Multiple Sclerosis and Related Disorders (2013) 2, 4–12

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REVIEW

Cognitive and neuropsychiatric disease manifestations in MS$ A. Feinsteina,n, J. DeLucab, B.T. Baunec, M. Filippid, H. Lassmane a

University of Toronto, Department of Psychiatry and Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada M5R 3B6 b Kessler Foundation Research Center, West Orange, New Jersey, USA c Department of Psychiatry, University of Adelaide, Adelaide, Australia d Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy e Center for Brain Research, Medical University of Vienna, Vienna, Austria Received 1 May 2012; received in revised form 25 July 2012; accepted 1 August 2012

KEYWORDS

Abstract

Multiple sclerosis; Neuropsychiatry; Neuropathology; MRI; Cognition; Depression

Multiple sclerosis is associated with a wide array of behavioral problems. This brief overview begins with a summary of the pathophysiology and treatment of MS. Thereafter, sections are devoted to psychiatric syndromes and cognitive decline linked to MS. The immune basis and brain imaging data associated with these changes are subsequently reviewed. The frequency and severity of these changes in mentation highlight the point that MS patients should, as part of their routine care, have access to psychiatrists, neuropsychologists and allied mental health specialists. & 2012 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Multiple sclerosis pathophysiology and current treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Neuropsychiatric disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.1. Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.2. Bipolar affective disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.3. Pathological laughing and crying. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.4. Anxiety disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

$ Anthony Feinstein, John DeLuca, Bernhard Baune, Massimo Filippi and Hans Lassman contributed equally to conceptualizing and writing the manuscript. The content of this manuscript was presented at the 24th ECNP meeting in Paris in 2011. The seminar had the above five speakers, each of whom appears on this manuscript having written sections corresponding to the individual talks given. n Corresponding author. Tel.: +1 416 480 4216; fax: +1 416 48 4613. E-mail address: [email protected] (A. Feinstein).

2211-0348/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2012.08.001

Cognitive and neuropsychiatric disease manifestations

4. 5.

6.

7.

1.

5

3.5. Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Cognitive dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Role of the immune system in cognitive dysfunction and neuropsychiatric disturbance in multiple sclerosis . . . . . 8 5.1. Interrelationship between the immune system and CNS function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.2. Inflammation and neuropsychiatric symptoms in MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.3. Inflammation and cognitive impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.4. Biomarker in MS: Relevance for neuropsychiatric symptoms? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Pathological and MRI correlates of cognitive and neuropsychiatric disturbance in MS . . . . . . . . . . . . . . . . . . . 8 6.1. Pathological correlates of cognitive deficits in MS patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 6.2. MRI and cognition in MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 6.3. MRI and depression in MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Introduction

For a long time the concept prevailed that multiple sclerosis (MS) is a disease of the central nervous system, in which focal white matter lesions give rise to specific neurological deficits, which are dependent on lesion location. However, it was clear already from the earliest descriptions of the disease that the clinical spectrum of MS is much broader, including neuropsychiatric disease manifestations and cognitive disturbances (Charcot, 1880). Despite the accumulation or a large body of data on these issues during the last decade, they are still in part neglected in the daily management of the patients as well as in MS research. In particular, their pathological substrate and their pathogenesis are still poorly defined and evidence based guidelines for their treatment are sparse or absent. It is the aim of this review to describe the state of the art in this field and to highlight the areas, where future research efforts are needed.

2. Multiple sclerosis pathophysiology and current treatment Multiple sclerosis (MS) is a complex neurological disease, which in its early phases presents with a relapsing remitting course, which changes with increasing disease duration into a progressive stage with slow and uninterrupted neurological deterioration. A minority of patients lack the relapsing remitting disease phase, but develop a primary progressive course from the onset (Lublin and Reingold, 1996). MS is a chronic inflammatory disease of the central nervous system, which has originally been defined by the presence of focal demyelinating lesions with partial axonal preservation, which are randomly distributed throughout the brain and spinal cord (Lassmann et al., 2007). Current concepts suggest that MS is an autoimmune disease, mediated by T-lymphocytes, directed against various antigens of the central nervous system and in particular against the myelin sheaths (Hohlfeld and Wekerle, 2004). Focal demyelinated lesions are induced on the background of an inflammatory reaction, which is dominated by T-lymphocytes and activated macrophages and microglia. The mechanisms of demyeliation and tissue injury are complex and heterogeneous between patients (Lucchinetti et al.,

