Summary Medical Neuropsychology
Domain 1 – Neuro-oncology
Introduction
Neuro-oncology is the study of (1) brain tumors, which arise from neurons and other brain tissues,
and (2) effects of treatment on (1). Neurocognitive effects of brain tumors are variable and require
close examination on the neurocognitive underpinnings of test scores.
Risks for developing a brain tumor
Risk factors for developing a tumor are not fully known. The onset of a tumor often cannot be
estimated for most tumor types: a brain tumor is usually found incidentally after an individual falls or
has an accident.
Known risks include:
- Serious head injury
- Prior radiation exposure (e.g; radiotherapy for a brain tumor, diagnostic x-rays)
- Immune suppression
- Genetic disorders
Suspected risks: environmental carcinogens and viruses
Severity of tumors
Tumors are classified (and named) according to the cells from which they were generated, and then
graded by level of severity. A tumor type can range in severity, yet some are generally malignant or
generally benign.
Tumors are graded on a four-level system, determining the degree of malignancy and level of
differentiation of cells.
- Low grade/I: Benign. Tumor cells remain well differentiated. Tumor cells grow slowly and
rarely grow into surrounding tissue.
- Low grade/II: Benign. Tumor cells are moderately differentiated, but have a greater chance of
de-differentiation, spreading into surrounding tissue, and transforming into a more malignant
tumor.
- Anaplastic/III: Malignant. Tumor cells are poorly differentiated, tumor has likely spread into
surrounding tissue.
- High grade/IV: Highly malignant. Undifferentiated, and highly aggressive.
Neuropsychological evaluation
Tumors have a diffuse nature; typical syndromes and agnosias are not seen. For its assessment, an
individualized approach is required.
Neuropsychological tests are more sensitive to tumor recurrence than MRI. Neuropsychological test
scores decline as much as 6 weeks before MRI demonstrated tumor growth. As tumors are associated
with highly variable cognitive impairments, it’s most successfully tested it with a subject-specific
model.
The most predictive measures of tumor recurrence were found to be a test of verbal memory (recall
and recognition of a word list). Patients with aggressive tumors performed poorly on the Trail Making
Test, showing poor cognitive flexibility. Measures of reaction time in neurocognitive tests are often
more sensitive to the effects of brain tumors than accuracy rates.
In addition to cognitive evaluation, it is important to screen for mood disorders and other emotional
abnormalities.
Cause of cognitive impairments
..describe how brain tumors can result in functional brain damage (e.g. cognitive impairments) and
the influence of tumor histology, grade and location (i.e. left or right hemisphere)
,Tumors and resulting injury
Brain tumors can damage normal tissue by compression and infiltration. Compression might happen
directly or indirectly (e.g: indirect by obstruction of interventricular cerebrospinal fluid, resulting in
hydrocephalus (=abnormal ventricular enlargement)). However, tumors generally do not destroy
tissue until they are massive. Most tissue damage results from:
- Tumor mass effects
- Vasogenic edema (= disruption of the blood-brain barrier)
- Indirect effects of tumor; injury related to hydrocephalus, ischemia (=reduction of blood
supply to tissues resulting in hypoxia), encephalomalacia (=softening of the brain; certain
parts become ‘mushy’) and seizures.
The resulting injury, then, depends on whether critical regions were either damaged or left spared:
connectivity and functionality are key words here. Disconnection of important white matter tracts may
lead to disconnection syndrome, and a relatively small tumor may lead to a unique and striking
impairment in the context of otherwise unimpaired cognition if it’s an important functional area. In
turn, an extensive tumor can, in some individuals, have remarkably little effects if critical regions
were spared.
Course of disease
Tumors usually allow for some neural function, and the relatively slow growth of brain tumors likely
permits a neuroplasticity response in the brain. Slow growth of many tumors may be followed by
reduced cognitive recovery, and over time, slow decline in specific cognitive functions or stability
(the latter especially in the presence of a stable tumor).
Influence of tumor characteristics
Histology
Tumor histology does not appear to influence the severity or type of cognitive impairment (only
indirectly, through association with tumor location)
Grade
Tumor grading (so, level of severity) is associated with severity of neuropsychological deficit. High-
grade tumors grow more aggressively and quickly, are larger, and are thus generally more disruptive
of neural connectivity. However, different biomarkers of the differently graded tumors do not lead to
significantly different cognitive functionality after resection.
Location
A general pattern for hemispheric specialization is seen in tumors, but these do not always hold: few
significant group differences are found in much of research. (as a broader point, left/right hemisphere
dissociations in neuropsychological test outcomes have been challenged mainly due to complexity of
cognitive tasks (and the multitude of tasks and strategies involved); what can poor task performance
be attributed to?
