Infection and Inflammation in Neurodegenerative Conditions

Increased levels of chronic inflammation accompany aging, and this drives faster progression of a range of age-related conditions, spurring greater damage and loss of function in tissues. Researchers here ask to what degree this is due to opportunistic infections and a weakened immune system rather than being caused by the more general dysfunction and overactivation of the aged immune system that would occur even absent such infections, the state known as inflammaging. Like many such investigations, this serves to emphasize the need for effective means to rejuvenate the age-damaged immune system, such as through clearing and recreating immune cell populations, restoring the thymus to youthful levels of activity, or replacing blood stem cells.

The immune system undergoes many changes with age that leaves the elderly more susceptible to infection, indeed older individuals are more vulnerable to bacterial or viral infections of the urinary or respiratory tract, with influenza-related morbidity also increased in this group. Sepsis, which is caused by severe infection, can also lead to permanent cognitive dysfunction, particularly in older individuals. Importantly, infectious burden in the elderly is associated with mini-mental state examination (MMSE) scores below 24, which indicate dementia. Unfortunately, the symptoms of infection often present atypically in this group and, as dementia patients are often unable to communicate their symptoms, diagnosis is difficult. To further complicate matters, bacterial resistance is often increased in older patients.

Individuals with Alzheimer's disease (AD) are even more vulnerable to the effects of peripheral infection. In a 10-year follow-up study, delirium (which is often caused by infection) correlated with an eightfold increase in dementia development. Furthermore, the cognitive capabilities of AD patients worsened significantly after an episode of delirium, which has been confirmed by others. Indeed poor health and viral burden have been linked with cognitive impairment and AD development in the elderly. It was found that the incidence of many infectious conditions such as pneumonia, lower respiratory tract, or urinary tract infections is higher in AD patients than healthy, age-matched controls. Previous studies have demonstrated that numerous infections over a 4-year period doubled the risk of AD development. Indeed cognitive decline has been observed just 2 or 6 months after a resolved peripheral infection, with an association between cognitive impairment and circulating proinflammatory cytokines.

The emerging evidence strongly indicates that infection has a significant role in the development of, and progression to, dementia, with a growing list of pathogens specifically associated with AD or amyloid-β deposition. This may be due in part to some of the changes that are known to occur to the immune system with age. One of the key changes in the adaptive immune system is the involution of the thymus, resulting in a dramatic decrease in the production of new T cells. With age, there is an overall decrease in naive T cells, and a corresponding increase in memory T cells. This is associated with a reduction in naive T cell diversity after the age of 65, with clonally expanded subsets of memory T cells often observed in this age group, which can occur from chronic or repeat infections. Together, this can limit the capacity of the individual to induce a sufficient immune response to new infectious challenges.

It is clear from the evidence that AD patients are more vulnerable to the effects of peripheral infection than their age-matched, healthy counterparts. Importantly, it is indisputable that many specific viral, bacterial, and fungal infections are associated with AD development, although whether these pathogens are a direct cause of dementia or instead are advantageous, infiltrating microorganisms that exacerbate the neuroinflammation already ongoing in these individuals remains to be confirmed. Importantly, the blood-brain barrier of AD patients is significantly leakier than in healthy subjects, which facilitates infiltration of peripheral immune cells and possibly these infectious pathogens. Together, this demonstrates the critical need for early detection and treatment of infections in the elderly and in those with dementia. As infectious diseases can present atypically in this group, frequent screening and vaccination are key to preventing infection-related deterioration of cognition until new therapies are established that can protect the elderly from these unnecessary insults.

Link: https://dx.doi.org/10.1186/s13195-017-0241-2

Comments

So I understand this would kill two birds with one stone, yes? Reduce/remove erroneous inflammation and regain ability to adapt to new pathogens.

I just wonder how this would play out in practice. The patient needs to have their thymus and marrow replaced, right? And wouldn't they have to destroy the existing immune system prior to this? How invasive and (temporarily) debilitating might this prove to be, if this is (as I understand it) basically a new immune system that has to be re-taught everything, if you will?

My imagination could be way off base here, I'm just trying to understand what this sort of rejuvenation might look like in the clinic.

Posted by: Seth at March 9th, 2017 3:29 PM

@Seth: I think that either restoring immune cell production rate or removing the existing population would be beneficial on their own, if properly managed. In the oldest people it might not be possible to do the latter without the former, however, as they won't regenerative their immune system rapidly enough otherwise.

I'd imagine you'd have to get all your vaccinations again, and the existing immune reboot studies make it apparent that minimizing the time in which you are without immune coverage is important.

Posted by: Reason at March 9th, 2017 5:21 PM

SENS was working on a replacement Thymus IIRC at Wake. Is there any news on this?

MMTP is planning immune system rejuvenation as our next step though we have a different approach planned than replacing the thymus. Cannot say more currently as it is early days and we are in talks with researchers.

Posted by: Steve Hill at March 10th, 2017 3:33 AM
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