Case 8 Flashcards
What is the three functional subdivisions of the striatum?
Sensorimotor - Putamen and caudate
Associative - Globus Pallidus
Limbic/Ventral - Ventral Tegmental Area
What are the dopamine pathways?
Nigrostriatal, Mesocortical, Mesolimbic and Tuberofundibular
Where does the nigrostriatal project from and to?
Substantia nigra to striatum (caudate and putamen)
Dorsal striatum is associated with involuntary motor control (Parkinson’s Disease)
Associative striatum w/ learning, habituation, volition, memory, attention and motivation
What does the nigrostriatal pathway control?
Motor function and movement
What does deficit in Dopamine via nigrostriatal pathway cause?
Movement disorders characterised by rigidity, Akinoso’s/bradykinesia and tremor
What is akathesia?
A type of restlessness produced by dopamine deficiency in basal ganglia
What is dystonia?
Twisting movements especially of the face and neck
What does hyperactivity of dopamine cause in nigrostriatal pathway?
Emotional behaviour - positive symptoms of psychosis (delusion and hallucinations)
Motivation, pleasure and reward
Hyperkinetic movement disorder
What is neuroleptic-induced tardive dyskinesia?
Hyperkinetic movement disorder caused by chronic blockade of D2 receptors
Where does the increased dopamine associated with schizophrenia occur?
Associative striatum of the nigrastriatal pathway
Where does the mesocortical pathway project to and from?
Ventral tegmental area of brain stem to prefrontal cortex
What is the the mesocortical pathway associated with?
Mediating cognitive symptoms (dorsolateral prefrontal cortex,DLPFC) of SCHZ
Mediating affective symptoms (Ventromedial Prefrontal Cortex, VMPFC) of SCHZ
Mediating negative symptoms (DLPFC AND VMPFC) of SCHZ
What causes negative, cognitive and affective symptoms in mesocortical pathway?
Deficit of Dopamine projections
What is the Mesolimbic pathway projections?
Ventral tegmental area (ventral striatum) to nucleus accumbens in ventral striatum
What is the nucleus accumbens?
axon terminals in one of the limbic areas of the brain
What does deficient function of Mesolimbic pathway cause?
Negative Symptoms: Loss of motivation and interest, anhedonia and lack of pleasure
What is anhedonia?
Inability to feel pleasure in normally pleasurable activities
What does an increase dopamine in Mesolimbic pathway cause?
Positive symptoms
What is the projections of the tubetoinfundibular dopamine pathway?
Hypothalamus you’re anterior pituitary gland
What is the activity of projections of tuberoinfundibular pathway?
Inhibition of prolactin release - required for lactation during breastfeeding
What is elevation prolactin associated with?
Breast pathology, amenorhea (loss of ovulation and menstrual periods), sexual dysfunction
Caused by reduced dopamine activity
What is schizophrenia (ICD-10 definition)?
A severe and enduring mental disorder with fundamental and characteristic distortions of thinking and perception l, and affects that are inappropriate or blunted. Clear consciousness and intellectual capacity are usually maintained, although cognitive deficits may evolve in the course of time”
What is schizophrenia?
A major psychosis characterised by disintegration of the process of thinking, of contact with reality and of emotional responsiveness
It can be remittent, run a course with infrequent or frequent relapses or become chronic
What are the positive symptoms
of schizophrenia?
Existence of an abnormal phenomenon, delusions, hallucinations, though disorder, bizarre behaviour and Catatonia
Symptoms are associated with acute episode
What are negative symptoms of schizophrenia?
Absence or reduction of normal function and reactions - apathy, affective blunting, poverty of speech(Alogia)c inability to experience pleasure (anhedonia); lack of desire to form relationships (asociality), social withdrawal, impaired judgement, lack of motivation (avolition), lack of interest in personal hygiene, difficulty in planning and impaired problem solving
Associated with chronic schizophrenia
What are cognitive impairment of schizophrenia?
Memory and executive functions
What is delusion?