Tumor depth
- Patients with deeper tumors tend to have the lowest scores on neuropsychological tests.
Left hemisphere
- Cortical tumors are associated with verbal dysfunctions (e.g: semantic fluency) and slower
reaction time on memory and attention tests.
- Cerebellar tumors result in greater visuospatial impairment.
Right hemisphere
- Cortical tumors are associated with visuospatial dysfunctions (e.g: visual memory tasks).
- Cerebellar tumors result in greater linguistic and sequential processing dysfunction.
Frontal lobe
- Frontal lobe tumors are associated with memory impairment in the encoding and/or retrieval
and recognition of material requiring association.
Thalamus
- Thalamic tumors are associated with multi-tasking problems and other attentional deficits.
, Cognitive impairments in patients with tumors
..describe cognitive impairments and neurobehavioral disturbances that are most often observed in
patients with brain tumors.
Cognitive dysfunctions are
- problems of working memory,
- memory encoding and retrieval,
- attentional dysregulation
- slowed information processing.
Less common but occurring cognitive dysfunctions include
- aphasia,
- dyspraxia,
- amnesia
- executive dysfunction.
Severity of cognitive impairments
Brain tumors are associated with less functional damage than other, more rapidly acquired brain
injuries (i.e: TBI, stroke). Change in function can be major (and tumors can at times masquerade as
dementia and as psychiatric syndromes), but they generally result in less functional injury than you
might expect based on their dramatic presentation in some brain scan images.
The actual effects of a tumor are hard to research, because pre-tumor scores on neurocognitive tests
are rarely known. Cognitive effects of brain tumors of similar histology (=cell structuring) and
location are highly variable.
Neuropsychiatric disturbances
Brain tumors can lead to a number of psychiatric syndromes:
Frequently Associated Location of
Psychiatric Syndrome Extra comments
Tumors
Prevalent in all cancer
patients. Avg. levels of
Depression and fatigue Frontal Lobes depression for population
increases over time after
emergence/diagnosis
Anxiety Right cortex, often Temporal lobe
Tumor patients rarely have
Asperger’s syndrome/mild autism Cerebellum, temporal lobe full criteria: they can display
autistic-like characteriscs
Marked by significant deficits
in executive function
Bilateral or large unilateral lesions in (planning and set shifting),
posterior cerebellar lobes, (co-occurance spatial cognition,
Cognitive Affective syndrome: of cognitive and affective symptoms language(expressiveness),
arises from disruption of cerebello- abstract reasoning, attentional
thalamo-cortical tract) regulation, memory and
personality (hyperactive,
impulsive)
OCD arising from brain tumor
Obsessive-compulsive disorder Frontal lobe may have atypical
characteristics, difficult to
, treat (usually, anxiety is
targeted, but this is often not
primary mediating factor
here).
Associated with disorders of
eating behavior (e.g: anorexic
symptoms due to loss off
Hypothalamic syndromes Hypothalamus appetite), growth rate,
emotional lability, sleep
disturbances, headaches,
sometimes seizures.
Effects treatment on cognitive functioning
..describe and explain the effects of neurosurgery, radiation therapy and chemotherapy (alone or in
combination with each other) on cognitive functioning.
Neurosurgery
Surgical techniques attempt to resect the tumor, sparing functional, normal-appearing cortex and
subcorticial white matter in the process.
Associated cognitive deficits:
- Exacerbation of current tumor effects
- Sudden on-set disruptions in speech, motor function and affect
Immediately following a resection, cognitive function and behavior can be dramatically disturbed,
even if it was relatively stable before in the presence of a stable tumor. 73% of patients experience an
immediate decline in neurological functioning. Sometimes resection causes an immediate
improvement in cognition, personality, or mood, often related to alleviation of mass effects.
Over a course for multiple years (a little over 2) after resection, morphological adjustment and neural
plasticity leads to significant improvement – the 73% remits to 23% after 3 months of discovery.
