‘Molecular basis of cognitive decline
in multiple sclerosis’
Master Thesis - Neuroscience and Cognition Master’s program
Gkountidi Anastasia-Olga
Supervisors : Geert Schenk1 , Jeroen Geurts1 , Martien Kas2
1
2
VU University of Amsterdam, Department of Anatomy and Neuroscience
Utrecht University, Department of Neuroscience and Pharmacology
Summary
Multiple sclerosis is a chronic neurodegenerative disease affecting the central nervous system, i.e brain
areas, spinal cord. It is characterized as a neurodegenerative disease because of the absence of myelin that
facilitates a good flow of electricity along the nervous system of the brain. Multiple sclerosis can affect
people from all ages, but it is more common between ages 20 to 50 years. People of all ancestries can
have it although people European descent are more prone to developing multiple sclerosis. The clinical
course is variable and among the symptoms observed in patients memory loss, difficulties in processing
speed information, attention, learning decision making, problem solving are cognitive processes mainly
affected. Depending on the stage of the disease, the cognitive abilities that are affected are presented
below as well as the possible molecular mechanisms that are involved.
Abstract
Multiple sclerosis is a neurodegenerative disorder studied from the beginning of the 20 th century with
many unanswered questions so far. For many years, main attention was given to the white matter areas
and developing technologies and techniques that would further shed light to the mysteries of this disease.
Even though the implication of grey matter was originally noticed in the 1960s, it was at the beginning of
the 21st century, that its importance became greater and grey matter damage was found to be more
extensive and frequent than lesions in white matter. Attention to grey matter areas has enhanced as the
cognitive deficits that accompany multiple sclerosis much more often than wan initially assumed were
more linked to it. This report presents evidence of the molecules in grey matter areas that underlie the
cognitive impairment in multiple sclerosis.
Glossary: Multiple sclerosis = MS, Central nervous system = CNS, Relapsing-remitting MS = RRMS,
Secondary progressive MS= SPMS, primary progressive MS = PPMS, Progressive-relapsing MS =
PRMS, Magnetic resonance imaging = MRI, Cognitive impairment = CI, information processing = IPS,
long term potentiation = LTP, Alzheimer’s disease = AD, Parkinson’s disease = PD, corpus callosum =
CC, neurofilament = Nf.
Introduction
Multiple sclerosis is a debilitating inflammatory-mediated demyelinating disease of the human
central nervous system. The name multiple sclerosis refers to scars (better known as plaques or lesions)
partially found in the white matter of the brain and spinal cord. The myelin sheaths around the axons are
damaged leading to demyelination as well as a broad spectrum of signs and symptoms (Compston &
Coles., 2008) which vary depending on the stage of the disease. The disease onset usually occurs in young
adults, targeting women more than men (Compston & Coles., 2008) and affects more than two million
people worldwide (Hauser & Oksenberg, 2006; Noseworthy, 1999; Noseworthy et al., 2000; Trapp &
Nave, 2008; Weinshenker, 1998).
The patterns of the disease have led to its classification in four clinical courses: 1) relapsingremitting MS, 2) secondary progressive MS, 3) primary progressive MS and 4) progressive-relapsing MS.
The majority of the patients (85%) belong in the first clinical course, where they experience unpredictable
episodes of neurological disability followed by remissions that can last months to years without sign of
disease disability (Hauser & Oksenberg, 2006; Noseworthy, 1999; Noseworthy et al., 2000; Trapp &
Nave, 2008). The secondary progressive disease course (sometimes called ‘galloping MS’) is
characterized by steady neurological decline (Noseworthy et al., 2000; Trapp and Nave, 2008
Weinshenker et al., 1989) where occasional relapses and minor remissions may appear (Lublin &
Reingold, 1996). The time that intervenes between the disease onset and conversion from PP-MS to SPMS is 25 years for the 90% of the MS patients. Primary progressive MS is characterized by the steady
decline in neurological function without recovery. The age onset of PP-MS is around 40 years. A very
small percentage of patients (5%) belongs to the last clinical course, PR-MS which prevents a steady
neurological decline but also suffer superimposed attacks.
