Christopher nolan- anxiety dementia

Question 1

define Anxiety

Answer 1

Anxiety is an intense, excessive and persistent state of apprehension worry or fear about real or perceived threats or future uncertainties. It may be accompanied by physical symptoms such as restlessness, increased heart rate, muscle tension, sweating and difficulty in concentration.

Question 2

Define pathological anxiety

Answer 2

1. Fear is greatly out of proportion to risk/severity of the threat.
2. The response continues even when the threat is gone or becomes generalized to other similar or dissimilar situations.
3. Social or occupational functioning becomes impaired.
4. The anxiety cannot be explained by an underlying medical condition e.g. metabolic, substance abuse, depression or psychosis.

Question 3

Define generalized anxiety disorder

Answer 3

GAD is a persistent state of anxiety which is not specific to any particular circumstance with symptoms persisting for >6 months.

Atleast 3 of the following (“BE SKIMS”)

Blank mind/difficulty concentrating
Easily fatigued
Sleep disturbances (difficulty falling asleep or staying asleep)
Kept up or restless
Irritability
Muscle tension
Sympathetic overdrive

Question 4

Describe the synthesis of serotonin

Answer 4

Tryptophan –> 5-hydroxytryptophan (tryptophan hydroxylase) –> 5-hydroxytryptamine (amino acid decarboxylase)

Question 5

list 3 regions in the body where serotonin is found

List 4 functions of serotonin in the body

Answer 5

Found in:
(i) Chromaffin cells of GI tract
(ii) Platelets
(iii) CNS

Functions in
(i) Platelet aggregation
(ii) GI motility
(iii) Stimulation of peripheral nociceptors
(iv) Mood regulation

Question 6

List 3 SSRIs

Answer 6

Sertraline
Fluoxetine
Citalopram
Paroxetine

Question 7

list 2 SNRIs

Answer 7

Venlafaxine
Duloxetine

Question 8

MOA of benzodiazepines in seizure control

Answer 8

Diazepam, Lorazepam, Midazolam

MOA
-Benzodiazepines enhance the activity of GABA to cause opening of neuronal chloride channels causing hyperpolarisation of the excitatory neuron—> reduces its excitability, preventing excessive depolarizations and seizure generation.
-It does so by binding to its site on the GABA-A receptor between the alpha-1 and gamma-2 subunit.
- Benzo’s only work in the presence of GABA

Question 9

List 4 contraindications to benzos

Answer 9

1. Hypersensitivity
2. Closed angle glaucoma
3. Respiratory depression
4. Myasthenia gravis
5. History of substance use disorder

Question 10

Define tolerance and list 3 key underlying mechanisms for its development

Answer 10

Tolerance refers to a reduction in pharmacological/physiological effects of a drug after repeated use at a dose that was once sufficient to achieve the desired effect. It therefore means that the dose must be increased.

Mechanisms

1. Receptor modulation: With chronic use of benzo’s, the GABA-A receptors can become down-regulated i.e. less receptors available for the drug to bind to or else they become less responsive to the drug. GABA-receptors with the alpha-2 subunit are especially effected in benzo use.
2. Dose: The higher the dose, the more GABA receptors that benzos will be occupied which accelerates the development of tolerance.
3. Duration of receptor occupancy
   Continuous use of benzos will likely cause greater receptor desensitization compared to intermittent or short term use (e.g. those using for sleeping aids will be less likely to develop tolerance than someone using long term at a much higher dose for seizure control)

Question 11

Differentiate between tolerance and dependance

Answer 11

Tolerance is a result of the brain’s initial adaptations, such as receptor downregulation (inhibitory systems) which reduce the effects of the drug over time. While tolerance requires higher doses, it doesn’t yet significantly disrupt the brain’s ability to maintain neurotransmission balance.

Dependence arises when the brain’s adaptations become more profound, and it begins to rely on the drug for balance, meaning the loss of intrinsic ability to regulate neurotransmission without the drug leads to withdrawal symptoms when the drug is discontinued. This is typically the result of GABA receptor downregulation and compensatory NMDA receptor upregulation in the presence of the drug.

Question 12

Describe the mechanism underlying dependance

Answer 12

Neuroplastic and neuroadaptive changes

Chronic exposure to benzodiazepines leads to neuroadaptive changes, including downregulation of GABA-A receptors and upregulation of NMDA receptors, as the brain attempts to compensate for the enhanced GABAergic inhibition caused by the drug. Upon withdrawal, there is continued underactivity of the GABAergic system due to reduced GABA-A receptor function, while the excitatory glutamatergic system remains hyperactive, primarily due to the upregulated NMDA receptors. This imbalance between inhibitory and excitatory transmission contributes to the withdrawal symptoms.

