Case 1: Dementia and Delirium
Chemical neurotransmission basics:
- is based on neurotransmitters and happens in the synapses between neurons
- signal can be going forward (presynaptic to postsynaptic), retrograde (backwards:
endocannabinoids, NO, NGF nerve growth factor), volume neurotransmission (by diffusion
from one synapse to other neurons in the area)
- Electrical signal VSSC (voltage sensitive sodium channels) open sodium influx signal
to presynaptic membrane VSCC (voltage sensitive calcium channels) open calcium
influx synaptic vesicles released into synapse containing NT (neurotransmitter).
Signal transduction cascades
- Neurotransmitter (1st messenger) G protein linked receptor activates enzyme that
produces (second messenger) activates inactive protein kinase (third messenger)
activates inactive ‘early’ transcription factor in nucleus of cell (fourth messenger) activates
RNA polymerase protein production from immediate early genes (cJun cFOS) (fifth
messenger) are TF for late genes end product (seventh messenger)
Epigenetics
- Genes are turned on and off by modifying chromatin structure. DNA is wrapped around
histones and if wrapped tightly will not be ‘used’/expressed:
A. Methylation by histone methyl transferases causes silencing of DNA. Can eventually
lead to deacetylation by HDACs
B. Demethylation by histone demethylases causes gene activation
C. Acetylation by histone acetylases causes gene activation
D. Deacetylation by histone deacetylases (HDACs) causes gene silencing
- Once the cell is of a certain type DMA methyl transferase 1 among others attempts to
maintain this status quo. However this is not irreversible, another DNMT enzyme can for
example cause de novo DNA silencing or activation. -> ground for genetic disorders?
Transporters, receptors, and enzymes as targets for psychoactive substances:
- Transporters; neurotransmitter transporters have 12 transmembrane regions. We have
different transporters:
, A. Plasma membrane:
B. Intracellular vesicle transporters:
- G-protein linked receptors: have 7 transmembrane regions and each has a central core that
contains NT binding site. Also there are allosteric sites where drugs can bind and influence
the receptor. Types of drugs acting on these receptor (the agonism spectrum)
A. Agonists: if bind to receptor activate second messenger maximally by binding to NT
binding site or by blocking NT breakdown/inactivation
B. No agonist: does not maximally activate but can still have some constitutive activity
at locations with high receptor density
C. Antagonist: returns G protein receptor to baseline state
D. Partial agonist:
E. Inverse agonist: produces change in g protein receptor that stabilizes it in a totally
inactive form
- Enzyme: can be inhibited reversibly or irreversibly. Enzymes which we target clinically are
MAO and GSK. (keep in mind that a lot of drugs also act on CYP in the liver).
Cytochrome P450 enzymes as targets for psychoactive substances:
- CYP is a hepatic enzyme. The majority of psychotropic agents are transformed by this which
can lead to significant drug interactions.
A. inhibitory interactions with cytochrome p450 inhibiting this system increasing
plasma levels and toxicity of co-administered drugs
B. hepatic enzyme induction by psychoactive agents causing the cytochrome p450
system to accelerate and thus increase speed of metabolism of co-administered
drugs resulting in abnormally low plasma levels (ex. cardiovascular drugs)
- CYP assignments on patients are done if they have no effects of drug (fast metabolizer) or
very sever response with lots of side effects for low dose of drugs (slow metabolizer). CYP2D6
(most common) and CYP2C9, CYP2C19.
Ion channels as targets for psychoactive substances:
There are different types of ion channels that can be a target of psychoactive substances:
- Voltage gated ion channels:
A. VSSC
B. VSCC
- Ligand-gated ion channels (also called ion channel linked receptor): opening is regulated by a
NT, the NT can act across the agonist spectrum. They can also be influenced by molecules
interacting at other sites on the receptor:
A. PAM: positive allosteric modulator – boosts the action of the neurotransmitter
B. NAM: negative allosteric modulator – diminishing the action of the neurotransmitter
The ion channels exist in several states: open, resting, closed, inactivated, desensitized.
,The structure of ligand gated ion channels
Composed of a transmembrane domain which includes the ion pore and an extracellular domain with
ligand binding location (and allosteric binding site). Function: convert chemical signal NT into
postsynaptic electrical signal. There are diffent families of these channels:
- Pentameric subclasses:
A. Nicotinic receptors (Ach)
B. GABA receptors
C. Strychnine sensitive glycine receptors (Gly)
D. 5HT3 receptors (5HT)
- Tetrameric substances
A. AMPA, NMDA, kainate (Glu)
AMTS score
The Abbreviated mental test score (AMTS) is a test for rapidly assessing elderly patients for the
possibility of dementia. It was first used in 1972, and is now sometimes also used to assess for mental
confusion and other cognitive impairments. The following questions are put to the patient. Each
question correctly answered scores one point. A score of 7–8 or less suggests cognitive impairment
at the time of testing, although further and more formal tests are necessary to confirm a diagnosis of
dementia, delirium or other causes of cognitive impairment. Culturally-specific questions may vary
based on region.