2000) and may involve direct T-cell mediated cytotoxicity, specific auto-antibodies and cytotoxic molecules, produced by activated macrophages and microglia. This plaque centered view of multiple sclerosis has recently been challenged in clinical studies as well as by new data obtained by magnetic resonance imaging and neuropathology (Lassmann et al., 2007). These data clearly show widespread demyelinated lesions in the cortex and deep gray matter and profound diffuse damage within the normal appearing white and gray matter (Kutzelnigg et al., 2005; Vercellino et al., 2009, Cifelli et al., 2002). Thus, multiple sclerosis is a disease, which in addition to the formation of focal white matter lesions also affects the brain in a generalized and diffuse manner. In addition, it is not the myelin sheath alone, which is the target of destruction, but axonal and neuronal degeneration is widespread and is a major culprit for irreversible clinical deficits in the patients (Bjartmar et al., 2000). Thus, inflammation starts the disease and triggers a cascade of events that lead to oligodendrocyte destruction, demyelination and neurodegeneration. This damage is counteracted by remyelination in some MS patients, but these regenerative processes largely fail in the later chronic phases of the disease (Bramow et al., 2010). An alternative view suggests that there is an intrinsic neurodegenerative process in MS, which is superimposed and possibly aggravated by the inflammatory reaction. In support of this view inflammation has been described to be absent in initial stages of MS plaques (Barnett and Prineas, 2004), and in patients with progressive disease clinical deterioration and neurodegeneration occurs in the absence of Gd-enhancing lesions or an effect of anti-inflammatory treatments. In addition there are animal models of genetic demyelinating diseases, in which inflammation in the lesions aggravates tissue injury (Trapp and Nave, 2009). However, in MS brains active demyelination and neurodegeneration is invariably associated with inflammation, even in initial stages of lesion formation (Frischer et al., 2009), and recent genome wide association studies did not find evidence for a link between MS and genetic mutations related to demyelination or neurodegeneration (International Multiple Sclerosis Genetics Consortium (IMSGC), 2010). Current treatments of MS mainly target the inflammatory response and their efficacy is well documented in large

6

A. Feinstein et al.

multicenter trials (Lutterotti and Martin, 2008; Giacomini et al., 2009; Wiendl and Hohlfeld, 2009). Currently the basic therapy includes high dose steroid treatment of disease relapses and immunomodulatory treatment with either ß-interferons or glatiramer acetate. These treatments have a moderate effect on relapse prevention in the absence of major side effects. Escalating immunotherapies have been developed and tested during the last decade, which include antibodies against global T- and B-lymphocytes (anti-CD56, Capath H) or B-cells (anti-CD20, Rituximab). In addition other treatments block the egress of T-cells from the lymph nodes (Fingolimod) or the migration of inflammatory cells through the blood brain barrier (anti-a4 integrin, Natalizumab). Alternatively, global immunosuppression with mitoxantron or cyclophoshamide is also effective in relapse prevention. These second line therapies, in particular the treatments with Natalizumab, Campath H or Fingolimod, seem to be more effective compared to the first line treatments, but this occurs in part at the expense of more serious side effects. An example is the appearance of progressive multifocal leukoencephalopathy, a serious papova virus infection of the central nervous system, which occurs in a small subset of patients treated with Natalizumab. All of the current therapies, targeting the immune system are effective in the relapsing remitting stage of the disease, but they lose their beneficial effects, when patients have entered the progressive phase of the disease. The reason for the lack of efficacy in progressive MS is currently unknown, but one mechanism, which may be involved, is that in the late stages of MS inflammation becomes trapped at least in part within the central nervous system behind a closed or repaired blood brain barrier (Serafini et al., 2004; Hochmeister et al., 2006).

3.

Neuropsychiatric disorders

Multiple sclerosis is associated with a range of behavioral disorders in addition to cognitive dysfunction. These include depression, bipolar affective disorder, anxiety disorders, euphoria, pathological laughing and crying and psychosis. This brief review will discuss the essential clinical features, prevalence rates and treatment options for each of these conditions.

3.1.

