Larochelle C, Uphaus T, Prat A, Zipp F. Secondary Progression in Multiple Sclerosis: Neuronal Exhaustion or Distinct Pathology? Trends Neurosci. 2016. pii: S0166-2236(16)00025-4
Prevention of progression in neurological diseases, particularly in multiple sclerosis (MS) but also in neurodegenerative diseases, remains a significant challenge. MS patients switch from a relapsing-remitting to a progressive disease course, but it is not understood why and how this conversion occurs and why some patients never experience disease progression. Do aging and accumulation of neuronal damage induce progression, or do cognitive symptoms and accelerated grey matter (GM) atrophy point to distinct processes affecting networks? This review weighs accepted dogma against real data on the secondary progressive phase of the disease, highlighting current challenges in this important field and directions towards development of treatment strategies to slow or prevent progression of disability.
It is clear that the development of progressive MS, on balance is a product of age/ disease duration.
What are the mechanisms of progression suggested?
1. The Same Processes Driving RRMS Eventually Lead to SPMS
As we get older there is a switch from active plaques to slowly expanding inactive and smoldering plaques. Aging and accumulation of damage in the peripheral immune system and the CNS over time can lead to chronic immune activation, increased oxidative stress-related damage, exhaustion of repair mechanisms, and loss of trophic support, all of which could significantly contribute to SPMS onset. Here are some suggestions
So the only way to get a handle on this is get MS sorted early and then see what happens, quell autoimmunity and see if progression occurs. I think I know what happens in EAE, what will happen in MS, we need to use highly effective agents ASAP as we know that progressive nerve damage starts from the earliest time point.
- Alteration of the Peripheral Immune System with Aging
- Aging is Associated with ‘Low-Grade Immune Activation’ in the CNS and Mitochondrial Dysfunction
- Aging and Accumulation of Insults Result in Exhaustion of CNS Compensatory Mechanisms
- Aging of Immune and CNS Cells and Reduced T Cell Infiltration in SPMS Can Result in Loss of Trophic Factors
- High-Grade Chronic Inflammation’ Triggers New Independent Autoimmune Processes Within the CNS
- Chronic Demyelination and Neuronal Dysfunction Can Exert Reciprocally Deleterious Influences
- Reduced Social, Physical, and Cognitive Activity Impairs Remyelination and Neurogenesis
- Microglial Profile in SPMS Can Hamper Neuroglial Repair Mechanisms
- Intrinsic Neurotransmitter Imbalance in the CNS and loss of inhibitory molecules
Here are the views summarised
Mechanisms Underlying Secondary Progressive Multiple Sclerosis (SPMS) Pathophysiology.
(A) Proposed schematic representation of events underlying relapsing-remitting multiple sclerosis (RRMS). Because the first trigger of MS relapse and the exact sequence of events leading to lesion formation or to remission are not known, a wheel (black circle and arrows) is used to represent the cycle of peripheral immune activation, central immune activation, and neuroglial damage observed in RRMS. Regulatory mechanisms (in blue) in the peripheral immune system and CNS are intervening to induce remission, and lead to partial or complete clinical recovery.
(B) Proposed schematic representation of events underlying SPMS. Hypothesis 1 (upper panel): exhaustion of resources through aging and lesion accumulation as the mechanism underlying the clinical shift from RRMS to SPMS. Aging as well as lesion accumulation exacerbate and chronicize the RRMS pathophysiological mechanisms (bold black circle and arrows). Neurosenescence (green), characterized by microglial activation, iron deposition, mitochondrial dysfunction, and decreased network efficiency, is associated with reduced capacity of neuroglial cells to tame inflammation and to repair and regenerate (broken green line). Immunosenescence (orange) is characterized by (in specific immune cell populations) increased cytotoxic capacity, enhanced expression of adhesion molecules, and decreased trophic factor production, and is associated with impaired immunoregulatory capacity (broken orange line). The broken grey line represents the largely unexplored relation between the neuroglial compartment and the BBB alterations found in SPMS.
Hypothesis 2 (lower panel): distinct CNS-restricted processes triggered by high-grade inflammation and neuroglial injury as the mechanism underlying the clinical shift from RRMS to SPMS. Upon reaching a given inflammatory threshold (shown by red arrow), aggressive immune cells can create an environment that supports the organization and persistence of a chronic inflammatory immune response within the CNS compartment. The CNS inflammatory environment, together with ensuing demyelination and neurotransmitter imbalance, impairs neuronal function while increasing energy demand. This initiates a vicious cycle of chronic demyelination, energy failure, neuronal degeneration, loss of function, disuse, and decreased remyelination and neurogenesis, exposing remaining neuroglial cells to further stress and energy demand, and sustaining independent degenerative and inflammatory processes in the CNS. The broken grey line represents the largely unexplored relation between the neuroglial compartment and the BBB alterations found in SPMS. The broken blue lines underline the impairment of regulatory mechanisms because peripheral regulatory immune cells cannot influence intra-CNS immune processes, and chronic neuroglial injury and neurological disability impair CNS repair mechanisms.
Abbreviations: BBB, blood–brain barrier; CIS, clinically isolated syndrome; GM, grey matter; WM, white matter.
Every thing is caused by autoimmunity, this is the average EAEologists world view that every thing to do with MS is caused by autoimmunity, crack autoimmnity you crack the lot...only problem is....therapy in MS does not support this...hey if you look hard enough EAE does not support this view either.
Maybe we have been flogging a dead horse too long and this is why treatments for progressive MS are lacking.
But what do the reviewers do...yep do what I would do and sit on the fence! Abit of this here and a bit of that there
"When weighing up the above-mentioned data for and against a specific pathology in SPMS, there is a degree of balance, and it is conceivable that both (i) the sum of aging and cumulative inflammatory injury exhausts resources and drives the system towards failure, and (ii) distinct intrinsic mechanisms in the CNS, emergent or present from onset, are triggered at some point and lead to chronic sustained neuroglial injury. In fact, aging and lesion accumulation could contribute to a threshold of inflammation and neuroglial dysfunction being reached upon which distinct intra-CNS mechanisms are triggered and in turn contribute to accumulation of damage.
It remains to be determined if both (i) and (ii) are necessary to eventually lead to the typical disability progression seen in later stages of the disease".