Radiation Therapy
Uses radiaton to 1) focally destroy tumor cells and 2) prevent metastasis
Associated cognitive deficits:
- Memory (e.g: working memory, verbal memory, spatial)
- New problem solving
- Attentional control
Main problems of radiation are due to it damaging vascular tissue and the hippocampus. It causes
damage to endothelial cells (needed for blood vessels), glial cells (needed for myelination (->
expected to be responsible for symptoms in subacute phase) and neuron regulation) and hippocampal
neural stem cells (the hippocampal granule cell layer; this is the main reason for memory problem). It
then induces an immune system recovery/repair response leading to oxidative stress (too many
radicals from burning 02 present; disruption of mitochondrial function of hippocampal neural stem
cells) and chronic inflammation (usual swelling and heat of inflammation, but the inflammation stays,
usually because cause of inflammation isn’t removed)
Radiation leads to greater cognitive impairment with greater radiation dose, higher age, and with
multiple treatments (e.g: in conjunction with chemotherapy, stronger dose effects and greater risk of
white matter changes). However, radiation effects are diffuse and very difficult to separate from other
disease-related changes in the brain.
,There are three phases to side effects of radiotherapy (they don’t all need to be experienced: one may
start at 3):
1. Acute phase (during radiation). Sleepiness, depression, nausea. Experienced differently by
most.
2. Subacute phase (2 weeks – 6 months posttreatment). Temporary decline in memory. In
absence of disease progression, this effect reverses by 1 year after treatment.
3. Late delayed phase (5 years posttreatment) Continuously declining and more general memory
impairment
Chemotherapy
Tumor cells are stopped from replicating by (neurotoxic) drugs that interfere with its growth and
replication.
Associated cognitive deficits:
- Fatigue (ranges from minor problem to complete debilitation)
- Acute effects (during treatment, called ‘chemobrain’): short-term memory, learning, memory
retrieval, executive function.
- Long term effects: verbal memory, psychomotor functioning
‘Chemobrain’ is often experienced during chemotherapy. The exact cause of chemobrain is unclear,
but multiple mechanisms exist. Chemotherapeutic agents affect various healthy tissues; resulting cell
death, inflammation and anemia can lead to cognitive deficits. (Rapidly) dividing cells are most
sensitive to drugs used in chemotherapy: as such, healthy (dividing) cells may also be affected (brain
tissue, bone marrow). Some drugs may cause white matter or focal brain cell death. Direct injury to
neurons can also occur by inflammation (due to autoimmune mechanisms) and neurotransmitter
deficits. Some drugs may have an effect on neurogenesis in hippocampus and subventricular zone,
leading to impairment of spatial learning and memory. Similar to radiotherapy, chemotherapeutic
agents can damage blood vessel endothelial cells, damaging cerebral blood vessels (-> reduction in
oxygen, ischemic stroke). Due to the effect on the bone marrow, chemotherapy patients have a high
risk of anemia; this anemia may also be associated with cognitive deficits.
Decreasing chemotherapy-induced cognitive decline
..describe suggested interventions to prevent or decrease chemotherapy-induced cognitive decline.
1. Antioxidants decreasing free radical formation
Chemotherapeutic agents injury blood vessels. Damage to blood vessels can be reduced
by decreasing the amount of free radicals in the blood: they damage vessels even further.
Antioxidents can decrease free radical formation, decreasing vascular injury and
preventing cognitive decline after chemotherapy. Examples of antioxidents are Vitamin
E, the herb “Ginkgo biloba”
2. Exercise
Exercise increases blood flow to the brain and improves oxygenation. Studies have
already demonstrated that aerobic exercise shows an improvement in reaction time and
memory.
3. Cognitive behavioral challenges such as complex intellectual work
Performing complex intellectual work increases intellectual flexibility. Occupations
associated with complex intellectual work strongly correlate with intellectual flexibility.
Cognitive stimulation also improves memory, verbal fluency and problem solving.
4. Pharmacologic interventions
,Reduced hemoglobin levels are associated with greater levels of fatigue and reduction in
cognitive abilities. Recombinant human erythropoietin (EPO!) increases hemoglobin
levels, and improves of life and cognitive abilities in general in cancer patients with
anemia undergoing chemo
Methylphenidate improves concentration, attention and memory in adult cancer patients.
,Domain 2: Cardiovascular disease
Introduction
Cardiovascular diseases are broadly defined diseases of the circulatory systems. Cardiovascular
diseases are the leading cause of morbidity and mortality in most countries in the West.
Cardiovascular diseases and risk factors lead to problems with blood pressure and damage to the
vascular system. They are comprised of
- coronary heart disease (narrowing of coronary (= directly surrounding or supplying heart)
arteries)
- cerebrovascular disease (affect blood vessels in the brain, cerebral circulation)
- peripheral artery disease (affects peripheral arteries such as in legs and stomach)
- heart failure.
- Subclinical diseases (affects high percentage of healthy population. e.g: calcification, blood
pressure problems)
The health of the brain is at risk in the context of cardiovascular disease. In a process occurring across
the life span, there is a continuum of neurocognitive and neurobiological impairment associated with
increasingly severe manifestations of CV disease that can ultimately lead to dementia and/or stroke.