Multiple sclerosis has been classified as a white matter disease although later studies (Dawson,
1916; Brownell & Hughes, 1962) have shown that grey matter areas are affected. White matter atrophic
areas, studied with MRI techniques can explain some of the physical characteristics of MS patients like
epilepsy and depression. However, memory and attention impairment along with reduced information
processing are abilities controlled by grey matter brain areas that are affected in 45-65% of MS patients
(Rao et al., 1991; Rao et al., 1995).This evidence makes the implication of grey matter even more
important.
Cognitive impairment is a well-known consequence of MS acknowledged since the early
description of MS (Charcot, 1877). It affects roughly 50% of the patients especially in the domains of
memory and information processing and it can develop at any time during the course of the disease in the
presence or absence of neurological disability. Among the cognitive impairments that patients manifest
are also bradyphrenia, impaired abstract thinking and concentration and language deficits (Rao et al.,
1991; Newman,2001). Many brain areas, during MRI examination, show grey matter demyelinationthalamus, hippocampus, caudate, putamen, globus pallidus, frontal and temporal cortex, cingulate gyrus,
hipothalamus, substantia nigra, amygdala and spinal cord grey matter (Kutzelnigg et al, 2005; Gilmore et
al, 2009; Vercellino et al., 2005; Kutzelnigg et al, 2007; Geurts et al,2007; Huitinga et al., 2001; Gilmore
et al., 2006). Although improved imaging techniques have opened up the possibility to study grey matter
abnormalities in greater detail, not much is known about the underlying molecular mechanisms that lead
to gray matter damage and associated cognitive deficits.
The aim of this study is therefore to investigate the molecular basis of cognitive decline in
multiple sclerosis and identify a possible correlation between affected brain areas that are important for
cognition and the molecules involved.
Cognitive impairment in multiple sclerosis
Cognitive impairment in multiple sclerosis is a known concomitant of multiple sclerosis affecting
45-65% of cases (Rao et al., 1991; McIntosh-Michaelis et al., 1991; LaRocca, 2000). During the course of
their lives, MS patients will experience CI at any time simultaneously to neurological disabilities.
Clinically, the effect of the disease on the individual differs depending on the stage of the disease. Among
the early beliefs about MS was that cognitive impairment appears several years after the disease onset,
manifesting itself as it has already progressed (Butler et al., 2009). However, this assumption has been
declined and it is clear that CI can present itself early in the disease process. Many patients diagnosed
with clinically isolated syndrome (CIS) indicative of MS, who also had abnormal MRI findings, in a very
early stage converted to a diagnosis of MS (Brex et al., 2002; Morrissey et al., 1993; Tintore et al.,2006)
showing that cognitive impairment can be early diagnosed (Feuillet et al., 2007; Achiron et al., 2003;
Callanan et al., 1989; Feinstein(a) et al., 1992; Feinstein(b) et al., 1992).
Neuroimaging studies have provided indications on the brain areas affected. And although white
matter was first reported to be affected, the last years more attention is given to grey matter. Memory
impairment, attention deficit, bradyphrenia, impaired abstract thinking, information processing and
concentration are appearing symptoms in MS because of grey matter damage. The importance of these
forms of cognitive impairment in everyday life is needless to be mentioned (Morrow et al., 2010).
Areas affected in cognitive impairment (imaging studies)
Structural neuroimaging techniques have revealed atrophic brain areas in MS patients.
Demyelination of axons in the cortical area is of importance as well as demyelination in the white matter
but so far it has not been feasible to assign precisely the brain regions to the features of cognitive
impairment presented in this disease (Moriarty et al., 1999; Lazeron et al., 2000; Rovaris et al., 2000;
Sokic et al., 2001; Spatt et al., 2001; Benedict et al., 2004; Feinstein et al., 2004). While studying MS,
many groups reported that in the tissue they examined (post mortem material), many if not all grey matter
areas exceeded in total the white matter volume of demyelination found in SPMS patients (Bo et al., 2003
(a),(b); Geurts & Barkhof 2008; Hulst & Geurts 2011; Lublin & Reingold 1996; Gilmore et al., 2009). So
far though, grey matter demyelination seems to be better explaining cognitive deficits like memory
impairment and attention deficits. Patients with cognitive decline have more cortical damage than
cognitively preserved patients (Amato et al., 2004; Amato et al., 2007), proof that underscores the
previous statement. Cortical atrophy is progressive in MS patients and follows a course different than that
observed in normal aging. It is more prominent in areas that have extensive connections like the
cingulated gyrus and insular, temporal, frontal and parietal cortices (Charil et al., 2007).
