Why is cognitive assessment important in multiple sclerosis?
Why it is important to do research in multiple sclerosis?
Cognitive deficits are common in individuals with multiple sclerosis, affecting up to 70% of patients. These cognitive symptoms are associated with loss of self-esteem and functional impairment3. Many different cognitive domains can be affected, reflecting the heterogeneous nature of the underlying white matter pathology3,4.
Commonly affected domains include psychomotor speed, sustained attention, memory and executive functioning. Severity of impairment can differ depending on whether the multiple sclerosis is Primary Progressive (PP) or Secondary Progressive (SP), with the former often manifesting itself with greater impairment4. Cognitive abilities can deteriorate over time and this often predicts loss of everyday functioning5.
What is multiple sclerosis?
Multiple Sclerosis (MS) affects around 2.5 million people worldwide. It is typically diagnosed between the ages of 20 and 30 and is nearly three times more common in women than in men1. It is characterised by damage to white matter sheathes (myelin) protecting neurons in the central nervous system, thought to be caused by autoimmune processes.
The condition can cause a myriad of symptoms, the most common of which include fatigue, limb weakness/numbness, tremor, gait difficulties, double-vision and other visual problems, difficulty speaking, and dizziness2.
In relapsing-remitting MS, people experience acute symptom attacks (onset over hours-days), with symptoms resolving gradually afterwards (partially, or fully). In secondary progressive MS, symptoms can develop more gradually and tend to persist. Both types of MS are associated with impaired quality of life and disability.
Diagnosis of MS requires specialist input, because it can be easily overlooked or mistaken for other conditions (and vice versa). In most cases, two or more symptom attacks separated in space (in terms of the brain regions affected), and in time, are necessary to meet the strict diagnostic criteria.
Currently available, licenced drug treatments for MS act as ‘disease-modifiers’, reducing the risk of new symptom attacks, typically by dampening aspects of the body’s immune response. Examples of disease-modifying medications listed by NICE for the treatment of relapsing-remitting MS under certain circumstances include alemtuzumab, teriflunomide, and fingolimod.
The search continues for well-tolerated pharmacotherapies capable of stemming disease progression and for ameliorating cognitive dysfunction in multiple sclerosis, representing a key unmet need.
Why is it important to do cognitive research in Huntingdon’s disease?
Cognitive deficits are common in individuals with Huntington’s disease, some of which are detectable up to ten years before formal diagnosis5. Our recommended test battery for Huntington’s disease is highly sensitive to these cognitive deficits in patients and also to cognitive deterioration over time, even in early disease7.
What is Huntingdon’s disease?
Huntington’s disease is an inherited, progressive neuropsychiatric condition associated with behavioural, cognitive, and motor difficulties¹. This can include involuntary jerking movements; difficulties in speaking, memory, and concentration; and the development of depressive symptoms²,³.
Huntington’s disease affects approximately six people in every 100,000 in the developed world4 and usually begins around the ages of 30-45. Over time, symptoms worsen leading to progressive functional impairment.
Cognitive impairment is found up to ten years before Huntington’s disease is able to be diagnosed using existing methods5.
Many types of treatment are available that can provide symptomatic relief in Huntington’s disease, to maximise comfort, dignity, and independence. It is helpful to focus treatments on specific target areas6. For example, psychotherapy can be helpful for coming to terms with the disorder and its consequences, and in the treatment of comorbid depression.
What is epilepsy?
Epilepsy is a neurological condition characterised by a history of two or more seizures. Seizures are acute episodes during which there is a surge of uncontrolled electrical activity in the brain. This causes involuntary movement in either a part of the body or the whole body. It may cause loss of consciousness1.
Epilepsy affects approximately 50 million people across the globe, with an estimated 5 million new cases being diagnosed each year1.
Many types of epilepsy are associated with cognitive impairment2. In addition, epilepsy can severely affect an individual’s quality of life and ability to function. People with seizures are at increased risk of psychological conditions such as depression and can experience physical consequences such as bruising and bone fractures.