Depression

The most common behavioral disorder is major depression which has a lifetime prevalence approaching 50% (Sadovnick et al., 1996). This figure, which is derived from tertiary referral clinics, is supported by community based data, where the 12 month prevalence of 25% exceeds that of other disabling neurological conditions (Patten et al., 2003). The syndrome can present a diagnostic challenge because certain symptoms such as insomnia and fatigue may be attributable directly to MS rather than the depression. To offset these potential somatic confounders, self report rating scales have been developed for use in a general medical context where the emphasis falls on the presence of depressive cognitions (guilt, hopelessness) in addition to the sadness. Two of these self report instruments have been validated for use with MS patients, namely the Hospital Anxiety and Depression Scale (Zigmond and Snaith, 1983;Honarmand and Feinstein, 2009)

and the Beck Fast Screen (Beck et al., 2007; Benedict et al., 2003). While undoubtedly useful as screening instruments in a busy clinic or as part of a clinical trial, no self reporting rating scale in psychiatry is able to provide a formal diagnosis. Major depression is one of the main determinants of quality of life in MS patients (D’Alisa et al., 2006) and when severe may also adversely affect cognition (Arnett et al., 1999). The deleterious consequences of depression are further underscored by the close association with suicidal intent. One third of MS patients harbor the thought of suicide at some point in their disease (Feinstein., 2002). Allied to this finding the suicide rate in MS patients is twice that found in the general population (Stenager et al., 1992). For all these reasons, detection and treatment are important, but data show that the disorder is frequently overlooked or under treated in a busy neurological out-patient setting. These oversights must be viewed against data showing that depression responds well to cognitive behavior therapy (Mohr et al., 2001), antidepressant medication (where side effects can limit the attainment of optimal dosage) (Ehde et al., 2008) and, if necessary, electroconvulsive therapy (Mattingley et al., 1992).

3.2.

Bipolar affective disorder

Bipolar Affective Disorder, formerly called Manic-Depressive Disease, is characterized by the triad of abnormal mood (elevated, irritable), grandiose or paranoid thoughts, and increased energy/activity. Bipolar, as the name suggests, can also encompass depressed mood, should patients present in the depressive phase. It occurs twice as often in MS patients than in the general population, and should be distinguished from the syndrome of euphoria, also called euphoria sclerotica (Cottrell and Wilson, 1926) a phenomenologically distinct entity more likely confined to patients with marked physical disability, significant cognitive compromise, and a heavy lesion burden and atrophy on brain MRI (Rabins et al., 1986). Euphoric patients are defined by a cheerful affect and an unrealistic optimism that recovery is likely notwithstanding their confinement to a wheelchair, for example. The prevalence rate has been estimated at 9% (Fishman et al., 2004). The syndrome is untreatable, unlike bipolar affective disorder, which may affect patients across the spectrum of disease severity, and which responds well to mood stabilising drugs like lithium carbonate and, where necessary, antipsychotic medication (Feinstein, 2007).

3.3.

Pathological laughing and crying

Pathological laughing and crying (also called pseudobulbar affect) may affect upto 10% of patients and may be broadly defined as tears without sadness and/or laughter without mirth (Feinstein et al., 1997). It is thought to arise from a disconnection of disparate, yet interconnected tracts that involve the motor cortex, dorsolateral and orbitofrontal cortices, sensory association areas, amygdala, cerebellum, and bulbar nuclei (Feinstein, 2007). The syndrome responds moderately well to an array of pharmacologic treatments that include tricyclic and selective serotonin reuptake inhibitor antidepressant and a recently developed compound that

Cognitive and neuropsychiatric disease manifestations contains dextromethorphan and low dose quinidine (Panitch et al., 2006).

3.4.

Anxiety disorders

Anxiety disorders have received scant attention in MS patients, which should not belie their clinical relevance, for data show elevated rates relative to the general population (Korostil and Feinstein, 2007). Moreover, anxiety in its various manifestations has been associated with suicidal intent and excessive alcohol consumption in MS patients (Quesnel and Feinstein, 2004). It is frequently found together with depression. To date there are no treatment studies of anxiety disorders associated with MS.

3.5.

Psychosis

Finally, prevalence rates of psychosis are also elevated in MS patients, with the 15–24 year age group particularly vulnerable (Patten et al., 2005). The phenomenology on an individual basis may be indistinguishable from schizophrenia, but as a group patients with neurologic disease who become psychotic have few of the negative features that characterize the defect state of schizophrenia, i.e. lack of volition, impoverished thought content, blunted affect. Thought disorder is likewise rare. Instead the psychosis is dominated by delusions and to a lesser extent hallucinations. There are again no RCT data on which to base treatment decisions. Isolated case reports suggest the newer antipsychotic drugs are to varying degrees effective.

