Causes and mechanisms of cognitive impairment

Histology, disease progression, treatment-related neurotoxicity, neural reorganization, individual psycho-physical conditions, and co-morbidity are factors that determine how severe and which type of cognitive impairment follows from a brain tumour. Brain tumour does not only cause focal neuron disruption, but is also involved in alterations in brain connectivity. When an alteration in amplitude and synchronization of low frequency connectivity is found in combination with toxic and metabolic insults, this can result in whole brain dysfunction. Very important for the onset, progression and severity of the cognitive deficits are the histology and location of the brain tumour. Tucha et al. discovered that in 91% of patients with a brain tumour have deficits in executive functions, memory and attention prior to a surgery (for removing a brain tumour), which states that the deficit is not only the effect of the surgery. Radiotherapy can also be responsible for negative cognitive changes. Klein et al. found that the increase of radiotherapy predicts an increase in severity of the cognitive changes produced by the radiotherapy. Klein et al. also discovered that the changes in executive function and attention were due to hemispheric location and antiepileptic drugs, which means that these deficits were not due to damage from surgery. Studies have shown contradictory results: some studies also show that the radiotherapy has no effect on the brain. This result suggests that the tumour (low-grade glioma, LGG, used here) itself is the most important part for the cognitive decline and radiotherapy can only make it worse or have no effect. But it must be noted that the studies used to make this conclusion lack of baseline evaluations, homogenous groups and are retrospective.

While studying high-grade glioma (HGG) Steinbach et al. and Hottinger et al. found that HGG patients have a decline in attention, information processing and psychomotor speed. Patients with tumour recurrence or patients who had medication with corticosteroids and antiepileptic drugs had the biggest decline. The decline in attention, information processing and psychomotor speed is also found in glioblastoma patients by Corn et al. Longitudinal studies show that specific cognitive impairments can be related to tumour location, but it is the growth of the tumour and the treatment that determine the severity of the cognitive impairments. Additional possible impairments are impairments in motor speed, manual dexterity, memory and executive function, but not verbal memory. Meyers et al. showed that verbal memory was related to survival, adjustments for age, Karnofsky performance status and the number of surgical resections. When people are treated with chemotherapy their cognitive functions can improve or remain stable. But it is hard to distinguish between the effects from radiotherapy and the negative effects from chemotherapy. As a result of surgery the cognitive functions may improve, or they remain the same.

Cognitive patterns

Brain tumours do not always have the same effect on a location in the brain. Sometimes focal deficits are masked because of compensation and substitution from the neural mechanisms (slow-growing tumours) or the focal deficits are surpassed by physical symptoms (high-grade tumours). Absence/presence of a particular psychological-behavioural pattern, can be related to a specific brain area. Frontal tumours lead to problems with working memory, inhibition of interference on ongoing actions, social cognition, risk assessment, decision making, use of external feedback, initiative, abstraction, flexibility and expression. Temporal tumours lead to verbal, comprehension, memory, semantic and social cognition problems. Memory failure can be caused by tumours in the diencephalon and corpus callosum. Visuospatial recognition, semantic competence and social cognition are also affected by occipital-parietal tumours. Occipital-parietal tumours may impair visuospatial recognition, semantic competence, and social cognition. Tumours of the cerebellum cause problems with modulating and checking mental operations. Areas specific for language cause problems with memory, attention, word fluency and verbal learning.

Objectives of neuropsychological assessment

Neuropsychological assessment is done for different reasons. The most common assessment is identification of individual strengths and deficits and the correlation with brain areas. Attention should be paid to the length of the assessment, which may cause fatigue and distress. Which assessment is used differs also in relation to the phase of the disease and treatment. Neuropsychological functioning is often combined with quality of life assessment. Deficits of memory and verbal comprehension can affect how patients report their QOL, but deficits itself can also cause a decline in QOL. Neuropsychological assessments are also used to support prognosis. Test scores may predict future behaviour and survival. Furthermore neuropsychological assessment can be used for non-pharmacological treatment planning (psychological support/therapy).

Neuropsychological testing

To create a full image of the neuropsychological change, most of the time multidimensional tests have to be done. One should also be cautious with pre-structured tests, because of their instability towards specific deficits they cannot give as precise results as tests tailored for clinical and research purpose. It is also important that a neuropsychological test should have standardized procedures, adequate consent/structure/validity/reliability, and have alternative forms. Test results should be showing clinically significant changes, not statistical significant changes. To show these results, baseline (pre surgical) testing must be done.

Meyer and Hess showed that a 40min set of test is enough to predict the radiological progression of brain tumour. When disease-related variables are added to the test battery survival rates can also be predicted. Tests assessing memory, executive function, and memory are the most likely to detect cognitive deficits in adults with tumours. Other studies showed that assessing social cognitive deficits are also very likely to show cognitive deficits because of the lesion itself, seizures or altered brain connectivity (in this case the brain area should be screened).

