WEEK 8 NEUROLOGICAL DISEASES Flashcards
1
Q
What is the second leading cause of death for Australians?
A
Dementia
2
Q
In 2020 how many Australians are living with dementia?
A
459, 000 Australians, and 50 million worldwide
3
Q
What is the ADNeT registry?
A
- the backbone (spine) of the dementia research project
- Clinical quality registry for persons newly diagnosed with dementia or Mild Cognitive Impairment (MCI)
4
Q
What is the estimated percentage of dementia among people aged 65 and over?
A
10%
5
Q
What is the estimated percentage of dementia among people aged 85 years and over?
A
30%
6
Q
In which settings might a person receive diagnosis work up and assessments for dementia?
A
General practice, memory clinics, other Hospital outpatient clinics, hospital inpatient wards, private specialists including geriatricians and neurologists, aged care assessments, residential aged care facility
7
Q
What are some of the early signs of dementia?
A
- Confusion
- Forgetfulness
- Memory loss
- Impact language use.
8
Q
is a dementia diagnosis done with a combination of different assessments or just one?
A
- Combination of different assessments
- This is to assess cognitive capabilities e.g. mini mental state exam in a memory clinic for example
9
Q
What does ADNeT mean?
A
- Australian Dementia Network Registry
10
Q
What are clinical quality registries (CQR)?
A
- Organisations which systemically monitor the quality (appropriateness and effectiveness) of healthcare, within specific clinical domains, by routinely collecting, analysing and reporting health – related information.
11
Q
What are three benefits of clinical quality registries?
A
- Driving continuous improvements in patient-centred health care and outcomes.
- Improving the value of healthcare.
- Contributing to the sustainability of healthcare systems.
12
Q
What did the Framework for Australian clinical quality registries develop?
A
- A prioritised list of clinical domains for clinical quality registry development
13
Q
What is ADNeT collecting data for, that will hopefully change the standard of care?
A
- Dementia
14
Q
What is the vision of ADNeT?
A
- To incorporate all diagnostic settings and services for dementia in Australia, and register the entire population of persons newly diagnosed with either dementia or MCI, and in doing so, systemically drive improvements and quality of care and patient outcomes.
15
Q
What is the primary aim of ADNeT?
A
- To collect and analyse data to monitor and enhance the quality of care and patient outcomes for people diagnosed with dementia or MCI.
16
Q
What is the secondary aim of ADNeT?
A
- To facilitate recruitment of participants into research projects, and establish a resource to facilitate further study into the risk factor for, and trajectory of dementia and MCI in Australia
17
Q
What are the three different types of data collection source for the CQIs?
A
- Participating sites (Patient demographic information, and baseline and follow-up clinical data)
- Registry participants and carers (if appropriate, and only following recruitment into the registry)
- Linkage with administrative datasets (information on aged care, hospitilisation etc)
18
Q
What is the primary endpoint from the ASPREE study?
A
- Death from any cause OR incident dementia OR persistent physical disability
19
Q
What were some examples of the secondary endpoints for the ASPREE study?
A
- cancer, cardiovascular events, death from any cause, dementia, depression, major hemorrhage, mild cognitive impairment.
20
Q
What is a heart failure hospitaliation endpoint defined as for the ASPREE study?
A
- Unplanned admission to hospital for greater than 24 hours where heart failure was the primary reason for admission
21
Q
What is the dementia endpoint defined as in terms of the ASPREE study?
A
- Adjudicated from 3MS, pharmacological and diagnosis data
22
Q
What % of the body’s energy at rest does the brain use?
A
- 20%
23
Q
What is the cerebral cortex responsible for?
A
Sensing, thinking, learning, emotion, consciousness, and voluntary movement.
24
Q
What is the amygdala responsible for?
A
Part of the limbic system involved in emotion and aggression.
25
What is the cerebellum responsible for?
- Structure that coordinates of thigh muscle movement in balance
26
What is the hypothalamus responsible for?
Part of the limbic system involved in learning and memory
27
What is the medulla responsible for?
Regulating largely unconscious functions such as breathing and circulation.
28
Approximately how many neurones does the adult human brain contains?
- Approximately 86.1 billion with 16.3 billion in the neocortex.
29
How many synapses are contained in the neocortex, and how many synapses does each neuron receive?