A fixed, false belief unshakeable by superior evidence to the contrary, and out of keeping with a person’s cultural norm
What are the types of delusions?
Reference
Persecution
Control
Buzz are and impossible
What is hallucinations?
A perception, internally generated, in the absence of an external stimulus which can occur across all sensory modalities
Auditory is most common
What are the classifications of Schizophrenia?
- Paranoid SCHZ - dominated by delusions and hallucinations (positive symptoms)
- residual SCHZ- predominantly negative symptoms
What is the epidemiology of SCHZ?
prevelance in the world = 1%
Average age of onset is 15-25 m; 20-30 w
Men have poorer response to treatment than women and worse long-term outcome
How is SCHZ diagnosed?
ICD-10 criteria:
At least 1 first-rank symptom for at least 1month:
- thought echo, insertion or broadcasting; delusions of control; auditory hallucinations; impossible and persistent delusions
Or at least 2 second-rank symptom for at least 1month:
- persistent hallucinations in other modality; thought disorder; catatonic behaviour; negative symptoms not due to depression or medications
What are the risk factors of SCHZ?
Significant genetic component
What is the anatomical division of striatum?
Ventral striatum: nucleus accumbens and olfactory tubercle
Dorsal Striatum: caudate and putamen nucleus
What are the dopamine receptors?
They are divided into D1 and D2 receptors
D1 - activate adenylyl Cyclase
D2 - inhibit formation of cAMP by inhibiting adenylyl cyclase
What are the D1 receptor division and where are they found?
D1- motor, associative and ventral striatum; cerebral cortex
D5 - hippocampus and hypothalamus
What are the D2 receptor divisions and location?
D2(L+5) - motor, ventral and associative striatum (affect dopamine synthesis, metabolism and release)
D3 - ventral and associative striatum, hippocampus and amygdala (affect dopamine release)
D4 - frontal cortex, medulla, midbrain and amygdala
What are the dompamine abnormalities in SCHZ?
Excessive dopamine release in associative striatum correlating with positive symptoms and good treatment to antipsychotic drugs
Inadequate dopamine in prefrontal and ventral striatum correlating cognitive impairment and negative symptoms (respectively)
What is the link between DLPFC, Striatum and Dopamine?
Decreased dopamine in DLPFC causes increased release in striatum through feedback (vice versa)
This causes vicious cycle in SCHZ
What is the dopamine hypothesis?
Psychosis is associated with increased dopamine presynaptic function in nigrostriatal pathway (specifically part to associative striatum) rather than Mesolimbic pathway
What is the primary abnormality in SCHZ?
Glutamate or GABA system In DLPFC
What are the glutamate receptors?
NMDA, AMPA, Kainate and mGluR1-8
What happens in NMDA hypofunction?
Positive, negative and cognitive symptoms of SCHZ
Hypofunction > excessive GLU release causing excitotoxicity > impaired neuronal development > worsening of SCHZ and disease progression
What are the environmental factors of NMDA dysfunction?
Pre/perinatal insult, development neurotoxicity, activity/nutritional Status, metabolic variation
What is genetic factor of NMDA dysfunction?
Neuroregulin, dysbindin, DAAO/G72, isolated variants
When can the increase in dopamine in associative striatum be detected?
3 yrs before onset of first episode of positive symptoms SCHZ
What is cognitive deficits associated with SCHZ?
Decreased mesocortical DA (in DLPFC)
What is the combination of SCHZ treatment?
Drug therapy and psychosocial support
What treats acute psychosis and reduce the risk of future psychotic episode?
Antipsychotic drugs
What does SCHZ treatment aim?
Decreased dopamine binding to D2 dopamine receptors
What are the two types of antipsychotics?
Typical - chlorpromazine
Atypical - risperidone
These are all reversible antagonists at D2 dopamine receptors (block excessive production and release of dopamine in psychosis)
What is the threshold for antipsychotic efficacy?
65% D2 receptor occupancy
What is the difference between the D2R occupancy over time for atypical and typical drugs?
Typical - barrow dose range for efficacy vs overdose
Atypical - wife dose range between efficacy vs overdose
Where does D2R occupancy occur?