4.

Cognitive dysfunction

Impairment of cognitive function is observed in upto 65% of persons with multiple sclerosis (MS), and significantly affects everyday life functioning such as employment, activities of daily living, social and family functions as well as overall quality of life. Cognitive impairment has been detected across all stages of the disease including its earliest manifestations (e.g., clinically isolated syndrome), tends to progress with time, and is most severe during the secondary progressive phase. Although the underlying pathophysiology of cognitive impairment in MS is complex and not well understood, it likely involves inflammation earlier in the disease, and with time progresses to more of a degenerative process in the brain later in the disease (Chiaravalotti and DeLuca, 2008). Impaired cognition occurs relatively independently of physical impairment, although both increase in severity with time. While the nature and severity of cognitive impairment varies markedly across individuals, the most frequently observed impairments are in the areas of slowed processing speed and episodic memory, followed by difficulties with executive functions. Predictors of cognitive decline include male gender, gray matter atrophy, early age onset, secondary progressive course, and low baseline cognitive reserve (Benedict and Zivadinov, 2011). History of higher intellectual enrichment has a protective effect resulting in less cognitive impairment despite the same degree of brain atrophy as MS patients with lower intellectual enrichment (Sumowski et al., 2010a).

7 Proper and early assessment of cognitive impairment is essential. However, the standard neurological examination is unlikely to be diagnostically sensitive. Impaired cognition can only be validly assessed with a neuropsychological assessment. Patient self report correlates more with emotional distress than actual cognitive impairment (see Chiaravalloti and DeLuca, 2008). Brief neuropsychological test batteries that are sensitive to primary areas of cognitive impairment observed in MS have been developed and include the Brief Repeatable Neuropsychological Battery and the Minimal Assessment of Cognitive Function in MS (Strober et al., 2009). A very brief cognitive assessment has been recently recommended by an international expert consensus committee (Benedict et al., 2012). While much has been learned about the nature of cognitive impairment in MS over the last 3 decades, very little published work exist concerning cognitive rehabilitation, with most studies suffering from significant methodological limitations (see O’Brien, 2008 for an evidence-based review). Ever since it was shown that impaired acquisition of new information (and not retrieval failure) is the primary problem in learning and memory in persons with MS (DeLuca et al., 1994), intervention studies have targeted improving learning efficiency. For example, several studies have shown that techniques employing self-generated learning, where patients generate the right answer versus being told what to remember, can significantly improve the learning of new information, and has been shown to significantly improve recall of everyday functional activity such as the recall of names, appointments and object locations as well as financial management and meal preparation (Goverover et al., 2008). Another targeted behavioral technique called spaced learning (or ‘‘spacing effect’’), where learning trials are spread over time rather than repeated consecutively, has also been shown to significantly improve everyday functional performance. Interestingly, a recent study found that utilizing both self-generation and spaced learning was better than a single intervention alone (i.e. spaced learning) resulting in almost 50% greater recall than the single technique alone (Goverover et al., 2011). Yet another technique known as the ‘‘testing effect’’ (also called retrieval practice) has also shown that targeted interventions can significantly improve learning and memory (Sumowski et al., 2010b). Simply being ‘‘tested’’ on verbal material that they were exposed to during a single previous learning trial resulted in learning almost twice the amount of verbal material than being given two opportunities to learn the same material. In a double-blind, placebo-controlled, randomized clinical trial (RCT), Chiaravalloti et al. (2005) demonstrated that training in using context and imagery to improve the strength of encoding resulted in significantly improved recall on neuropsychological testing as well as self-report of everyday activities (Chiaravalloti et al., 2005). Regarding rehabilitation of other cognitive functions, despite the fact that impaired information processing speed may be the most frequent cognitive impairment in MS, there are no behavioral studies specifically designed to improve processing speed in persons with MS. Although there is published work in the area of attention, overall results are somewhat contradictory and unclear. The work on executive functions tends to be more promising although there are only a handful of studies in this area.

8

5. Role of the immune system in cognitive dysfunction and neuropsychiatric disturbance in multiple sclerosis Inflammation and neurodegeneration are considered important mechanisms for depression and cognitive decline. An upregulation of inflammation (Sharief and Hentges, 1991) is assumed to be particularly relevant to the development of neuropsychiatric symptoms in MS. It is proposed that psychopathological symptoms in MS are potentially due to focal inflammatory damage, more general effects of an upregulated immune system, or widespread neurodegeneration or a combination thereof (Stadelmann, 2011).