The neocortex is one of the first regions where grey matter lesions were classified in four
different categories. Type I which is mixed white-grey matter lesion and types II, III and IV intracortical
lesions (Bö et al.,2003 a,b; Geurts et al., 2007). Volume reduction in the neocortex is linked to cognitive
performance that distinguishes cognitively preserved patients and those with cognitive impairment
(Benedict et al., 2007).
Apart from neocortex and other neocortcal areas, like motor cortex, frontal, temporal and parietal
cortex, other deep gray areas like thalamus, caudate, putamen, globus pallidus, amygdala, hypothalamus,
hippocampus, substantia nigra and spinal cord grey matter, show demyelination too (Kutzelnigg et al.,
2005; Gilmore et al., 2009; Vercellino et al., 2005; Kutzelnigg et al., 2007; Geurts et al., 2007; Huitinga
et al., 2001; Gilmore et al., 2006).
The hippocampus is a main region for the formation and retrieval of memories through a series of
events. It is a region well studied in MS because it is affected by demyelination in a subsequent
progressive stage of the disease. In a subgroup of patients studied by Dutta (2011), low white matter
lesion load in addition to minimal physical disability, was an indicator that demylination in the
hippocampus can lead to memory dysfunction. Magnetic resonance imaging measures correlated
increased hippocampal atrophy to memory dysfunction (Roosendaal et al., 2008). Demyelination in the
area was found in 53% to 79% in post mortem tissue with significantly decreased synaptic density (Dutta
et al., 2011).
Atrophy and enlargement of ventricles of corpus callosum is linked to cognitive dysfunction in
MS (Tsolaki et al., 2004; Clark et al., 2002; Comi et al., 1993). Although a white matter structure, it
connects grey matter areas, having therefore importance to cognitive deficits. Atrophy and axonal
integrity is related to speed of information processing, semantic fluency and sustained attention, features
impaired in this disease (Cristodoulou et al., 2001). Patients who suffer from these kinds of lesions
present decreased information processing speed (Rao et al., 1991), impaired verbal fluency (Pozzilli et al.,
1991), visuospatial difficulties (Ryan et al., 1996) and sign of interhemispheric disconnection (Huber et
al., 1987). In a detailed study conducted by Swirsky-Sacchetti, the authors tried to correlate the
neuropsychological characteristics with different kind of measures of the lesion area in corpus callosum
(size of the corpus callosum in frontal, temporal, and parieto-occipital regions, where it was cognitively
functional, total lesion area etc.). The total lesion area was the strongest predictor of cognitive
impairment. In addition to that, the left frontal lobe was related to memory, word fluency and abstract
problem solving deficits. Verbal learning and visuospatial skills were predicted from the left parietooccipital lesions (Swirsky-Sacchetti et al., 1992). In another four year study (Sperling et al., 2001), the
authors tried to link the correlation between the lesion burden and the cognitive performance in a group of
patients. Most of the lesions related to complex attention and verbal working memory were found in the
frontal and parietal white matter.
Info processing speed is also another primary cognitive deficit in MS regulated most likely by the
basal ganglia and the thalamus. Compared to normal controls the volume of the two areas shows
significant reduction (Houtchens et al.,2007; Benedict et al., 2009). The study of Batista (2012), is the
first one to show that each area affects independently and predicts the IPS deficit.
Left frontal cortical atrophy has been linked to performance on verbal memory tests and right
frontal atrophy to visual memory deficits and working memory. Cognitive status of patients is also linked
to the width of the third ventricle (Benedict et al., 2004).
Molecules related to cognitive decline: comparison to Alzheimer’s and Parkinson’s disease
Given the fact that 30-40% of patients demonstrate memory impairment, the hippocampus region
related to memory was investigated. Among the studies conducted so far, the one by Dutta (2011) can
answer the question of which molecules are involved in cognitive impairment in MS to a large extent.
Although the molecular basis of this aspect hasn’t been defined so far, many changes occurring in MS
brain tissue are especially attributed to the hippocampal region. Molecules involved in synaptic plasticity,
synaptic integrity, axonal transport and memory and learning formation are affected.
Comparing morphological and molecular changes, Dutta (2011) found that in more than half of
the patients, the demyelination was extensive. Neuronal density was decreased by 10-20% in some of the
investigated areas but axonal densities were similar in myelinated and demyelinated hippocampi. Among
the genes found to be changed in demyelinated MS hippocampi, the mRNAs that encode neuronal
proteins related to memory function and synaptic integrity were altered.
