Neuroinflammation v 'increased central immune signalling'

[Marco]

While this paper primarily relates to the influence of the immune system in major depressive disorder it also proposes the more general need to distinguish between 'neuroinflammation' associated with diseases such as Alzheimers' and Parkinsons where there is progressive and irreversible damage to the CNS and lower level immune activation which may be transitory and reversible.

They suggest that making this distinction should avoid confusion as to what exactly 'neuroinflammation' means.

Hopefully if central immune activation plays a role in ME/CFS it's the latter type :

Toll-like receptor 4: innate immune regulator of neuroimmune and neuroendocrine interactions in stress and major depressive disorder

Classically, inflammation involves swelling, heat, and pain, coupled with a coordinated infiltration of various immune cells into the affected area. In many neurological conditions, this large-scale damage is not seen unless in terminal stages, or in cases of major BBB compromise. Thus, the use of “neuroinflammation” to refer to central immune activity can become confusing, and a clear distinction between high magnitude and submaximal immune states is required.

We thus propose the use of the terms “increased neurokine signaling” or “increased central immune signaling” to apply to these sub-inflammatory states, and only when there is large-scale damage as a result of immune cell derived neurotoxicity and inflammation should the term “neuroinflammation” be applied in order to reduce confusion within the literature.

http://journal.frontiersin.org/article/10.3389/fnins.2014.00309/full

 

[Sidereal]

On the other hand, the study illustrated that simply inhibiting microglia chronically would not be a viable treatment option, since microglial activation states change from an initial proliferative state to later decline from acute to chronic models, and central immune suppression exacerbates depressive-like behavior in a chronic model. Instead, the authors proposed that depression is related to either an over or under activation of microglia, and treatments should strive toward a balance in activation states. Taken together, microglia appear important in central immune signaling and immune to brain communication in MDD, but this relationship is not is not uni-directional, and appears to be time-dependent.

Interesting. Those who think taking microglial inhibitors for ME/CFS is a good idea should take note of these findings.

 

[heapsreal]

Only had a quick read but suprised memantine wasnt mentioned in treatments like ssri and snri.
memantine is used in Parkinsons as it protects dopamine receptors , possibly through its nmda antagonist effects. I think it may also reduce TNFa. Been some research showing it can help some fibro patients ?

interesting to read cox2 inhibitors show anti neuro inflammatory effects .

I wonder if a combination of drugs eg snri, memantine and celebrex etc etc depending on if
One can tolerate them, could help with the neuro-immune inflammation in cfsme? Im sure theres more meds with anti neuro/immune inflammatory effects.

 

[JPV]

Im sure theres more meds with anti neuro/immune inflammatory effects.

This might also explain why LDN has been so beneficial for many people...

The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain

So many of the more effective supplements, drugs and diet regimens that people on the forum are experimenting with seem to have some sort of anti-inflammatory properties.

 

[Marco]

This exerpt outlines a very familiar scenario (my bold) :

"The immune-priming effect of stress is proposed to mediate stress-induced side effects such as allodynia (Loram et al., 2011), and drug abuse (Frank et al., 2011), and could potentially be involved in MDD as well. PBMCs isolated from patients admitted for severe depressive episodes are more responsive to interferon-γ (IFN-γ) stimulation (Schlaak et al., 2012). Along with increased TLR4 mRNA and expression on PBMCs of patients with MDD (Kéri et al., 2014), the increased immune signaling in MDD patients could be indicative of a primed immune system, rather than chronic inflammation."

 

[pattismith]

While this paper primarily relates to the influence of the immune system in major depressive disorder it also proposes the more general need to distinguish between 'neuroinflammation' associated with diseases such as Alzheimers' and Parkinsons where there is progressive and irreversible damage to the CNS and lower level immune activation which may be transitory and reversible.

it may be that even with Parkinson and Alzheimer, neuroinflammation may be reversible if taken early.

@Pyrrhus

This recent paper says:

"Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum.

Large-scale genome-wide association studies point out several genetic variants—TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, and HLA-DRB5-HLA-DRB1—potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking.

However, a recent meta-analysis indicates a potential biological effect of NSAIDs. "

(full text available)

 

[Pyrrhus]

The paper described at the beginning of this thread is one of many papers that constituted a "backlash" against the new term "neuroinflammation". This paper isn't nearly as bad as some others I have seen, though.

So this paper proposes a linguistic distinction between reversible and irrreversible neurological conditions that come with neuroinflammation. That's like proposing a different name for cancer that kills you and for cancer that you recover from, arguing that the word "cancer" is too confusing otherwise.

What the authors fail to recognize is that neuroinflammation is just a symptom of Alzheimers and Parkinsons, it is not the cause of the disease. It doesn't make any sense to use different names for the exact same symptom in different diseases.

The paper that @pattismith describes shows how the symptom of neuroinflammation starts decades before the other symptoms in Alzheimers and Parkinsons. This implies that the causes of Alzheimers and Parkinsons are already in motion decades before the diagnosis. But this paper also falls into the trap of assuming that neuroinflammation must be part of the cause, and not just a symptom.

To support its view that neuroinflammation is a part of the cause, this new paper says:

A recent meta-analysis including 16 investigations demonstrate that present or previous utilization of NSAIDs is linked to a decreased relative risk of [Alzheimers] (0.81; 95% confidence interval, 0.70–0.94) (206)
...
Despite the observational epidemiological data suggesting a protective effect of NSAIDs, all placebo-controlled trials of a wide range of anti-inflammatory agents (NSAIDs, corticosteroids, and others) in both mild-to-moderate [Alzheimers] patients (Table 1) and MCI subjects (Table 2) are negative.

These authors suggest that taking NSAIDs may therefore reduce your risk of being diagnosed with Alzheimers. This may be true, but in this case, I would just call neuroinflammation an "aggravating factor", not a "cause". And, of course, correlation does not imply causation. There are multiple explanations for the results of the meta-analysis.