First off, each person affected with MS has their own unique and different experience. The severity and symptoms rely on a multitude of variables like the extent of damage, locations, repairs, epigenetics, and so on. Anyhow, about 85% of people that come down with the disease present with relapsing remitting multiple sclerosis (RRMS). Around 60 to 70% transition into secondary progressive multiple sclerosis (SPMS) within 10 to 20 years. Though, most people don’t notice it at the time and it’s only seen in hindsight.
In early MS, immune cells become activated in the periphery by an antigen derived from the CNS. CD 4 + T cells orchestrate and adaptive immune system attack against it. They secrete chemokines and neurotransmitters to signal other immune cells to join in and spark an adaptive immune response. They migrate to the CNS barriers and loosen their tight junctions by secreting cytokines, protease, etc. and use adhesion molecules to cross into the CNS. There they are reactivated by resident innate immune cells or infiltrating dendritic cells (DCs) and home into the damaged site. Once there, they release damaging inflammatory mediators causing demyelination and axon damage that result in lesions. Some axons, neurons, and oligodendrocytes (OLs) are destroyed directly by the attack, but the BBB is only transiently opened that allows inflammation to eventually resolve. However, partially preserved remyelinated and unremyelinated axons have to use compensatory measures to continue action potential conduction. Remyelinated sheaths are much thinner and more pale, why they are called shadow plaques, and require more mitochondria and energy demand. Unremyelinated axons move even more mitochondria out into the axon and redistribute ion channels along the entire axon. This causes slow action action potential conduction, ectopic firing, and requires even more energy. It also increases oxidative stress. Redistributing the ion channels increases sodium in the axon that needs enhanced Na+/K+ ATPase pump activity, needing even more energy. High intra axonal sodium levels can reverse the Na+/Ca2+ exchanger, which lets Ca2+ enter the axon. Ca2+ overload degenerates the cytoskeleton, activates the cell death pathway, and increases proteolysis by activating Ca2+ sensitive proteases. Increased pro-inflammatory cytokines, reactive oxygen species (ROS), and the pro-inflammatory environment can cause mitochondrial dysfunction that decreases their energy output. This decreases the neuron’s ability to move mitochondria and other supplies from the cell body out along the axon. Their fragility and susceptibility to oxidative injury causes axonal stress and they upregulate MHC class I molecules that opens them up to CD8+cytotoxic T lymphocyte attack. Unaffected axons also increase their diameter and G ratio to compensate for decreased signaling by damaged neurons that can open them up to injury. Without the support of OLs, these adaptations can’t and aren’t meant to maintain in the long term. They become worn out by increased energy demands, toxic byproducts, continued immune attacks, oxidative stress (OS), and decreased glucose metabolism and antioxidants that occur in the aging process. Much neuronal damage is spread along connected neural networks by upstream axon damage.
There are four different kinds of active lesions in MS. They show that MS isn’t a single disease process, but has numerous different mechanisms that can lead to demyelination. However, these patterns occur in active lesions and are only snapshots in time and the underlying mechanisms are complex and change over time.
Pattern I: T-cell and macrophage-mediated demyelination that attack and destroy the myelin sheath.
Pattern II: T-cell and antibody-mediated demyelination is similar to Pattern I, but also sees antibodies and complement proteins deposited on myelin sheaths. These include a humoral immune response that leads to “smoldering or iron rimmed lesions.
Pattern III: Distal oligodendrogliopathy that targets OLs for apoptosis, not the myelin itself. Citrullinated myelin proteins or EBV mimcry/cross-reactivity in the most distal parts of OL processes in the periaxonal region may be the targets causing this process.
Pattern IV: Oligodendrocyte apoptosis that starts in the cell body and extends outward.
The cellular aging theory says each dividing cell has a finite number of replications before entering a senescent state that terminates cell division. Cells divide 40–60 times in culture prior to exiting the cell cycle and entering a ‘senescent state’. However, ‘Premature cellular senescence’ (stress-induced cellular senescence), occurs when a cell exits the cell cycle prior to using its maximum divisions. It becomes senescent due to stressors, like epigenetic alterations and oxidative or DNA damage.
