Schizophrenia and Multiple Sclerosis: An Intriguing Parallel

OVERVIEW:

Schizophrenia (SCZ) and multiple sclerosis (MS) are such different diseases, but the similarities in their underlying features is striking. The actual cause or causes is/are unknown in both cases, but are clearly rooted in the brain. Studies have found associations between MS or SCZ with abnormalities in the immune system, infections, especially with viruses, and the inheritance of some genes, each abnormality belying one of several mechanisms that together may lead to disease in each case.

There are also striking differences between the two conditions, first of all, in their symptoms, of course. The distribution between the sexes in SCZ and MS differ, where MS is more common in women than in men. SCZ affects more people than MS. MS tends to affect Caucasians more often, while SCZ is reported to affect more people of African American descent in the U.S., but there may be overdiagnosis of SCZ in African Americans.

They both start in early adulthood (sometimes in late adolescence for SCZ) and they affect both twins in pairs of identical twins at similar rates. It is a mystery how a disease that involves hallucinations and delusions (SCZ, a disease of the mind, so to speak) can be similar in so many ways to a disease mainly characterized by physical symptoms.

DETAILS

When you think of schizophrenia, an association with multiple sclerosis doesn’t usually spring to mind. But the connection has occurred to some scientists, who see similarities in the underlying features of the two disorders. The abnormalities and damage seen in both diseases occur in the central nervous system (CNS), which is made up of the brain and the spinal cord. But the symptoms of the two are strikingly different: while hallucinations, delusions, and abnormal emotional reactions are typical signs of SCZ, MS is characterized by an extremely wide variety of symptoms, including numbness or weakness in limbs and loss of coordination.

M. Arneth recently wrote an article that outlines some of the striking similarities and differences between the two conditions (Arneth, 2017). Both are chronic illnesses that appear to be caused by a complex interplay of genetic, immunological, and possibly environmental factors whose effects accumulate over a period of years. But they have markedly contrasting manifestations. He suggests that subgroups of MS and SCZ may be related disorders.

DEMOGRAPHICS AND GENETICS

The age at which disease sets in is similar in SCZ and MS: late adolescence and early adulthood for SCZ, with early adulthood being the more common age of onset in women, and early adulthood for MS.

On the other side of the coin, MS affects twice as many women than men, whereas SCZ is distributed equally between the sexes. In the US, for instance,  more people of African descent are diagnosed with SCZthan Caucasians, (although overdiagnosis of SCZ in African Americans is suspected) and the reverse is true for MS.

Schizophrenia is much more common, affecting roughly 2.2 million people in the US compared to an estimated 400,000 people with MS in that country. The Multiple Sclerosis Society of Canada estimates that roughly 100,000 people in Canada have MS. The number of people in Canada with SCZ is estimated at roughly 140,000.

It is clear that genetic factors associated with MS and SCZ are extremely complex, but the rates at which identical twins (who share exactly the same set of genes) both develop MS is 30-80% and 50-60 % in SCZ, a rough indication that genes appear to be part of the cause, but that other factors must also come into play to trigger the conditions.

LINK TO INFECTIONS

Patients with SCZ often have a history of infections in their mothers during gestation, known as prenatal maternal infections. Also, viral infections are associated with psychotic episodes in SCZ and aggravations of symptoms, or exacerbations, in MS.

Antibodies specific to a diversity of viruses are found in the cerebrospinal fluid (CSF, the fluid that bathes the CNS) of patients with MS and in the blood of people with SCZ. Oligoclonal bands are characteristic of MS and have also been reported in SCZ. Usually, antibodies in CSF are indicators of an ongoing infection in the CNS, but mysteriously, no evidence of CNS infections by most of these viruses has been found in MS.

Everyone has human endogenous retroviruses (HERVs) in their DNA. They are inherited viruses passed from parents to offspring. Normally, they do not appear to cause illness, and a physiological role has only been assigned yet to one type, HERV-K. “Two neurological disorders in particular are associated with HERVs: multiple sclerosis (MS) and schizophrenia,” Tove Christensen wrote (Christensen, 2010). However, there are reports of differing HERV activity in both SCZ and MS, especially the type W HERV.  “HERV-H/F and HERV-W are specifically activated both in the circulation and the central nervous system (CNS) in a majority of MS patients… The expression of anti-HERV-W Gag reactive epitopes is reported to be down-regulated in the brain but up-regulated in the blood from schizophrenia patients,” he wrote.