Clock drawing test: is that it can detect problems in executive functioning even when someone
scores well on the MMSE, a common screening tool. Executive functioning can be impaired before
any memory problems are evident, and identifying this early allows early treatment.
For example, your father could perform well on the MMSE, which would show that his memory still is
quite intact, his language and calculation skills remain functional, and his orientation remains fairly
normal. You, however, may notice that his decisions are not always appropriate. He may be able to
get dressed, but not be able to determine that he should wear a warm coat out if it is cold outside.
Mini-cog test: is not strongly influenced by education, culture, or language; it was perceived as less
stressful to the individual than other longer mental status tests. The accuracy of the Mini-CogTM in
heterogeneous groups may increase the identification of dementia in populations less diagnosed
thereby increasing minority participation in research and improving parity of early treatment.
The MMSE test can be used by clinicians to help diagnose dementia and to help assess its
progression and severity.
It consists of a series of questions and tests, each of which scores points if answered correctly.
The MMSE tests a number of different mental abilities, including a person's memory, attention and
language.
MMSE is only one part of assessment for dementia. Clinicians will consider a person's MMSE score
alongside their history, symptoms, a physical exam and the results of other tests, possibly including
brain scans.
The MMSE can also be used to assess changes in a person who has already been diagnosed with
dementia. It can help to give an indication of how severe a person's symptoms are and how quickly
their dementia is progressing.
, Again, results should be considered alongside other measures of how the person is coping together
with clinical judgement. But we still need some neuropsychological testing:
- Interview to discuss symptoms
- Symptom validation interview (tests to see if sbd is exaggerating/underreporting) on which
people with severe dementia score well, so confront if they score bad.
A. AKT
B. Theory of malingering
- (cognitive function testing)
A. Attention testing: number sequence repeating, repeat numbers backwards, STROOP
test
B. Memory testing: remember 15 words test
Diagnosis
Delirium is a state of acute confusion that often happens to a patient with a somatic illness,
medication use or use (withdrawal) from substances which are addictive. 1-2% in general population
higher in hospital and elderly, also more inhospital (ICU). 3x higher risk for dementia by delirium
(higher susceptibility/ vulnerability). It can be classified by the DSM V into: delirium caused by:
intoxication with a substance, withdrawal from a substance, mediation, somatic disease, multiple
causes and unspecified delirium.
There are different psychomotoric forms of delirium.
- Restless/hyperactive from: motoric restlessness ang agitation, decreased self-control (cannot
sit still if needed), restless (mental), scream, swear, defend against caretakers. Often
caretakers seek help quickly because care of the patient is difficult.
- Apathic/hypoactive from (silent delirium): decrease in movement, slow, decreased
interaction with surroundings, decreased and slower speech, decreased consciousness
(passive, indifferent), apathy, withdrawing behaviour, decreased attention. Often
experienced a san easy patient and often not recognized as delirium but depression or
dementia.
- Mixed: hyper and hypo switching (a lot in the elderly)
Criteria for delirium:
A. Disturbance of consciousness: with decreased ability to focus attention, concentrate, retain
or switch attention to new stimulus. It is a change in functioning of the patient.
B. Change in cognitive function: memory, disorientation, perception disorder, language disorder
that can not be better attributed to a present, or developing dementia
C. Happens within a short time span (hours until days) and is more fluctuating during the day =
ACUTE.
You should do a lab test to find a somatic cause, however often it cannot be found. Medication is a
common cause for delirium so that also should be taken into account.
First symptoms which we come acoss is sleeplessness during the night and being ‘suf’ during the day,
vivid dreams or nightmears, illusionary deceptions, difficulty with thought and concentration,
restlessness and withdrawal, irritability, anxiety, tension. The severity duration and prognosis of
delirium depend on the somatic problem, vulnerability of the patient and the effect of the treatment.
Often a delirium lasts several days up to several weeks, however older patients in particular have the
chance to have a delirium which takes over 1 month.
Clinical signs:
- Consciousness and attention: decreased consciousness expressed a disturbed attention and
increased or decreased alertness FLUCTUATING
- Orientation: disorientation in all three fields