Question 13

List 4 regions of the brain involved in language processing and describe the role of each region

Answer 13

1. Angular gyrus
   -Located in the inferior parietal lobule
   -Receives information from the visual cortex
   -Helps in reading aloud by converting graphemes (written symbols) into phonemes (sounds) — a process known as phoneme retrieval.
   -Passes phoneme information to Wernicke’s area for comprehension and to Broca’s area for speech production.
   -Damage results in Alexia
2. Wernicke’s area
   -Located in Superior temporal gyrus on dominant side (usually left)
   -Receives information relating to phenomes from bilateral primary auditory cortices and functions to comprehend the sounds heard, i.e. puts meaning to sounds.
   -Also receives information from the angular gyrus in relation to grapheme (understand written language).
   -Damage results in loss of comprehension of language/word salad
3. Broca’s area
   -Located in inferior frontal gyrus
   -Allows for co-ordination and planning of speech output by communicating with the motor cortex to allow for appropriate muscle contraction to produce speech.
   -Also functions in the comprehension of syntax.
   -Damage results in telegraphic speech + Dysprosody (long gaps between words)
4. Arcuate fasciculus
   - Channel of communication between wernickes and broca’s area.
   - Believed to function in comprehension of syntax
   - Damage results in loss of repetition of spoken words.

Question 14

list 2 types of long term memory

Answer 14

(1) Explicit (declarative)
-> Episodic memory: Recall of personal experiences or events including geographic location, times, and other contextual info: Hippocampus, medial temporal lobe, pre-frontal cortex

-> Semantic memory: Recall of facts, general knowledge, concepts: Anterior temporal cortex, lateral prefrontal and neocortex.

Semantic memory would be remembering what a cat is, but episodic memory would be recalling a time when you were scratched by a particular cat.

(2) Implicit (non-declarative)
->Procedural memory: Does not require conscious recollection e.g. riding a bike, tying shoe laces: Basal ganglia, motor and associated cortex, cerebellum.

Key areas of brain for long term memory
Hippocampus: Encoding episodic and declarative memories.
Amygdala: Emotional modulation of memory.
Neocortex: Long-term storage of consolidated memories.
Lateral Prefrontal Cortex: Facilitates retrieval and organization of memories.

Question 15

Outline the key areas of the brain involved in anterograde and retrograde amnesia

Answer 15

Anterograde
Inability to form new memories, old memories remain intact
(i) Hippocampus
(ii) Mamillary bodies
(iii) Fornix
(iv) Anterior thalamic nuclei
(v) Pre-frontal cortex

Retrograde
-Inability to remember old memories, new memories intact
(i) Medial temporal lobe (including the hippocampus)
(ii) Neocortex

Question 16

list 4 acute effects of benzos

Answer 16

Acute

-Sedation due to GABAergic activity in limbic system, reticular activating system of brainstem and hypothalamus

-Anti-anxiety due to GABAergic activity mainly amygdala and
prefrontal cortex

-Anticonvulsant

-Muscle relaxant due to GABAergic activity in the spinal cord

-Anterograde amnesia due to GABAergic activity in hippocampus

Question 17

list 4 chronic effect of benzos

Answer 17

Chronic

(i) Emotional blunting
-chronic GABAergic activity in prefrontal cortex (involved in emotional processing)
-Reduced dopamine release in mesolimbic dopamine pathway also contributes to flattened affect

(ii) Rebound anxiety
- Cessation of benzo’s can lead to rebound anxiety, due to downregulated GABA receptors unable to counteract the now hyperactive excitatory neurons in areas like the amygdala

(iii) Depression
-Due to disruption of dopamine, noradrenalin and serotonin neurotransmission in the brain, particularly pre-frontal cortex

(iv) Cognitive deficits

(v) Loss of libido/sexual dysfunction
-Due to dampening of excitatory neuronal signals in areas like the hypothalamus and limbic system.

Question 18

Describe the key theories surrounding the aetiology of anxiety

Answer 18

(1) Reduced Functional Connectivity Between the Prefrontal Cortex and Limbic System:
-Prefrontal cortex is not sufficiently mediating emotional responses in the limbic system, particularly the amygdala –> leads to these regions becoming overactive/dysfunctional

(2) Single Nucleotide Polymorphism (SNP) Variations in the 5-HT Transporter
-Same as the monoamine hypothesis in depression –> reduces serotonin signaling in the brain leads to anxiety

(3) In anxiety disorders, the HPA axis can become dysregulated, often resulting in overactivation of the stress response. Chronic activation of the HPA axis and sustained elevated cortisol levels are thought to contribute to the development and maintenance of anxiety and related disorders.