Because epilepsy exists in many forms, and can be mistaken for other disorders, investigation and treatment should be undertaken by specialists. For confirmed epilepsy, a comprehensive treatment plan should be formulated, which can include anti-seizure medication. Examples of medications used in some types of epilepsy include carbamazepine, lamotrigine, and sodium valproate.
Why is it important to do research in epilepsy?
Cognitive deficits are often seen in individuals with many different forms of epilepsy2; these cognitive difficulties can impede educational and vocational outcomes3.
Evidence-based treatments specifically targeting these cognitive problems are needed, and many clinical trials are yet to thoroughly assess the effects of pharmacological interventions on cognition in people with epilepsy4.
Why it is important to do research in drug abuse liability?
Objective measurement of the abuse potential of novel compounds is crucial to ensure the product is safe for the intended use, helping to mitigate in-market problems of incorrect consumption. We have developed an assessment battery for the subjective and objective measurement of human abuse potential of compounds.
What is drug abuse liability?
The ability to detect or refute drug abuse liability is critical in product development, licensing, and for post-marketing surveillance.
Comprehensive understanding of abuse liability contributes to accurate risk-benefit analysis and internal decision-making, as well as accurate product labelling. In academic settings, detection of abuse liability is important when considering new projects, and when making Institutional Review Board (IRB) / Ethics Committee applications.
Abuse liability is dependent not only on the drug properties (including neurochemical effects on the brain, formulation, and pharmacokinetics) but also on the population being studied (age, vulnerability for addiction, psychiatric and physical health morbidities)2.
Abuse liability has critical public health implications – for example, the US Drug Enforcement Administration (DEA) has highlighted the growing problem of prescription drug abuse, and that the economic cost of non-medical use of prescription opioids is more than $53 billion per year3.
Examples of drugs with high abuse liability include certain opioids and morphine derivatives, central nervous system depressants, and stimulants4.
What is Down’s syndrome?
Down’s syndrome (or Down syndrome) is a genetic disorder which is typically associated with a degree of intellectual disability, along with particular physical characteristics. It affects approximately 1 in every 1,000 babies1. Down’s syndrome is the most commonly occurring chromosomal disorder and has been getting more common in recent years2.
In addition to intellectual impairment, Down’s syndrome is associated with increased risk of medical problems including congenital heart defects, reflux, hearing loss, obstructive sleep apnoea, visual impairment, thyroid disease, and dementia3.
Children and adults with Down’s syndrome should have access to multi-disciplinary support, which can involve input from doctors, educational experts, speech and occupational therapists, and social workers4. Examples of medical interventions that may be needed include surgery to correct congenital heart defects or a special diet to minimise digestive problems5.
Why it is important to do cognitive research in Down’s syndrome?
Cognitive deficits in Down’s syndrome represent a key target for novel treatments, in order to maximise everyday functioning and improve quality of life. This is relevant in view of the intellectual disability occurring generally with the condition, but also due to the association between Down’s syndrome and elevated risk of Alzheimer’s disease as individuals get older.
Why it is important to do research in depression?
Cognitive deficits are often seen in individuals with mood disorders, potentially reflecting underlying dysfunction of monoamine neurochemical systems3 and emotional processing circuitry4.
The search is on for treatments that can reduce cognitive impairment in mood disorders, in order to maximise long-term outcomes and quality of life. Another key area of ongoing research is the search for objective markers capable of identifying, for a given individual, treatment options that are most likely to be effective and well-tolerated.
What is depression?
Mood disorders are highly prevalent across the world, affecting 5-10% of the adult population in a given year1, 2. The most common mood disorders are major depressive disorder, dysthymia, and bipolar disorder.
Major depressive disorder (also known as depression) is characterised by low mood and/or loss of interest in previously pleasurable activities; in addition to a combination of several other symptoms such as impaired attention, changes in body weight, sleep disturbance, fatigue, excessive feelings of guilt, and negative thoughts.
In bipolar disorder, individuals experience at least one episode of manic symptoms, but depressive episodes are also common. Mania refers to a distinct period of elevated, expansive, or irritable mood coupled with excess energy.
Collectively, mood disorders cause considerable distress to affected individuals and can have a devastating impact on quality of life and everyday functioning.