The major microtubule motor in charge of fast anterograde axonal transport KIF1A was
decreased at the mRNA and protein levels along with KIF3A, KIF15, KIF5B and KIF5C. Kinectin
(KTN1), important for kinesin- driven vesicle transport was reduced in the protein level.
The synaptic vesicle proteins synaptophysin and synaptotagmin that are related to KIF1A were
also reduced in demyelinated tissue. Synaptostagmin is a calcium sensor in the regulation of
neurotransmitter release and hormone secretion. Synaptophysin has been studied in more detail in mice,
where its elimination lead to reduced spatial learning and impaired novelty recognition (Schmitt et
al.,2009). The above evidence show that proteins essential for anterograde and retrograde axonal transport
are negatively affected. Similarly to this, in a study by Reddy (2008), the levels of presynaptic protein,
synaptophysin, were decreased in Alzheimer’s patients and in another study by 77% (Sze et al., 1997) in
the hippocampus. This protein is indeed involved in the progression of AD in areas linked to the
magnitude of memory impairment and most likely plays a role in multiple sclerosis (Sze et al., 1997).
It has also been found that cognitive dysfunction is enhanced by synaptic pruning that leads to
reduced long term potentiation (Neves et al., 2008). LTP is a long-lasting enhancement in signaling
between neurons and believed to form the cellular basis of learning and memory formation (Bliss et al.,
1993). Demyelinaton in the hippocampus leads to a decrease n the number of synapses in MS tissue. To
be more precise, molecules that help contact between pre- and post- synaptic specializations (Sudhof
2008) like neurexins and neuroligins are significantly decreased in demyelinated tissue. Proteins directly
related to them, PSD95 and CASK, were also decreased at the protein and mRNA level. The above
evidence shows that loss of myelin leads to changes in the number and formation of synapses.
Reduced glutamate receptors and transporters were also found in the Dutta study. Reduced
mRNAs for AMPA1 and AMPA3 receptors, NMDAR2A, 2B, 2C, 2D, and 3B subunits and MGLUR1,
MGLUR2, MGLUR3, and MGLUR4 metabotropic receptors were noticed. Glutamate neurotransmission
is also affected in demyelinated hippocampi. Apart from the internal regulation of glutamate, the
extracellular compartment is affected as well. Glutamate synthetase that removes glutamate from the
synapse and recycles it by metabolism is decreased as well as the glutamate transporters EAAT1 and
EAAT2.
Continuing the hippocampal investigation, differences were found in the cholinergic
neurotransmitter system in MS hippocampus. The cholinergic neurotransmitter system plays an important
role in the process of learning and memory (Drachman & Leavitt 1974; Everitt & Robbins 1997) and the
hippocampus is a major region of cholinergic input from the basal forebrain (Mesulam, 2004). The
activities of the enzyme choline acetyltransferase (ChAT) as well as its absolute protein levels were
decreased in contrast to the degrading enzyme acetylcholinesterase (AChE), which was unaltered.
Compared to controls the ChAT activity was reduced by 43% in MS hippocampi and by 45% in AD
hippocampi. In MS patients the ChAT immunoreactivity decreased by 80% in CA4, in CA3-2 by 57%
and in CA1 by 59%. On the other hand in AD patients it was decreased by 92% in CA4, by 81% in CA32 and in CA1 by 85%. The AChE activity was found unaltered in CA4 and CA1 but there were no
differences found in AChE protein expression in MS and control hippocampus. These findings of Kooi
(2011), reveal a selective imbalance in the MS hippocampal area.
In relation to other neurodegenerative diseases, Parkinson’s patients with dementia seem to be
suffering from extensive reduction of choline transferase and less extensive reductions of AChE in the
temporal neocortex, correlated with the degree of mental impairment. Alzheimer- type dementia has
almost identical cortical cholinergic biochemical activities but different neocortical involvement. The
nucleus of Meynert in AD is accompanied by neurofibrillary tangles and senile plaques whereas neuronal
loss is regularlyshown in PD (Perry et al., 1985).