Limbic striatum
Occupancy treats positive symptoms not negative
At what percentage of occupancy does side effects of D2 antagonist occur?
> 72%
What are the side effects of D2 antagonist?
Nigrostriatal - extrapyramidal side effects (EPSE) - Parkinsonism
Mesolimbic - worsen negative symptoms
Mesocortical - deformation un cognitive function
Tuberoinfundibular - hyperprilactinaemia
Which other receptors do antipsychotics antagonise?
Muscarinic, alpha-2adrenergic and 5-HT2 receptors causing receptor-mediated side effects
What is the mechanism of action is risperidone?
Blockade of D2R in ventral striatum alleviating positive symptom
Blockade of 5HT2R in mesocortical tract increases dopamine transmission and an elimination of core negative symptoms
What are side effects of risperidone?
Hypotension, weight gain, rash, vomiting and constipation
What is the mechanism of action of Clozapine?
D2R blockage in Mesolimbic pathway and 5HT2R in frontal cortex relieving positive symptoms and alleviating negative symptoms (respectively)
Side effects of clozapine?
Sedation, hunger, Hypersalivation, diabetes
What causes the major side effects of antipsychotics?
High serum prolactin level is due to D2R antagonism in tuberoinfundibular pathway
Parkinsonian symptoms - D2R antagonism in nigrostriatal pathway
Weight gain - antagonism of H1 and 5HT plus effects on leptin
Detoriorated working memory - antagonism of D2 in mesocortical pathway
Blurred near vision - M1 antagonism
Sedation - H1 and Alpha-adrenergic antagonism
What is the psychosocial treatment for SCHZ?
Cognitive and occupational therapy help cognitive improvement through social skill development and cognitive behavioural treatment
Family and supportive service
CBT
When is Detainment under MHA 1983(2007) allowed?
Suffering from a mental disorder
Unwilling to accept hospitalisation voluntarily
Safety of patient or those around them is at risk
What is MHA Section 2?
Hospitalised first 28days
Signed by 2 doctors or approved clinicians and nearest relative or approved mental health worker
Purpose = assessment and treatment
Who can discharge a patient detained under MHA section 2 or 3?
Responsible clinicians
mental health Act managers
nearest relative (although this can be overruled by the responsible clinician)
Tribunal
What is CPA?
Care programme approach - a care plan for after care arranged before discharge from hospital
What is compliance?
Degree to which patient follows the advice of a medical professional
What is coercion?
Practice of forcing another party to act in an involuntary manner by use of intimidation or threats or some other form of pressure or force
What is MHA section 3?
Duration is 6 months (can be renewed)
Agreed by 2 doctors or approved clinicians plus nearest relative or approved mental health worker
Purpose is for treatment
How are afferent information brought to the cerebellum?
Dorsal spinocerebellar Tract - lower extremity
Cuneocerebellar tract - upper extremity
Travel to ipsilateral cerebellum via inferior cerebellar peduncle
How are efferent information carried by the cerebellum?
Ventral spinocerebellar tract - lower extremity
Rostral spinocerebellar tract - upper extremity
How are output from cerebellum carried?
Purkinje cells to the deep cerebellar nuclei or vestibular nuclei
Where do the axons from the dentate, fastigial and interposed nuclei go?
Ventral lateral nucleus of the thalamus
Which then projects to motor cortex effectingncorticospinal and Corticobulbar UMN
What is cerebellar ataxia?
Difficulty to produce smooth and well-coordinated movements due to lesion in cerebellum
What does lesion in vermis of spinocerebellum eliminate?
Ability to reduce motor error in the oculomoteur system caused by cut of lateral recrus tendon causing weakened horizontal eye movement
What is Parkinson’s Disease?
A disease that is characterised by rest tremor, rigidity, bradykinesia and gait impairment associated with degeneration of dopaminergic neurons in SNcp - causes low L-DOPA production
What is Parkinsonism?
Clinical picture characterised by tremor rigidity, slowness of movement, and postural instability
What is the epidemiology of Parkinson’s disease?