Treatment options for mood disorders can vary, but may include pharmacological treatments such as selective serotonin reuptake inhibitors (SSRIs) for depression and lithium or divalproex for bipolar disorder. Psychotherapy, particularly Cognitive Behavioural Therapy (CBT) may also be recommended, especially for those with depression.
Why is it important to do research in core cognitive function?
Brain disorders are common, debilitating and economically crippling. Existing treatments often do not reverse underlying cognitive impairment or cannot be tolerated by patients. Our core cognition test battery incorporates the core cognitive domains often impaired in brain disorders, as well as those affected by cognitive enhancing drugs or interventions.
What is core cognitive function?
Cognitive functions are critical for everyday functioning, including in the workplace and social situations.
Problems with cognition are central to understanding psychiatric and neurological conditions across the lifespan. Examples include childhood-onset conditions such as Attention Deficit Hyperactivity Disorder (ADHD) or autism, conditions with onset in adolescence or early adulthood such as schizophrenia and depression, and disorders of older age including dementia.
In a given year, approximately one-third of the adult population will experience a mental disorder, but less than one-third of these individuals receive any form of treatment1,2.
Collectively, brain disorders represent a leading cause of morbidity across the globe, and this burden of disease is likely to increase over time3.
Treatments capable of reversing cognitive dysfunction in brain disorders can help maximise quality of life and everyday functioning for affected individuals, in turn minimising suffering and the economic impact of these illnesses.
Cognitive enhancement is also relevant in our daily lives, even in people without brain disorders. Caffeine consumption is an everyday occurrence in much of the world, and is used to regulate alertness and concentration, including in high-level athletes4. “Brain training” products are being investigated as a means of maintaining ‘brain health’ as we age5.
Certain conditions that cause cognitive dysfunction do have evidence-based treatments available. For example, ADHD can be successfully treated with psychostimulants or selective norepinephrine reuptake inhibitors such as atomoxetine. However, many people cannot take these medications due to intolerance or because of contraindications. Many other conditions, including schizophrenia and multiple sclerosis, do not have treatments that modify the underlying disease at all. This means that there is still a great need for novel interventions that can treat conditions with cognitive dysfunction.
Why it is important to do research in cognitive safety?
Cognitive impairment is increasingly recognised as an important potential adverse effect of medication. Medications can exert untoward cognitive effects both via direct effects on the brain (by crossing the blood-brain barrier) and via indirect actions (peripheral mechanisms in the body). However, many drug development programmes do not incorporate sensitive cognitive measurements.
This field is still at an early stage, and precisely what designs should be adopted, what outcome measures should be used, and what statistical approaches are most appropriate will vary depending on the drug in question and the indication.
Even if a drug is shown to induce some cognitive impairment, it might still be beneficial to prescribe it; but pharmaceutical companies, regulators, clinicians, and patients need to understand the possible cognitive risks and their implications for everyday function.
What is cognitive function?
Cognitive functions are vital for everyday functioning, including in the workplace and in social situations. They are especially crucial in safety-critical scenarios, such as when driving a car, or operating machinery.
Detection of negative cognitive effects of pharmaceutical interventions is of vital importance from the perspective of patients, clinicians, and the public. Cognitive Safety signals are also an increasing focus of regulatory agencies including the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)1.
Assessment of the cognitive effects of medication is crucially important in drug development, licensing, and post-marketing surveillance. During drug development, objective measurement of cognitive effects can inform key decisions such as selection or rejection of compounds, choice of doses, and in support of the target indication(s).
Safety-relevant cognitive data are extremely valuable in support of regulatory submissions and drug differentiation claims. Testing for cognitive function, motor skills and mood has been highlighted by the FDA as being important when conducting clinical trials for medications suspected to impact brain function2.
Why is it important to do research in autism?
Individuals with autism spectrum disorder often exhibit cognitive deficits that reflect underlying abnormalities in brain structure and function5,6. Our recommended test battery for research of autism spectrum disorder’s assesses the core domains impaired in ASD, as well as those likely to be affected by novel interventions.