Senescent cells have a senescence-associated secretory phenotype (SASP). This combines pro-inflammatory chemokines, cytokines. and factors like migration inhibitory factor (MIF), ILs, proteins, growth factors like angiogenin, receptors, like epidermal growth factor receptor (EGF–R), and factors like NO and fibronectin.
This can prevent tumor generation and flag dysfunctional cells for immune clearance. However, it depends on efficient clearance, with only short exposure of surrounding cells to them and their SASP. Their reduced clearance in MS and aging creates accumulated and persisting SASP. This damages neighboring cells via paracrine signaling that triggers a cascade of premature cellular senescence, chronic inflammation, and tissue degeneration.
Cellular senescence increases p16INK4A, p21, and senescence-associated β galactosidase expression in astrocytes, microglia, and neurons in MS as in aging brains. It reduces myelin debris clearance, and senescence can affect OLs via SASP from neighboring senescent cells in the CNS. Astrocytes and microglia release SASP components, like TNF-α, IL-1β, IL-6, and SA-β-gal when activated. These accumulate, and their clearance by senescence-reversing (‘senolytic’) compounds can trigger apoptosis in senescent cells. It seems that numerous inflammatory mediators involved in MS are SASP components. In fact, those that don’t present with RRMS initially, about 15%, present with primary progressive multiple sclerosis (PPMS) that is characterized by diffuse low level BBB leakage. They never improve because inflammation never resolves. It seems that in SPMS, senescent BBB endothelial cells allow for this type of leakage.
Cortical demyelination refers to lesions in the cortex or outermost layer of the brain parenchyma (functional brain tissue). It consist mostly of grey matter (GM) that surrounds the inner white matter (WM). Simply put, WM in the CNS is made of axons coated with myelin. They conduct, process, and send nerve signals up and down the spinal cord. It’s damage effects movement, senses, and reaction to external stimuli. GM in the CNS contains neuronal cell bodies, axon terminals, dendrites, and nerve synapses. It has high concentrations in the cerebellum, cerebrum, and brain stem with a butterfly shape in the central spinal cord. About 40% of the CNS is composed of GM with WM making up the other 60%. GM involvement is MS has a more aggressive disease course.
Cortical lesions increase in chronic SPMS and are different than WM lesions. They mostly contain activated microglia, with much less T- and B-cells. The damage here is caused by soluble factors released by inflammatory infiltrates in the meninges and/or BBB leakage into the CNS. These highly activate microglia and DCs that drive a proinflammatory immune response by highly secreting cytokines and producing ROS. Immature DCs can act as phagocytes and clear myelin debris to help restore homeostasis.
Cortical lesion contribute significantly to cognitive decline and disease progression in MS. Cortical and deep GM demyelination can exceed that seen in WM in SPMS. Extensive lesions can be seen in GM structures in the cerebellar cortex, hippocampus, and deep GM nuclei. This diffuse pathology transects neurons, injures OLs and axons, and reduces presynaptic terminals. Cortical atrophy patterns with or without concomitant WM lesions in SPMS. In CNS autopsy, various cortical lesions are seen in about 90% of MS patients. MS brain tissue contains three types cortical lesions.
Leukocortical lesions (Pattern 1) start in subcortical WM and extend into cortex layers V and VI . They occur in early MS by lymphocytes and microglia/monocytes, but are mostly in subcortical WM.
Intracortical lesions (Pattern 2) are in the cerebral cortex, but don’t directly contact pia mater or subcortical WM, and are small and perivascular.
Subpial lesions (Pattern 3) are the most abundant cortical lesions, and most increased in SPMS. They occur mostly in layers I-IV and highly associate with SPMS meningeal inflammation. They lack most WM lesion features like BBB breakdown, immune cell infiltration, perivascular cuffs, astrogliosis, OPC loss, and complement activation.