1.5/1000 in UK
Mean onset age is 60
Increased risk with exposure to pesticides, rural living, and drinking well water and reduced risk with cigarette smoking and caffeine
What are the signs of PD?
Cardinal signs - rest tremor, rigidity, bradykinesia, fait impairment
Non-dopaminergic features = Micrographia, impassive face, postural instability, speech difficulty, mood disorders, cognitive impairment
What is the gene considered in patients with PD onset prior to 40?
Parkin (recessive) gene
When do symptoms of PD show?
Once the dopamine content is around 20-40% of the normal
With hypokinesia showing first
What are secondary consequences that occur after damage to nigrostriatal tract?
Hyperactivity of remaining dopaminergic neurones - increase. Rate of transmitter turnover
Increased number of dopamine receptors - state of denervation hypersensitivity
What is tremor in PD?
Characteristic 4-6Hz pill-rolling tremor at rest - which decreases or stops with action or sleep
What is rigidity?
Stiffness developing throughout movement and equal in opposing muscle groups (lead pipe like increase in tone - plastic rigidity)
Where is plastic rigidity more seen?
One one side and in the neck and axial muscles
What is cogwheeling?
When stiffness occurs with tremors, smooth lead-pipe rigidity is broken up into a nearly resistance to passive movement
What is akinesia?
Difficulty initiating movement
Shown in decreased facial expression and spontaneous blink rate
Voice is monotone and speech poor
What is a Anarthria?
Loss of speech
What is the characteristic of reflexes in PD?
Brisk and asymmetrical (follows the increased tone)
Plantar responses remain flexor
Which factors are most important in cause of PD? I
Environmental in over 50yo
Genetics in under 40yo
How is PD caused by mutation in Parkin enzyme distinguished from sporadic PD?
Absence of Lewy bodies
What leads to cell death in PD?
Oxidative stress, intracellulaire calcium accumulation with exocitotoxicity, inflammation, mitochondrial dysfunction (apoptosis), protéolytique stress
Death is via apoptosis or suicidal process
What is Lewy bodies and Lewy Neurites?
Composition of misfolded and aggregated proteins
What causes protein aggregation?
Increased formation (mutation in alpha-synuclein) or impaired clearance of proteins
How are proteins normally cleared?
By the ubiquitin proteasome system of autophagy/lysosome pathway
What are the changes in dopamine pathway in PD?
Less activation of D1R - decreased dynorphin and decreased stimulation of direct pathway
Less activation of D2R - increase enkephalin and decreased inhibition of indirect pathway
What is a PET scan?
Positron Emission Tomography
3D image of functional processes in the body through detection of pairs of gamma-rays
18F-Fluorodopa is used in PD to show decreased dopamine in SN
18F-Fluorodeoxyglucose measures metabolic activity and used to catch cancer metastasis
What is a SPECT scan?
Single Photon Emission Computed Tomography
2D pictures via gamma camera arranged to make 3D dataset
Cheaper but lower resolution compared to PET
Easier to prepare due to more availability of radioisotope used and longer half-life
What is Co-Beneldopa?
Combination of Levodopa and Benserazide
What is the MOA of Levodopa?
Crosses BBB and is decarboxylated into dopamine which then stimulates Dopaminergic receptors
Levodopa is short acting and effectiveness declines over time
It is inactivated by MAO in the small intestines
What is MOA of Benserazide?
Peripherally acting DOPA decarboxylase inhibitor
Used to reduce peripheral side effects as it can not cross BBB
What are some unwanted Levodopa side effects?
Dyskinesia (involuntary writhing of movements)
Rapid fluctuations in clinical state - worsening of hypokinesia and rigidity
What is the MOA of selegiline?
It is a selective MAO-B inhibitor which protects dopamine from extraneuronal degradation
Selegiline combined with levodopa is more effective than levedopa alone to relieve symptoms and prolong life
What is QoL?
Quality of Life - a simple biological criteria for success seen as inappropriate used for treatment choice