5.1. Interrelationship between the immune system and CNS function The neurobiological interrelationship between the immune system and complex functions of the CNS such as memory and learning has been demonstrated in animal studies. A model of severe combined immunodeficiency (SCID) showing deficient B and T cells, demonstrated worse spatial learning and memory and on replenishment with T cells, SCID mice showed an improvement in cognitive tasks (Kipnis et al., 2004). Among the various inflammatory cells, Th1 (T helper cells), CD4+ cells that produce IL-17 are shown to be up-regulated in studies on murine experimental autoimmune encephalomyelitis (EAE) (Fletcher et al., 2010). During pathological conditions such as MS, microglia cells interact with neurons, possibly via P2  7 receptors, to induce a neuroinflammatory response characterized by an up-regulation of cytokines, such as, IL-1, IL-6 and TNF altering synaptic plasticity and learning and memory (McAfoose and Baune, 2009). In addition, chronic inflammatory conditions in the CNS may lead to pathological morphological changes such as gray matter hypointensities and associated iron deposition in basal ganglia as seen in multiple sclerosis (Brass et al., 2006) being associated with cognitive impairment and neuropsychiatric symptoms.

5.2. Inflammation and neuropsychiatric symptoms in MS Experimental administration of pro-inflammatory cytokines can induce symptoms such as weight loss, fatigue, sleep disturbances, motor retardation, dysphoria, anhedonia and impaired cognition resembling depression-like behavior (Capuron and Ravaud, 1999; McDonald et al., 1987; Rosenstein et al., 1999). Upregulated pro-inflammatory cytokines (IL-1, IL-6, TNF-a, etc.), acute-phase proteins, chemokines and adhesion molecules interact with mechanisms of depression such as serotonin (5-HT) metabolism by reducing tryptophan (TRP) levels. Cytokines activate indoleamine-2-3-dioxygenase (IDO), an enzyme which metabolizes TRP, thereby reducing serotonin levels. Furthermore, inflammatory cytokines, such as IL-1b, may reduce extracellular 5-HT levels, via activation of the serotonin transporter mechanisms (Baune, in press). In addition, pro-inflammatory cytokines have a potent direct effect on the hypothalamic–pituitary–adrenal

A. Feinstein et al. (HPA) axis which may be impaired in depression. Cytokines, including IL-1, IL-6, TNF-a and IFN-a, have been shown to increase inflammatory responses (Baune, in press). Taken together, pathological cytokine up-regulation in the CNS as observed in multiple sclerosis may interact with neurobiological mechanisms inducing symptoms of depression.

5.3.

Inflammation and cognitive impairment

Neurodegeneration has been implicated in the pathology of MS, especially the progressive forms of the disease (Stadelmann, 2011). A shared pathology of neurodegeneration between multiple sclerosis and Alzheimer’s disease (AD) lends evidence to support the view that common disease mechanisms are implicated in the development of cognitive decline in MS (Lassmann, 2011). Specifically, it is suggested that a disease-specific induction of microglia activation, reactive oxygen and nitric oxide intermediates leading to mitochondrial injury, axonal and neuronal injury, synaptic degeneration and Tau pathology are shared pathological features that may lead to oligodendrocyte apoptosis, demyelination and impairment of remyelination in MS and to amyloid plaques and neurofibrillary tangels in Alzheimer’s Disease (Lassmann, 2011). Not only is neurodegeneration relevant to cognitive decline, the neurobiological evidence to date suggests a role of similar neurodegenerative process in depression (Catena-Dell’Osso et al., 2011).

5.4. Biomarker in MS: Relevance for neuropsychiatric symptoms? Various biomarkers of inflammation in MS (e.g., complement regulator factor H, Serum antibody titer against Epstein– Barr virus nuclear antigen-1) (Farrell et al., 2009; Ingram et al., 2010) and axonal neurodegeneration (e.g., Cytoskeleton marker: e.g., Neurofilaments-L, Tau, Tubulin, Actin; membrane marker: e.g., APOE, 24S-hydroxycholesterol; neuron specific enolase) (Teunissen et al., 2005) have been previously reported without a clear association with cognitive decline and depression in MS. However, a recent study in MS revealed a potential biomarker for both cognitive decline ((HLA) DRB1 1501 allele associated with (k) brain volume, (m) WM lesions and (k) N-acetyl-aspartate) (Okuda et al., 2009) and depression (HPA axis hyperactivity with (m) evening cortisol; CD8+ T cells producing cytokines such as TNF, IFN-y) (Gold et al., 2011).