Non-pharmacological treatment of cognitive deficits

Cognitive rehabilitation, using retraining or compensation strategies, has been showing improvement in attention and memory for patients with a brain tumour. Although the studies performed on this topic lacked randomized study designs, control group, and follow-up evaluations, because of the importance of the cognitive impairment to the patient to the prognosis, careful neuropsychological assessment and non-pharmacological treatment remains very important.

Introduction

Charcot was the first to investigate the cognitive consequences of multiple sclerosis. He found that at a certain stage of the disease memory losses, slower formed conceptions and emotional deficits arise. It was not until a hundred years after Charcot’s discovery that neurologists started to believe in the cognitive effects of MS, because they equated this cognitive effects to Alzheimer’s dementia. Still, a lot of patients cannot be accurately enough assessed by a neurologist to discover cognitive effects, which makes the patients more vulnerable to negative effects of their cognitive deficits in social skills, employment and daily activities. Now is recognized that cognitive impairments are one of the most disabling symptoms of the disease.

It has also been a challenge to find the optimal combination of cognitive tests to assess the multiple areas affected by multiple sclerosis. Benedict and colleagues conducted the Minimal Assessment of Cognitive Function in MS (MACFIMS) for this problem. When early discovered, cognitive impairments can possibly be helped with neuropsychological counselling, cognitive rehabilitation training and pharmacological interventions.

Cognitive functions in MS

MS is a multifocal demyelinating disease of the CNS, produced by neuroinflammatory and degenerative processes. MS affects not only the white matter tracts but also the axons of the association neurons in the cerebral cortex. Different areas of the CNS can be demyelinated and this makes MS a heterogenic disease. But despite of the heterogenic aspect of this disease, some areas are more affected than others. There are differences in subtypes: relapsing remitting (RRMS) patients perform usually better on cognitive tasks than patients with progressive subtypes. This difference can be diminished by reducing the physical aspects. The most affected areas by MS are information processing speed and verbal memory. Cognitive flexibility and executive functions are also impaired in many cases. Also deficits in attention, caused by a working memory deficit, are found in MS patients. The working memory deficit is a result from white matter lesions, which lead to a disruption of the rehearsal sub-loops. These deficits can also be detected in the early stages of MS. Dementia , language impairments, aphasia, amnesia, apraxia and neglect are usually not involved in MS.

Magnetic resonance imaging parameters related to cognitive impairment

Traditional magnetic resonance imaging was not able to show the impairments, and the cognitive deficits were not strongly correlated to damaged areas. In more advanced versions of MRI these correlations can be made because these versions of MRI can detect abnormalities in the white matter. Studies showed that patients with damage on a MRI can perform as well as controls on attention tasks, due to compensatory mechanisms. Another study showed that patients do perform worse on attention tasks, suggesting exhaustion of compensatory mechanisms. Because of the regional fibre tract injury, connections for communicating in the working memory can be disturbed. Neurological plasticity can also diminish this problem.

Contribution of comorbidities on cognitive performance

Cognition can also be influenced by neuropsychiatric abnormalities accompanying MS, like depression, anxiety or fatigue. Depression is the most represented, with 50% of MS patients suffering from it. Depression can also be a cause of cognitive impairment by influencing the executive component of the working memory. Cognitive decline can also increase due to the overestimation of cognitive deficits, caused by depression. It is not known if treatment in depression will diminish the cognitive problems.

Even though fatigue also impacts controls, it is established as an important factor for cognitive impairments in MS patients. Especially in sustained attention and processing speed. Furthermore, CNS-active medications (anti-epileptics and SSRI’s) are also able to cause fatigue, so this should be considered during cognitive assessment, even though there is no direct evidence of cognitive decline linked to this medication.

Assessment of cognitive dysfunction in MS

Neuropsychological assessment is very time-consuming and expensive, and even though they are very important for MS patients, they are not always done. Besides that not much research has been done on indicating risk factors, which makes identification of at risk-patients hard. Some already established risk factors are: advanced age, low level of intelligence and depression. Combination of an advanced age and low level of intelligence is an even bigger risk factor. Employment status is another risk factor. Assessment should not be conducted before 8 weeks after a relapse or steroid treatment, because they might also cause cognitive deficits. Possible comorbidities should also be considered.

Recommendation for the optimal assessment of cognitive impairment in MS

A neuropsychological test should be able to distinguish between MS patients and healthy individuals, but also between cognitive impaired MS patients and not cognitive impaired MS patients. Benedict’s MACFIM (as discussed in introduction) contains of five domains: processing speed/working memory, learning and memory, executive function, visual-spatial processing and word retrieval. Recent studies showed that the Symbol Digit Modalities Test (SDMT) was the best discriminator between MS patients and controls, and the Brief Visuospatial Memory Test the second best. These studies also showed that the MACFIM was able to discriminate between relapsing-remitting MS and secondary progressive MS. MAFCIM is declared valid.