So, the parallels are there: HERV activity, which is triggered by some viruses, and viral infections triggering exacerbations are common to both SCZ and MS. Clearly, some of the same actors are involved in the two diseases, but their actions appear to have different effects at the level of CNS biology, the responses to them may differ, or they may trigger different disease-causing mechanisms during the long-term evolution of each disease.

IMMUNE ABNORMALITIES

Abnormalities in the immune systems of people with SCZ have been noticed for decades now, leading to the notion that SCZ may be at least partly caused by a malfunctioning immune system. Proteins produced by the immune system known as pro-inflammatory cytokines circulating in the bloodstream can promote damaging inflammation in the CNS. There are abnormal blood levels of these cytokines in cases of SCZ, either stably over time or during psychotic episodes. There are also reports of increases in their levels during MS exacerbations. Higher levels of some pro-inflammatory cytokines in the CSF of people with MS and SCZ have been reported.

Examination of CNS tissues removed from deceased MS and SCZ patients (post-mortem tissues) revealed that in both conditions, there has been activation of microglia, cells of the CNS’s own immune defense system. Also, there is evidence that pro-inflammatory cytokines are present in brain tissue from patients with SCZ (Pandey et al., 2017). This would upset a delicate balance in the CNS, where the extent of immune reactions is normally limited in order to prevent immune reactions from injuring cells and tissues there. However, signs of immune activity and inflammation in the CNS are common to other neurological disorders, also, not only to SCZ and MS.

Autoantibodies, antibodies that target the body’s own cells, are present in patients with MS, and autoantibodies with a different target than those found in MS, but autoantibodies nonetheless, have been reported in a subgroup of people with SCZ, leading Arneth to suggest that “subgroups of these two diseases may belong to the same class of disorders.”

MYELIN

Myelin is the substance that is wrapped around axons, or the arms, of neurons (nerve cells). MS is known to be a demyelinating disease (a disease that destroys myelin) in which visible regions of sclerosis, or scarring, called plaques, occur in the white matter of the CNS. The gaps in the myelination of axons is thought to cause the symptoms in MS by slowing the speed at which signals are transmitted in neurons.

In SCZ, no plaques are formed, but abnormalities in the activities of some of the genes responsible for the regulation of oligodendroglia (the cells that produce myelin proteins in the CNS) have been reported (Karoutzou et al., 2007, Wang et al., 2015). The hypothesis is that dysfunctional oligodendrocytes cause abnormal myelination of axons, affecting the transmission of signals in neurons.

CONCLUSION

There are no simple answers when it comes to SCZ and MS. Clearly, their causes are complex in nature and they characteristically declare themselves in early adulthood. They both appear to be caused by an interplay of genetic, immunological, and certain environmental factors whose effects accumulate over a long period of time. There are points of convergence in the biology of the two diseases that make comparisons between them a promising way forward to understanding disease mechanisms in the CNS, ultimately leading to better care, and hopefully prevention and cures.

Typical of biomedical research in SCZ, it is impossible to know at present which of the many abnormalities found in SCZ are causes of episodes, bona fide causes of the disease, or are merely the consequences of dysregulation in the CNS. Likewise for MS. MS and SCZ are both enigmas: we have many of the pieces of the two puzzles in hand, but the pieces have yet to fall into place.

In future blogs, I will focus on schizophrenia alone and cover various aspects of possible disease mechanisms in more depth.

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REFERENCES

Arneth, BM. 2017 “Multiple Sclerosis and Schizophrenia” International Journal of Molecular Sciences 18:1760 doi:10.3390/ijms18081760

Christensen, T. 2010 “HERVs and Neuropathogenesis” Journal of Neuroimmune Pharmacology 5 (3):326–335 doi:10.1007/s11481-010-9214-y

Karoutzo, G, Emrich, HM, Dietrich, DE. 2007 “The myelin-pathogenesis puzzle in schizophrenia: a literature review.” Molecular Psychiatry 1245-260 doi:10.1038/sj.mp.4002096

Pandey, GN, Rizavi, HS, Zhang, H, Ren, X. 2017 “Abnormal gene and protein expression of inflammatory cytokines in the post-mortem brain of schizophrenia patients.” Schizophrenia Research doi:10.1016/j.schreds.2017.04.043

Schwieler L., Larsson MK, Skogh E. 2015 “Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia–significance for activation of the kynurenine pathway.” Journal of Psychiatry & Neuroscience 40(2):126-33. doi:10.1503/jpn.140126

Wang C, Aleksic B, Ozaki N. 2015 “Glia-related genes and their contribution to schizophrenia,” Psychiatry and Clinical Neurosciences 69(8):448-461 doi: 10.1111/pcn.12290

IMAGE ATTRIBUTION

Rollstuhl1972 by Soest

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