6. Pathological and MRI correlates of cognitive and neuropsychiatric disturbance in MS Magnetic resonance imaging (MRI) is instrumental to improve the understanding of the mechanisms responsible for the accumulation of cognitive and neuropsychiatric deficits in MS patients at different stages of the disease.

6.1. Pathological correlates of cognitive deficits in MS patients Unlike many of the neurological deficits, cognitive disturbances and neuropsychiatric symptoms in MS cannot be

Cognitive and neuropsychiatric disease manifestations related to single focal white matter lesions but rather reflect global functional disturbances or more diffuse brain injury. One potential correlate is the presence of multiple focal white matter lesions in strategic locations, which connect cortical areas important for information processing. Overall, however, the correlation between the number or total volume of white matter lesions with cognitive disturbances is weak (see below). Other potential culprits are demyelinated lesions in the cortex or diffuse injury of the normal appearing gray matter (Kutzelnigg et al., 2005). The vast majority of cortical lesions are characterized by widespread subpial demyelination. Such lesions are not randomly distributed but show a predilection for cortical areas, defined as the limbic circuit, areas which are of critical importance for cognitive information processing (Kutzelnigg and Lassmann, 2006; Geurts and Barkhof, 2008). Although such cortical lesions can be seen at all stages of the disease, their incidence and size increases with disease duration and they are, thus, most prominently present in the progressive stage of the disease. Interestingly, however, cognitive disturbances are frequent already in patients at the initial stages of the disease, in patients, where lesions in the white and gray matter are rare. New data suggest that they may be related to functional disturbances induced by the inflammatory process, for instance through the action of pro-inflammatory cytokines. A particularly important mechanism for neurodegeneration in MS, which recently emerged, is mitochondrial injury, induced by reactive oxygen and nitrogen species (Lassmann and van Horssen, 2011). Mitochondrial injury with subsequent energy deficiency could explain functional disturbances in the absence of structural brain lesions. Altogether, however, studies, which directly correlate cognitive disturbances in the living patient with post mortem pathology are virtually absent.

6.2.

MRI and cognition in MS

Seminal research found that in MS patients the global burden of T2-visible lesions in the brain white matter (WM) correlates with the performance on a wide variety of neuropsychological tests (Rao et al., 1989). Other studies demonstrated an association between lesion location (e.g., the frontal lobes, parieto-occipital lobes) and specific patterns of cognitive decline (Swirsky-Sacchetti et al., 1992; Arnett et al., 1994). More recently, Penny et al. (2010) showed that in patients with primary progressive (PP) MS baseline T2 lesion volume is the best MRI predictor of overall cognitive function and performance on tests of verbal memory and attention/speed of information processing after five years. Cortical lesions, demonstrated by double inversion recovery sequences have also been shown to be independent predictors of MS-related cognitive impairment (Roosendaal et al., 2009). In addition, correlations between MRI measures of brain atrophy and neuropsychological dysfunction have been shown to be more robust than with T2 lesion volume (Rovaris et al., 2006). Improvements in methods of analysis have allowed researchers to quantify the extent of tissue damage to the brain gray matter (GM) and WM both globally and regionally. Several cross-sectional and longitudinal studies have shown that GM atrophy is associated with cognitive impairment and

9 with its progression (Amato et al., 2004 and Amato et al., 2007). Using voxel-based morphometry (VBM), different patterns of regional GM atrophy were linked to cognitive impairment in MS patients with various clinical phenotypes (Riccitelli et al., 2011). Furthermore, the assessment of atrophy of strategic GM structures, such as the thalami, has been shown to contribute to explain deficits in selective cognitive domains (Houtchens et al., 2007). Several quantitative MR-based techniques, with the potential for an increased specificity to the more destructive pathological features of brain damage, have been applied to the study the normal-appearing brain tissues (NABT) of MS patients. A multivariate analysis of conventional and magnetization transfer (MT) MRI variables revealed that average MT ratio of the NABT is the factor most significantly associated with cognitive impairment (Filippi et al., 2000). Diffusion tensor MRI studies have also revealed that structural damage to strategic WM tracts helps explain overall cognitive impairment (Roosendaal et al., 2009; Dineen et al., 2009). fMRI studies demonstrate increased recruitment of selected cortical networks can preserve cognition (Mainero et al., 2004) while, conversely, their diminution may lead to a worsening of cognitive abilities (Penner et al., 2003). Recently, reduced fluctuations within the default-mode network have also been shown to occur in patients with progressive MS and cognitive impairment (Rocca et al., 2010). Intellectual enrichment has been demonstrated to protect against neurocognitive disturbances by better maintaining resting state activity during cognitive processing (Sumowski et al., 2010c).

