nursing. 2012;44(4):206-217. doi:10.1097/JNN.0b013e3182527690

4.           Wright CB, Sacco RL, Rundek T, Delman J, Rabbani L, Elkind M. Interleukin-6 Is Associated with Cognitive Function: The Northern Manhattan Study. J Stroke Cerebrovasc Dis. 2006;15(1):34-38. doi:10.1016/j.jstrokecerebrovasdis.2005.08.009

5.           Nguyen JCD, Killcross AS, Jenkins TA. Obesity and Cognitive Decline: Role of Inflammation and Vascular Changes. Frontiers in Neuroscience. 2014;8:375. doi:10.3389/fnins.2014.00375

6.           Caracciolo B, Xu W, Collins S, Fratiglioni L. Cognitive Decline, Dietary Factors and Gut-Brain Interactions. Mech Ageing Dev. 2014;136-137:59-69. doi:10.1016/j.mad.2013.11.011

7.           Ozawa M, Shipley M, Kivimaki M, Singh-Manoux A, Brunner EJ. Dietary Pattern, Inflammation and Cognitive Decline: The Whitehall Ii Prospective Cohort Study. Clinical Nutrition (Edinburgh, Scotland). 2017;36(2):506-512. doi:10.1016/j.clnu.2016.01.013

8.           Angevaren M, Aufdemkampe G, Verhaar HJ, Aleman A, Vanhees L. Physical Activity and Enhanced Fitness to Improve Cognitive Function in Older People without Known Cognitive Impairment. Cochrane Database Syst Rev. 2008(2):Cd005381. doi:10.1002/14651858.CD005381.pub2

9.           Colcombe S, Kramer AF. Fitness Effects on the Cognitive Function of Older Adults: A Meta-Analytic Study. Psychol Sci. 2003;14(2):125-130. doi:10.1111/1467-9280.t01-1-01430

10.         Nimmo MA, Leggate M, Viana JL, King JA. The Effect of Physical Activity on Mediators of Inflammation. Diabetes Obes Metab. 2013;15 Suppl 3:51-60. doi:10.1111/dom.12156

11.         Henderson VW. Three Midlife Strategies to Prevent Cognitive Impairment Due to Alzheimer’s Disease. Climacteric : the journal of the International Menopause Society. 2014;17(0 2):38-46. doi:10.3109/13697137.2014.929650

12.         Black SA, Rush RD. Cognitive and Functional Decline in Adults Aged 75 and Older. J Am Geriatr Soc. 2002;50(12):1978-1986.

13.         Hermida AP, McDonald WM, Steenland K, Levey A. The Association between Late-Life Depression, Mild Cognitive Impairment and Dementia: Is Inflammation the Missing Link? Expert Rev Neurother. 2012;12(11):1339-1350. doi:10.1586/ern.12.127

 

Dr. Ari Magill is a former staff neurohospitalist at Northwest Medical Center in Tuscon, AZ. Dr. Magill has a special interest in cognitive, behavioral, and memory disorders and is passionate about advancing dementia treatment through clinical research. He enjoys medical writing and  currently performs independent VA disability exams on veterans who sustained traumatic brain injury.  Dr. Magill completed neurology residency at the University of Arizona in Tucson, AZ and completed a movement disorders neurology fellowship at the University of Colorado Anschutz Medical Center in Aurora, CO. He received a B.S. in Zoology from University of Texas in Austin and his M.D. from UT Southwestern Medical School in Dallas.