Decreased glucose metabolism has been associated with a reduced cognitive index in MS
patients. Using positron emission tomography (PET) scan to measure regional cerebral glucose
metabolism (rCMRglc), Paulesu (1996) screened a group of MS patients. Patients with memory deficits
showed bilateral reduction of rCMRglc in the hippocampus, cingulated gyrus, thalamus, associative
accipital cortex and cerebellum. MS patients with memory impairment had significantly reduced global
CMRglc compared to normal controls but not when compared to MS patients whose memory was intact.
Between the memory impaired and unimpaired patients, the first had significant reduction of rCMRglc
bilaterally in the hippocampus and in the left thalamus and there was a trend of significance also in the
right thalamus.
As a region of interest, corpus callosum was also studied in relation to cerebral metabolic rates of
glucose (Pozzilli et al., 1992). Cerebral metabolic asymmetries were associated to CC asymmetry. MS
patients with CC atrophy have a left predominant hypometabolism indicating a more enhanced
involvement of the left hemisphere. Controls as well as MS patients without CC atrophy did not present
this type of metabolism, leaving evidence that it is an index of CC atrophy.
A variety of factors can regulate LTP by interfering between receptors in excitatory synapses
(Bliss & Collingridge, 1993; Malenka, 2003; Feldman, 2009; Kessels & Malinow, 2009; Minichiello,
2009). The isoform amyloid-β1–42, from amyloid-β , aggregates in oligomers that impair synaptic
plasticity mechanisms (Klyubin et al, 2005; Shankar et al, 2008; Walther et al, 2009; Townsend et al,
2010). Aβ is the main component of amyloid plaques, found in the brains of AD patients. A number of
studies, animal, biochemical and cell biology support the idea that Aβ plaques play a central role in AD
pathology (Ghiso and Frangione 2002; Selkoe, 2001). This isoform was consistently found to be reduced
in the CSF of AD patients and combined to its so far known implication in LTP, was studied in MS
patients (Mori et al., 2011). In their research, the authors claimed that acute inflammation in MS,
interferes with amyloid-β1–42 or τ metabolism, like in AD and subsequently is linked to cognitive function
and synaptic plasticity. In animals, cognitive performances and LTP induction are altered because of
amyloid-β and τ metabolism (Oddo et al, 2003; Klyubin et al, 2005; Rosenmann et al, 2008; Shankar et
al, 2008; Polydoro et al, 2009; Walther et al, 2009; Townsend et al, 2010), however in humans that option
had not been investigated. What was found in fact was that amyloid-β1–42 levels were significantly lower
in CSF patients with Gadolinium-enhancing (Gd+) lesions, showing an altered metabolism. The domains
that were linked to these altered levels were attention, concentration and information processing speed,
cognitive areas primarily known to be affected in MS. The evidence of low amyloid levels, combined to
Gd+ lesions that were associated to poor PASAT (Paced Auditory Serial Addition Test) performance
(Bellmann-Strobl et al, 2009) is an indication of the amyloid implication in synaptic plasticity. As a
candidate regulator of plasticity in the human brain, amyloid-β may important to understand the
mechanisms of cognitive impairment in MS.
Another category of proteins that have been implicated in MS are cytokines. Although the
complex interactions that occur among them haven’t made clear their role in cognitive decline, those that
worsen cognition are increased in SPMS and those that help cognition are reduced in SPMS
(http://www.msforumonline.net/Site/News/default.aspx ). As reviewed in Haase & Faustman (2007), the
network created by cytokines has been mainly studied in experimental autoimmune encephalomyelitis
(EAE) and in human MS (Ackerman et al., 1998; Arnason, 1995). Even though MS is considered a
demyelinating disease, it is also a T-cell mediated autoimmune disorder, influenced by cytokines. Tumor
necrosis factor (TNF) alpha and interferon (IFN) gamma are secreted by activated T-helper cells (CD4+)
of Th1- phenotype, affecting oligodendrocytes cytotoxically (Banks et al., 2002).Increased TNF-alpha
levels were linked to relapses in MS patients (Banks et al., 2001) and to physical disability (Besedovsky
& del Rey, 2002). The anti-inflammatory aspect of the disease includes also the implication of cytokines
(Ackerman et al., 1998; Arnason, 1995, Callanan et al., 1989; Cazullo et al., 2003) suggesting a complex
interaction within this group of cytokine proteins. INF-gama, TNF alpha, IL-1 alpha/beta and IL-6 have
been found to be mediating cognitive skills in animal models. Spatial memory has been linked to elevated
IL-1 beta (Pugh et al., 1999) and treatments with it lead to disturbed spatial and non-spatial learning and
memory (Larson & Dunn 2001). IL- 1 alpha application in animals lead to extensive changes in the
hippocampus and was identified as specific for learning during memory consolidation (Depini et al.,
2004; Schneider et al., 1998). Other cytokines were able to determine the extend behavior and cognition
in animals (Haddad et al., 2002). In humans these cytokines were regarded as responsible for the sickness
and malaise provoked to the patients but not necessarily for cognitive deficits (Haase & Faustmann, 2004;
Kühlwein & Irwin, 2001).