6.3.

MRI and depression in MS

The presence and extent of T2 lesion in selected WM regions (prefrontal cortex, temporal lobe, arcuate fasciculus) have been associated with depression (Feinstein et al., 2004; Pujol et al., 1997; Berg et al., 2000). Other studies found that depressed, but not euthymic patients have more severe atrophy of the frontal and parietal lobes (Bakshi et al., 2000). Interestingly, a study which has estimated hippocampal subregional volumes has demonstrated that depressed MS patients experience tissue loss in the cornu ammonis 2–3 (CA2–CA3) and the dentate gyrus (Gold et al., 2010). Using diffusion tensor MRI, abnormal diffusivity indexes in the normal appearing WM and GM of the left temporal lobe have been found in depressed vs. non-depressed patients (Feinstein et al., 2010). Finally, using fMRI during processing of emotional relative to neutral stimuli, abnormal responses of the ventrolateral prefrontal cortex, and lack of functional connectivity between prefrontal areas and the amygdala were found in cognitively preserved RRMS patients, suggesting that local reorganizations might contribute to limit the clinical expression of emotional symptoms in MS (Passamonti et al., 2009).

7.

Conclusions

Cognitive disturbances and neuropsychiatric disease manifestations are common in MS patients and have a major negative impact on the patient’s quality of life. Thus, they need special attention in the daily clinical management of the patients. This implies that psychiatrists and neuropsychologists should

10 play a much more prominent role in patient care and disease research as it is the case currently. In addition, more efforts are needed to validate treatments of cognitive disturbances or neuropschiatric disease manifestation through controlled clinical trials.

Conflict of interest Dr. Feinstein has served on scientific advisory boards for Merck Serono and Avanir Pharmaceuticals; has received speaker honoraria from Merck Serono, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Biogen Idec; serves on the editorial boards of Multiple Sclerosis and the African Journal of Psychiatry; receives publishing royalties for The Clinical Neuropsychiatry of Multiple Sclerosis (Cambridge University Press, 2007); serves on the Medical Advisory Committee for the Multiple Sclerosis Society of Canada; conducts neuropsychiatric evaluation, cognitive testing, brain imaging in neuropsychiatry in his clinical practice (20% effort); and receives research support from Teva Pharmaceutical Industries Ltd., Merck Serono, Canadian Institute of Health Research, and the Multiple Sclerosis Society of Canada. Dr. J. DeLuca reports no disclosures. Dr. B. Baune reports no disclosures. Dr. M. Filippi serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd. and Genmab A/S; has received funding for  Genmab travel from Bayer Schering Pharma, Biogen-Dompe, A/S, Merck Serono, and Teva Pharmaceutical Industries Ltd.; serves as Co-Editor in Chief for Journal of Neurology; serves on editorial boards of the American Journal of Neuroradiology, BMC Musculoskeletal Disorders, Clinical Neurology and Neurosurgery, Erciyes Medical Journal, Journal of Neuroimaging, Journal of Neurovirology, The Lancet Neurology, Magnetic Resonance Imaging, Multiple Sclerosis, and Neurological Sciences; serves as a consultant to Bayer Schering  Genmab A/S, Merck Serono, and Pharma, Biogen-Dompe, Teva Pharmaceutical Industries Ltd.; serves on speakers  Genmab bureaus for Bayer Schering Pharma, Biogen-Dompe, A/S, Merck Serono, and Teva Pharmaceutical Industries Ltd.; and receives research support from Bayer Schering Pharma,  Genmab A/S, Merck Serono, Teva PharmaBiogen-Dompe, ceutical Industries Ltd. and Fondazione Italiana Sclerosi Multipla. Dr. H. Lassman reports no disclosures.

Role of funding source There was no funding for this paper.

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