Cerebrospinal fluid (CSF) flows outside the cortex in the subarachnoid space (SAS) in the leptomeninges that abut the skull. The meninges are membranes covering the brain and spinal cord. They consist of dura mater, subarachnoid mater, and the pia mater, with the dura mater closest to the skull. CSF fills the subarachnoid space between the pia and subarachnoid matter. CSF is produced by the choroid plexus, ependymal cells lining the ventricles, brain capillaries, and maybe the cerebral BBB endothelium in the brain ventricles located deep inside the brain. They filter blood plasma into the interstitial space here epithelial cells transport certain ions and nutrients into the ventricles which creates an osmotic gradient that takes water from the blood into the ventricle to create cerebral spinal fluid. CSF brings nutrients into the brain and removes waste products by the glymphatic system. CSF in this area dives into the brain perivascular arteries (penetrating arterioles) branch off pial arteries in the meninges Are you eating here or dive into the brain parenchyma while carrying a sheath of pia mater with them. As they penetrate, they turn into parenchymal arterioles that branch into capillaries. This is accompanied by a surrounding perivascular space (PVS) or Virchow-Robin space, which is a fluid-filled area between the vessel and the surrounding brain tissue where CSF flows and removes waste products as the glymphatic system. These are separated by the BBB and the glia limitans which is made of astrocyte endfeet. Water channels in their endfeet are also disrupted if they become activated, yet another mechanism to help attack pathogens that’s corrupted by MS. Perivascular and paravascular are different spaces around blood vessels, but seem to be used interchangeably. Perivascular spaces are in the vessel wall surrounding arteries, and are bounded by smooth muscle cell basement membranes. Paravascular spaces are outside the vessel wall, in the subarachnoid or subpial space, and are bounded by the pial sheath (in arteries) or the vein wall (in veins) and the glia limitans. Paravascular spaces seem to be what they keep referring to so I’ll just use PVSs. Anyhow, the CSF bulk flow seems to be produced by arterial pulsations to keep it moving. However, respirations, specifically inhalations during wakefulness help the CSF move into PVSs and the brain tissue. Here, it can release its nutrients and accumulate waist products. Exhalations are relatively stronger during sleep that help move this debris filled CSF out to PVSs that run outside of veins and empty into the SAS in the meninges. Here, it can be removed through the cranial and spinal meningeal lymphatics and arachnoid granulations.
Anyhow, I’m making such a point of this because this system is highly affected in neurodegenerative diseases and in aging. Lesions in MS often occur in PVSs that affect the glymphatic system function. Sleeping on your right hand side elevates your heart and can increase arterial pulsation to help the system clear waste during sleep. This also stimulates your vagus nerve for autonomic parasympathetic functions and deep sleep (slow wave sleep) reduces inhalations.
The meninges and PVSs are highly inflamed in SPMS. Inflammatory infiltrates in the SAS CSF that flow into these PVSs first pass the brain subpial cortex layers. There they cause extensive cortical lesions that drives progressive neurodegeneration in GM. This area also sees highly activated microglia in clusters surrounding blood vessels. These areas likely leak blood components like fibrogenin into the CNS due to senescent BBB pericyte and endothelial cells and the increased inflammatory mediators. Cortical lesions highly increase in layers closest to the leptomeninges. Fibrogenin is converted into fibrin in the CNS by thrombin and potently stimulates microglia/macrophages. These perivascular spaces are also the channels used by the glymphatic system to clear waste products and cellular debris during sleep. Lesion that form here block and/or slow the flow allowing inflammatory mediators to persist for greater periods causing more damage or may be the original cause. It also creates persistent inflammation needed for ectopic lymphoid-like follicles (eLFs) to form here that are only seen in SPMS. These eLFs are like secondary lymph nodes that support germinal center reactions. They highly support EBV activity and EBV reactivation for lytic replication occurs mostly in cortical lesions for a chronic inflammation source.
DGM lesions are also seen in the thalamus and adjacent regions, esp. in caudate, medial, and anterior thalamic nuclei. They also see highly activated microglia and limited T and B cells. GM atrophy patterns occur in regions strongly connected to neuronal networks. DGM structures connect to cortical GM regions, so atrophy here could be from retrograde events caused by axon transection in WM extending from the thalamus, or secondary to losing nerve impulses from thalamic neurons. DGM loses volume quicker than in other brain regions in all MS types.
References included at end of SPMS series.