Cognitive screening in MS

Time limitation can be a problem with MACFIM. Sometimes short cognitive screening tests are used because of that, but they seem to be insensitive for MS. For this reason special tests for MS patients are developed. The Brief Repeatable Battery of Neuropsychological Tests (BRB) is the most used example of this. The authors of the BRB found that a 5-15 min. test with three subscales also had a high accuracy and made this a new test. According to Benedict and Zivadinov cognitive screening should idealistically done before medical examination. Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) was conducted with this purpose. This short screening can be filled in while waiting for an appointment in the hospital. A problem with the MSNQ is that self-reports are usually affected by the patient’s depression. Staff-training is very important for interpreting screening and tests.

Pharmacological and medical treatment of cognitive impairment in MS: Are we there yet?

Disease-modifying drugs/therapies can minimize the developing of new lesions, so minimizing the cognitive deficits. They are now the number one treatment of RRMS patients. It should be noted that research on this topic has not been optimal, because of a lack of control of confounding variable. Recent studies have shown that progressive forms of MS can be improved with mitoxantrone, improving physical abilities and cognitive status. For symptomatic treatment of MS there are four useful drugs, although not enough research is done yet on this topic. The used drugs are: donepezil, rivastigmine, galantamine and memantine. The first three are acetylcholinesterase inhibitors, which inhibit the breakdown of acetylcholine, so increasing the duration and activation of acetylcholine. Donezepil is found to increase memory and learning. Rivastigmine also inhibits butyrylcholinesterase, and seems to benefit MS patients’ cognition.

Non-pharmacological treatments

Currently there is no optimal non-pharmacological treatment but they may benefit some MS-patients. The purpose of these treatments is creating a therapeutic ambiance in which optimal cognitive function can be created. Another non-pharmacological treatment is changing life-style, like exercise, a balanced diet (reduced alcohol and caffeine), quitting smoking and better sleep patterns. Cognitive rehabilitation focuses on helping the patient coping with their physical and cognitive problems. There are two kinds of approaches: the restorative approach and the compensatory approach. The restorative approach is dependable on the brain’s plasticity. The compensatory approach focusses on modifying the patient’s environment. It is of great importance that these approaches are individualised, since no patient has the same comorbidity, lifestyle, and demographic characteristics.

Studies on non-pharmacological treatments show mixed results, with some showing improvements on mental speed and working memory and others showing no results. Recent fMRI studies showed that cognitive rehabilitation has a positive effect on the compensatory cerebral reorganisation.

Cognitive impairments can result in significant changes in employment status, relationships and quality of life, so the early identification of cognitive impairments is crucial.

Two types of dementia

Dementia is a disease which causes cognitive impairment. There are two typical types of dementia: Alzheimer’s dementia (AD) and vascular dementia (VD). AD is associated with cortical atrophy, and is called a cortical dementia. Memory impairments arise because of degeneration of mesial temporal structures, particularly entorhinal cortex and hippocampus.

Risk factors

Widespread, cortical neurotic plaques and neurofibrillary tangles are other important characters. Risk factors are being a woman, advanced age (60>), Down’s Syndrome, hypertension, and the presence of apolipoprotein E e 4.

Vascular dementia can result from an ischemic stroke, hemorrhagic stroke, and Binswanger’s Disease. Attenuation of periventricular white matter (leukoaraiosis), often observed in VD, is able to cause cognitive dysfunction. Risk factors are advanced age, history of hypertension, heart disease, hypercholesterimia, smoking, being a man and diabetes mellitus.

Diagnostic tools

DSM-IV is the most frequently used diagnostic tool for VD and AD. Also differentiations between subcortical/cortical and degenerative/non degenerative can be made. A problem with this is that a definitive diagnose of AD can only be established post-mortem. Another problem is the heterogeneous character of VD. To be diagnosed with VD or AD, according to DSM-IV, memory impairment plus another form of cognitive impairment and social or occupational impairment (compared to former functioning) should be found, but a delirium must be ruled out. To diagnose AD conditions of the central nervous system (Parkinson/Huntington/cerebrovascular disease), systemic conditions, substance-induced conditions and other Axis I disorders (for example major depression) should be ruled out.

Diagnostic challenges

Evidence of cognitive impairment is an important diagnostic feature, so standardized cognitive measures are needed. But there is no consensus found yet about this because of variability of participant inclusion criteria. Despite this there are two general findings: AD patients show more long-term memory impairment and VD patients show greater executive functioning impairments. Consino et al. found also that AD patients had significantly less leukoaraiosis and VD patients significantly more histories of hypertension and heart disease.

Because of these findings a new diagnosing system is proposed, based on neuropsychological test findings, neuroradiological findings, and vascular risk factors. It is very important that convergent date should be used to diagnose AD or VD. Cognitive profiles, medical information and neuroradiological information should all be used for discrimination between these two forms of dementia.