Cardiovascular disease leads to increased risk for ischemic and hemorrhagic stroke, contributes to the
development of vascular (small multi-infarct) dementia and Alzheimer’s disease, and overall
negatively impacts the brain and neurocognitive function.
Cardiovascular risk factors
..mention cardiovascular risk factors (i.e. traditional-, behavioral-, psychosocial- and
psychophysiological risk factors) and should be able to describe their direct and/or indirect relation
with cognition.
Cardiovascular risks
Often, various cardiovascular risk factors exist in an individual. The cumulative impact of more than
one risk factor can be multiplicative rather than additive. It is critical to intervene aggressively in high
risk profiles early in life course to prevent risk factors to develop into CV diseases, and stop current
damage of risk factors to the brain. The following factors increase risk for cardiovascular disease:
Biomedical (traditional):
- Hypertension (heightened blood pressure)
- Dyslipidemia (unhealthy levels of one (or more kinds of) fat, e.g: cholesterol)
- Obesity
- Diabetes (see chapter on diabetes)
- Metabolic syndrome: glucose intolerance, insulin resistance, dyslipidemia, hypertension
Behavioral:
- Smoking
- Excessive alcohol consumption
- Poor diet
- Physical inactivity
- Psychosocial factors (e.g; stress)
- Psychophysiological factors (e.g: autonomic nervous system dysfunction, Hypothalamic-
pituitary-Adrenocortical Axis dysfunction)
Relation to cognition
These risk factors are all associated with negative effects on cognition. All risk factors have an
indirect cause on cognition through them being a risk factor of Cardiovascular disease: as these risk
factors may lead to CV disease, they indirectly cause the effects CV diseases have on cognition.
However, most of these risk factors also have direct effects on cognition, explaining the relevance of
subclinical diseases (people with no CD disease but with some risk factors are negatively affected).
The most important direct effects of these risk factors are
, - Cerebral hypoperfusion
- Artherosclerosis
Traditional/biomedical risk factors
Hypertension
Effects of hypertension on cognition can be explained by:
1. Atherosclerosis/arterial stiffening
2. Cerebrovascular damage (infarcts, white matter disease)
3. Changes in blood flow
4. Disruption of the blood-brain barrier
5. AD pathological mechanisms (see: relation between blood pressure and AD)
Atherosclerosis is associated with increased risk of stroke, Vascular Dementia, and Alzheimer’s
Dementia.
Neuroanatomical findings in hypertension often include cerebral white matter disease, silent brain
infraction and brain atrophy.
Higher levels of blood pressure and arterial stiffening are associated with (future) lowered levels of
cognitive function on different domains. Patients with hypertension perform worse on tests of
executive function; learning and memory; attention; motor performance and visuospatial abilities.
Antihypertensive medication improves cognitive outcomes.
Lipids
Effect of dyslipidemia on cognition can be explained by:
1. Resulting atherosclerosis (often promoted by high levels of cholesterol)
2. The APOE genotype (Genotype associated with defective lipid metabolism, is also associated
with dementia)
3. Oxidative stress.
4. Increased formation of Beta-amyloids (also caused by increased cholesterol levels;
association with AD!)
A frequently experienced form of dyslipidemia is abnormal levels of cholesterol. Cholesterol is an
important component of neuronal and glial membranes and myelin sheaths, providing structural
integrity, modulating membrane fluidity and important for synaptic function, neurotransmission and
transport of nutrients to the brain.
Abnormal levels of cholesterol are associated with dementia, lower levels of intelligence, lower
performance on measures of abstract reasoning, attention/concentration, executive function and word
fluency.
There is also a genetic relation between dyslipidemia and dementia. At least two genotypes are known
as risk factors for both CV disease and AD (APOE genotype). Effects of genotype on AD are
probably indirect (CV disease -> AD; affected lipid metabolism -> AD). These genotypes are also
associated with lower levels of cognitive performance, cognitive decline and changes in brain
morphology prior to dementia.
Obesity
Effects of obesity on cognition can be explained by:
1. Endocrine (hormone-producing glands) dysregulation (i.e: hypercortisolemia (= high levels of
cortisol), low levels of growth hormones, hyperleptinemia (= high levels of leptin, hormone
with major role in fat metabolism).
2. Inflammation
3. Vascular problems
4. Direct enhancement of other CV risk factors (e.g: obese hypertension patients have worse
memory than non-obese.)
5. Indirectly: lifestyle factors (exercise is important!)