Question 19

Differentiate between delirium and dementia

Answer 19

Delirium is a reversible, acute and transient state of confusion associated with altered and fluctuating levels of consciousness. It is often associated with organic causes such as polypharmacy, dehydration, infections. Its onset is rapid (hours to days) with symptoms including disorientation, hallucinations and altered levels of consciousness/attention. abnormal EEG

Dementia is an irreversible, chronic and progressive state of confusion associated with progressive decline in cognitive function independant of attention/level of consciousness. Its onset is slow and insidious (months to years) and is most commonly associated with neurodegeneration of the brain. normal EEG

Question 20

List 3 tests that may be done as a work up for delirium

Answer 20

1. Bloods- FBC(anemia, infection, malignancy) U+Es, TFTs, LFTs (encephalopathy), Glucose, Cultures (sepsis), inflammatory markers (CRP, ESR), B12/folate
2. Urine dipstick
3. CT brain if concerns re intracranial hemorrhage

Question 21

what are the DSM-5 criteria to make a diagnosis of delirium

Answer 21

1. Disturbance in attention and awareness
   –> Attention (focus, sustain, shift )
   –> Awareness (orientation to environment)
2. Acute onset + fluctuating
3. An additional disturbance in cognition
   –> memory, disorientation, language, perception, visuospatial
4. Disturbances in cognition, attention and awareness are not explained by a pre-existing neurocognitive condition and don’t occur in the setting of coma/ reduced arousal.
5. Direct physiological cause established through history, exam or labs
   –> intoxication, withdrawal, polypharmacy causing drug interaction

Question 22

DSM 5 criteria for dementia?

Answer 22

1. Significant cognitive decline from baseline in one or more domains (memory, language, executive function, Complex attention, perceptual motor, social cognition)
2. Interference with independence and daily functioning
3. Progressive worsening
4. Exclusion of delirium
5. Exclusion of other medical conditions that could explain the symptoms.

Question 23

Describe the aetiology of early onset (familial) AD

Answer 23

Amyloid-beta protein

Early-onset Alzheimer’s disease (<60) is commonly associated with genetic mutations in the gene coding for amyloid precursor protein (APP) on chromosome 21, as well as mutations in PSEN1 and PSEN2, which regulate amyloid precursor protein cleavage. It is inherited in an autosomal dominant pattern.

Mutations in APP result in abnormal production and cleavage of the protein, leading to excess amyloid-beta (Aβ) peptide formation.

These peptides aggregate into beta-amyloid fibrils, contributing to the characteristic amyloid plaques seen in Alzheimer’s disease.

Tau proteins

Hyperphosphorylation of Tau proteins, which normally stabilize microtubules, disrupts their ability to bind microtubules. This results in microtubule instability, impaired intracellular transport, and synaptic dysfunction, ultimately leading to the formation of neurofibrillary tangles (NFTs) and neuronal cell death.

End result

Neuritic plaques composed of a central amyloid core, and surrounded by microglia, reactive astrocytes and dystrophic neurites

Commonly seen in: Cerebral cortex, hippocampus, amygdala, neocortex

Question 24

Explain the aetiology of Late onset AD

Answer 24

o Late-onset Alzheimer’s disease (LOAD) is associated with genetic risk factors on chromosomes 12 and 19. Chromosome 12 encodes the protein alpha-2-macroglobulin (A2M), which is involved in the clearance of beta-amyloid. Certain genetic variants of A2M may impair this clearance, increasing the likelihood of beta-amyloid accumulation in the brain.

o On chromosome 19, the Apolipoprotein E (ApoE) gene encodes a cholesterol transporter that plays a critical role in lipid metabolism and beta-amyloid clearance. The ApoE4 allele is associated with an increased risk of Alzheimer’s disease because it is less effective in clearing beta-amyloid, leading to its accumulation as fibrillar plaques in the brain.

Question 25

define the following:

Aphasia

Alexia

Dysprosody

Dysarthria

Dysphonia

Agnosia

Answer 25

Aphasia: difficulty in production or comprehension of speech (language disorder).

Alexia: Inability to read

Dysprosody: Abnormal innotation, rhythm of word production e.g. long gaps between words

Dysarthria: Difficulty in execution of speech due to damage to motor component of speech production.

Dysphonia: Difficulty in production of speech sounds, commonly caused by inability to oscillate vocal cords

Question 26

Describe the synthesis and degradation of acetylcholine

Answer 26

**Synthesis*

-Choline is taken up into the pre-synaptic terminal via choline transporter
-In the cytosol, choline acetyltransferase combines choline with Acetyl CoA (from krebs) –> Acetylcholine + CoA
- Ach is then packaged into vesicles by vesicular acetylcholine transporter

Degradation
-Acetylcholinesterase or Butyrylcholinesterase (glial cells)–> choline and acetate

Question 27

Name the 3 acetylcholine breakdown inhibitors

Answer 27

(1) Donepezil –> Acetylcholinesterase inhibitor

(2) Rivastigmine –> Acetylcholinesterase + Butyrylcholinesterase

(3) Galantamine –> Acetylcholinesterase

Question 28

Why give Memantine

Answer 28

Amyloid plaques can cause excessive release of glutamate which leads to neuronal excitotoxicity through hyperexcitation of NMDA receptors –> calcium influx, toxic free radical production and cell death.

Memantine is a weak NMDA receptor antagonist that blocks the NMDA receptor’s ion channel during periods of excessive glutamate activation –> this prevents large amounts of calcium influx through the channel in response to excessive glutamate activation.

This prevents excitotoxicity.

Memantine’s voltage-dependent blockade allows it to selectively block calcium entry during periods of excessive or prolonged glutamate release, while its blockade can be reversed during phasic bursts of glutamate to allow for normal glutaminergic transmission