There is evidence that neurofilaments are also involved in multiple sclerosis. They are abundant
axon- and neuron- cytoskeletal components involved in axonal transport and neuronal homeostasis (de
Waegh et al., 1992; Petzold, 1995). According to Kuhle and co-workers (2011), NfHSMI35 protein in CSF
is increased in the course of the evolution of the disease. This increase is thought as an indicator of
accelerating neuronal damage reinforcing the utility of NfH as a biomarker (Kuhle et al., 2011). In order
to verify the involvement of neurofilaments in multiple sclerosis, cortical regions were correlated to the
proportion of neurofilaments, specifically hyperphosphorylated neurofilament- H, NfHSMI34. The
interesting point was that the increase was observed in both demyelinated and non-demyelinated cortex in
MS. The observation that the number of neuronal cells with NfHSMI35 in non-demyelinated cortical areas
is higher than in controls suggests the existence of other contributing factors outside the lesions,
enhancing the idea of neurofilament phosphorylation contributing to the dysfunction of neurons to the
progression of the disease (Gray et al., 2012).
Disease
Region(s) studied
Results
Dutta et al.,
2011
MS
HP
Hippocampal
demyelination leads to
synaptic alterations
Reddy et
al.,2005
AD
Frontal and
parietal cortices
Sze et al.,
2007
AD
HP, entorhinal
cortex, caudate
nucleus, occipital
cortex
Kooi et al.,
2011
MS, AD
HP
Perry et al.,
1985
AD, PD
All four cortical
lobes
MS
HP, cingulate
gyrus, thalamus,
associative
occipital cortex,
cerebellum
Possible relation
between function of
post- and presynaptic proteins to
cognitive impairment
in AD
Synaptic
abnormalities in HP
correlate with the
severity of memory
deficits in AD patients
MS cholinergic
imbalance in HP can
be used for future
treatment options
Degeneration of the
cholinergic neurons
may have a direct or
indirect relation to
cog.decline in PD
Hypometabolism in
thalamic and deep
cortical gray
structures is
associated with
episodic memory
dysfunction in MS.
Paulesu et
al., 1996
Number and type of
patients
investigated
Postmortem tissue of
22 MS patients and 9
CP
Techniques
used
Involved
pathways
qRT-PCR
Western blot
Glutamate
pathway
Western blot
Immunohistochemistry
Synaptic
plasticity
Immunoblotting
Synaptic
plasticity
Enzymes: choline acetyltransferase (ChAT),
acetylcholinesterase (AChE)
Immunohistochemistry
Cholinergic
pathway
Enzymes: choline acetyltransferase (ChAT),
acetylcholinesterase (AChE)
Biochemical analysis
Cholinergic
pathway
MRI (1.5T)
Glucose
metabolism
Involved molecules or substances
Axonal transport proteins: KIF1A, KIF3A, KIF15,
KIF5B, KIF5C, KTN1
Synaptic vesicle proteins: ( pre-)synaptophysin,
(pre-) synaptotagmin
Synaptic CAM: neurexins, neuroligins
Synaptic density proteins: PSD95, CASK
Glutamate receptors: AMPA1, AMPA3,
NMDAR2A, 2B, 2C, 2D, 3B subunits, MGLUR1,
MGLUR2, MGLUR3, MGLUR4
Glutamate synthetase
Glutamate transporters: EAAT1 EAAT2.