The search is on for treatments that can ameliorate the core symptoms of ASD, and cognitive impairment, in order to maximise long-term outcomes and quality of life for affected individuals.
What is autism?
Autism is a neurodevelopmental disorder associated with problems with social communication and/or interaction, and occurrences of restricted or repetitive patterns of behaviour, interests, or activities.
Autism was previously distinguished from Asperger’s syndrome, but the latest version of the Diagnostic and Statistical Manual (DSM-5) instead uses a broader ‘umbrella’ category of Autism Spectrum Disorder (ASD).
The condition affects approximately 1 in every 100 children. It is not fully known what causes autism but it is thought to include a mixture of environmental and genetic factors1.
The UK National Institute for Health and Care Excellence (NICE) has a number of guidelines regarding the recognition, diagnosis, and treatment of autism2-4. Generally speaking, people with autism should be supported via a multidisciplinary approach, by people with expertise in the disorder. This can involve support from clinical psychologists, nurses, occupational therapists, psychiatrists, social workers, speech and language therapists, and other support staff.
What is ADHD?
Attention-Deficit Hyperactivity Disorder (ADHD), otherwise known as hyperkinetic disorder, is a condition that affects people’s behaviour. ADHD can cause restlessness, trouble concentrating and impulsive behaviour1. For example, children with ADHD may blurt out answers in the classroom, fidget and find it impossible to keep still and struggle to focus on what a person is saying.
ADHD is the most common psychiatric disorder of childhood, affecting at least 5% of children globally. Symptoms persist into adulthood in up to 60% of childhood cases2.
For a diagnosis of ADHD to be given, the symptoms must be functionally impairing and occur in at least two distinct settings, for example at home and at school.
Considerable research has examined the long-term consequences of ADHD, highlighting its global importance for society. In a systematic review of the data, untreated ADHD was associated with poorer long-term outcomes across all categories considered: these included academic performance, job performance and employment status, self-esteem, quality of life, and risk of driving accidents3.
ADHD is a treatable psychiatric disorder, with medium to large effect sizes in terms of symptomatic improvement, versus control conditions, over the short-medium term4.
ADHD is often misdiagnosed, and is frequently comorbid with other mental (and physical health) disorders. First-line treatment options for ADHD can include consideration of psychotherapy and/or medication, but these should always be offered as part of a comprehensive package of care. The most appropriate treatment options and sequencing of treatment options can vary considerably depending on factors such as the age of the individual, severity of disease, and patient/family preference.
Why it is important to do research in ADHD?
The core symptoms of attention deficit disorders are cognitive in nature (inattention, hyperactivity, and/or impulsivity). These cognitive deficits often reflect underlying brain circuitry dysfunction (including prefrontal regions) and of neurochemical transmission, including the dopamine and noradrenaline/norepinephrine pathways5-9. Our recommended test battery for attention deficit disorders assesses the cognitive domains most likely to be impaired, as well as those likely to be affected by interventions.
Recommended CANTAB® test battery for multiple sclerosis
Our recommended test battery for MS incorporates the key cognitive domains often impaired, as well as domains likely to be affected by medications.
Key research for CANTAB in multiple sclerosis
The tests included in this battery are highly sensitive to cognitive impairments in MS across the disease severity spectrum4,6. Poorer memory performance in this battery correlated significantly with higher hippocampal glutamate levels in patients with MS7. The MS test battery also detects cognitive effects of interventions in MS patients, both in terms of unwanted adverse events and cognitive enhancement8.
Foong et al., Brain, (1997)10
Pathology and functional impact of multiple sclerosis
Classical understanding of the underlying brain pathology in multiple sclerosis emphasises autoimmune-mediated damage to myelin, a fatty substance that surrounds and protects neurons in the central nervous system.
Damage to myelin means that electrical signals between neurons do not operate as they should, leading to the wide variety of neurological symptoms that can occur. The term ‘sclerosis’ refers to the scar tissue that forms in the damaged tissue as a result of these pathological processes.
The aetiology or fundamental causes of MS are poorly understood10. In a large meta-analysis of the available evidence, the factors most strongly associated with MS were smoking and previous infection(s) with the Epstein-Barr virus11.