Postmortem tissue of
18 AD patients and
18 CP
Synaptic vesicle proteins: (pre-)synaptophysin
Synaptic density proteins: PSD95, synaptopodin
Postmortem tissue of
2 AD patients and 13
cognitively intact
and possible AD
patients
Postmortem tissue
from 15 MS patients,
10 AD patients and
10 CP
Postmortem tissue
from 8 AD patients,
14 PD patients and 8
CP
Synaptic vesicle proteins: (pre-)synaptophysin
16 RRMS, 12SPMS
patients, 13 and
10CP
Glucose
[ F]FDG PET
18
Pozzilli et
al., 1992
MS
Corpus callosum
(CC)
Mori et al.,
2011
MS
CSF
Haase and
Faustman,
2007
EAE,
MS
HypothalamusPituitary-Adrenal
(HPA)-Axis
Kuhle et
al., 2011
MS
CSF
Gray et al.,
2012
MS
Cerebral cortex,
white matter
Left hemisphere
hypometabolism
indicates a higher
involvemet in corpus
callosum atrophy in
MS
Central inflammation
in MS can alter
amyloid-b metabolism
leading to impairment
of synaptic plasticity
and cognitive
function.
Review on the current
scientifically based
experimental and
clinical data of
neuroimmunological
influences on
cognition and vice
versa in MS.
NfH levels can be
used to measure the
neurodegeneration
rate in MS
MS is associated with
the widespread
accumulation of
hyperphosphorylated
neurofilament protein
SMI35
8 patients with CC
atrophy, 8 patients
without CC atrophy
and 10CP
Glucose
PET
Glucose
metabolism
30 RRMS, 5 PPMS
and 7 CIS patients
amyloid-β1-42
t protein
MRI
TBS
Amyloid-b
downregulation
τ-metabolism
Mainly mouse and
rat tissue
Cytokines: INF-gama, TNF alpha, IL-1 alpha/beta
and IL-6
Immunohistochemistry
Cytockine
network
63 CIS, 39 RRMS,
25 SPMS, 23 PPMS
and 73 CP patients
NfHSMI35
Electrochemiluminescence
immunoassay
Cytoskeleton
regulators
17 SPMS, 2 PPMS, 2
PRMS, 2 RRMS, 2
of unknown MS
course and 17 CP
NfHSMI34
Immunohistochemistry
Cytoskeleton
regulators
Table: Summary of all known molecules involved in cognitive impairment and possible pathways.
Abbreviations:
AD : Alzheimer’s patients, , CAM : cell adhesion molecules, CASK: calmodulin-associated serin/threonine kinase, CIS: clinically isolated syndrome, CP: control patients,
[18F]FDG PET: 18F-fluorodeoxyglucose positron emission tomography, HP: hippocampus, MRI: magnetic resonance imaging, MS: multiple sclerosis, Nf: neurofilament,
PPMS: primary progressive multiple sclerosis, PRMS: progressive-relapsing multiple sclerosis, PSD95: post-synaptic density protein, RRMS : relapsing-remitting multiple
sclerosis,
SPMS :
secondary-progressive
multiple
sclerosis,
TBS:
θ
burst
stimulation
Pathways involved in multiple sclerosis
Synaptic connections between neurons represent the ‘wiring’ that exists in the brain circuitry.
Connectivity between neurons is the basic element of brains function that mediates all known
neurological functions, learning, memory, etc. Changes in synaptic activity transmission occur because of
different forms of plasticity. In order to consolidate short-term memories into long-term memory,
synaptic plasticity undergoes changes. LTP is a process that produces a long-lasting increase in synaptic
strength, contrary to LTD that produces a long lasting decrease in synaptic strength (Kandel, 2001). Both
patterns have different molecular and cellular mechanisms and the brain region that seems to be more
important, the hippocampus, is importantly affected. Lesions there prevent the acquisition of new episodic
memories. Additionally, synaptic plasticity is a prominent feature of hippocampal synapses. Knowing this
background, the correlation between the necessity and sufficiency of synaptic plasticity and acquisition of
new information has been validated (Neves et al., 2008).
For this reason, and based on the studies presented in the previous sections, it is my belief that the
pathways involving synaptic plasticity as well as the neurotransmitters involved should be better studied
in multiple sclerosis.
Glutamate is the most important neurotransmitter for normal brain function. Almost every
excitatory neuron is glutamatergic and over half of all synapses release this neurotransmitter. This
predominance has lead to so much attention as a prominent target to study many related
neuropathological conditions like anxiety, epilepsy and neurodegenerative diseases. Many CNS diseases
have a complex etiology and neuronal dysfunction is normally attributable to a combination of defects
involving usually excitatory (or inhibitory) neurotransmission. The general model of signal transmission
at a chemical synapse in the glutamate pathway includes AMPA, NMDA and kainite receptors. All three
are glutamate gated cat ion channels that allow the inflow and outflow of Na+ and K+. For the same reason
Ca2+ channels would be expected to be implicated in the MS pathology as they are a key element in the
vesicle fusion. Key enzymes synthesize glutamate which is then transported in synaptic vesicles. When
glutamate is released it activates glutamate responsive ion channels initiating downstream G protein
signaling to propagate neurotransmission. An important feature of these receptors that are involved is the
ability to traffic in and out of synapses. Synaptic plasticity events occur because of the addition or
removal of receptors from synaptic membrane (Kandel, 2001).
In the case of multiple sclerosis recent studies (Dutta et al., 2011) have provided us with evidence
that demonstrate dysregulation in this pathway. Glutamate receptors mediate most of the excitatory
synaptic transmission; therefore, reduced levels of mRNAs indicate an obvious dysfunction that could
pose in a long-term scale, a therapeutic target in clinical interventions. So far, development of glutamate
receptor subunit knockout mice has provided the link between specific types of memory that depend on
different glutamate receptor subtypes (Bannerman, 2009). For example, GluA1 AMPAR subunitknockout mice, researchers detected memory mechanisms for short-term memory as well as for memory
working tasks (Schmitt et al., 2003; Schmitt et al., 2005). Respectively, similar techniques have been
employed to find possible existing links of NMDA receptors and different forms of memory. Their
regulation and trafficking plays an important role in many forms of plasticity.
The cholinergic system has also been linked to the MS pathology (Kooi et al.,2011). The
hippocampus as mentioned before is studied in memory function (Squire et al., 2004) given its known
importance in addition to its severely affected status in MS patients. Cholinergic neurons are involved in
neuropsychic functions, like memory, learning, arousal, sleep and movement. Their loss was observed in
AD (Perry et al., 1978; Whitehouse et al., 1982) as well as in other neurodegenerative diseases (Karson et
al., 1996; Mallard et al., 1999). Hippocampus is the main region that receives cholinergic input from the
basal forebrain (Mesulam, 2004) and in AD this malfunction has been recognized for some time now
(Bartus et al., 1982; Davies & Maloney, 1976; Francis et al., 1999; Henke & Lang, 1983; Perry et al.,
1978; Sims et al., 1983; Wilcock et al., 1982). According to Kooi (2011), the directly implicated enzymes
in the cholinergic pathway present differences in MS and AD and although more evidence exist in AD, it
is possible that the cholinergic neurotransmitter system in MS may show similar changes.
Conclusion
The current report presents the so far known evidence that have surfaced to answer at some level
the possible underlying molecular mechanisms in the cognitive aspect of multiple sclerosis. The body of
evidence that highlight the grey matter implication is growing with the help of the existing techniques.
The cognitive symptoms and signs present the side of the disease that has been linked to grey matter brain
areas in contrast to its first classification as a white matter disease. Unfortunately the mechanisms that
create this inter individual variation in grey and white matter pathology haven’t been discovered. The
answer to the MS etiopathogenesis would be a major step in towards its treatment. According to the
evidence presented previously it is my belief that the pathways regulating synaptic plasticity as well as the
neurotransmitters involved can be of essence in the ongoing study in the scientific community. Areas
where atrophy is significant and demyelination affects cognitive behaviors have been studied although the
accumulation of more information for a better understanding is essential. The neocortex, the
hippocampus, the grey matter of the spinal cord are a few of the areas so far mentioned with more to be
investigated in the future. Memory impairment is a feature commonly seen in MS patients whose majority
has an affected hippocampus. The absence of many important enzymes, primarily observed in
hippocampal areas, make the hippocampus and the areas connected to it, important regions for future
investigation. The synthesis of neurotransmitters would be a nice additional pathway to be checked, as
glutamate and acetylcholinesterase are important for synaptic plasticity. It is well known that there have
been many advances in understanding multiple sclerosis, however that still hasn’t been enough. It is
reasonable to say that the need for applying strategies for controlling certain aspects of the disease is
among the most emergent goals. The need to understand the molecular mechanisms could encourage at a
significant level the efforts to approach future treatments.
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