Estimated 164 trillion synapses in neocortex, with each neuron receiving b/w 7,200 and 80,000 synapses
30
At what time in development does the fetal brain resemble that of an adult brain?
- 9 months (at birth)
31
What does the ectoderm form?
- Nervous system and skin
32
What does the mesoderm form?
- Musculoskeletal, vascular and lymphatic systems, kidney and gonads.
33
What does the endoderm form?
- Gastrointestinal tract, glands, lung, liver, pancreas.
34
What occurs at the gastrula stage?
- Differentiation of cells information into three germ layers.
35
What are the three main steps in the formation of the neural tube?
1. The notochord forms from mesoderm cells soon after gastrulation is complete.
2. Signals from notochord cause inward folding of ectoderm at neural plate.
3. Ends of the neural plate fuse and disconnect to form an autonomous neural tube.
36
What is the notochord?
- A rod like structure in the middle of the embryo that secretes factors that provide position and fate information.
- by the end of 3 week gestation The notochord induces the formation of the neural plate from the ectoderm, which then folds and fuses to form the neural tube
37
Which week of gestation does the neural tube separate from the ectoderm?
- By the end of week 4
38
Which two main areas of the brain does the forebrain form at 5 weeks, and which brain structures are these as an adult?
- Forebrain forms the Telencephalon and Diencephalon at week 5
- Telencephalon forms the Cerebrum (hemispheres, cortex, white matter, basal nuclei) at adult
- Diencephalon forms the diencephalon (thalamus, hypothalamus, epithalamus) at adult
39
Which two main areas of the brain does the midbrain form at 5 weeks, and which brain structures are these as an adult?
- Midbrain forms Mesencephalon at 5 weeks.
- Mesencephalon forms the midbrain (part of brainstem) at adult --> this is a confusing one haha
40
Which two main areas of the brain does the hindbrain form at 5 weeks, and which brain structures are these as an adult?
- Hindbrian forms the Metencephalon and Myelencephalon at 5 weeks
- Metencephalon forms the Pons and cerebellum at adult
- Myelencephalon forms Medulla oblongata (part of brainstem)
41
Does layer 1 of the cortex have lots of neurons?
What is the organisation of layer 2 and 3 of the human cortex?
- NO
- Does not have many neurons
2- - These are packed with neurons!
- Contain small sized neurons which are mainly inhibitory
42
Are the small sized neurons in the cortex inhibitory or excitatory?
- They are inhibitory
- Exert an inhibitory tone on the excitatory neurons
43
What do the inhibitory neurons play an important role in?
- Brain development
44
Which type of neurons are present in layers 4 and 5 of the cortex?
- Excitatory neurons (larger neurons)
45
What are the 6 general steps of the cellular and molecular processes occurring in neural development?
1. Proliferation
2. Migration
3. Aggregation
4. Differentiation
5. Circuit formation
6. Pruning and programmed cell death.
46
What occurs in step 1 of the cellular and molecular processes occurring in neural development; Proliferation?
- Cell division to form billions of neurones.
47
What occurs in step 2 of the cellular and molecular processes occurring in neural development; Migration?
- Movement of neurones from site of birth to Final Destination the brain.
48
What occurs in step 3 of the cellular and molecular processes occurring in neural development; Aggregation?
- Adhesion of similar cells into specific brain structures.
49
What occurs in step 4 of the cellular and molecular processes occurring in neural development; Differentiation?
- Neuronal commitment to become a particular type of new one for example inhibitory or excitatory neurones.
50
What occurs in step 5 of the cellular and molecular processes occurring in neural development; Circuit formation?
- Growth of axons and dendrites followed by synapse formation (synaptogenesis)
51
What occurs in step 6 of the cellular and molecular processes occurring in neural development; Pruning and Programmed cell death?
- Loss of extra synapses on neurones.
52
When does pruning and cell death occur, and which condition does this NOT occur in?
- When the synapses are no longer used
- This doesn't occur in conditions like Autism
53
What is symmetrical division in terms of neuronal proliferation, differentiation and migration?
- Symmetrical cell division: Progenitor cells are like the parent cells. Neuronal precursor cells can continue to produce many more precursor cells, or they can go and create glial cells (cell proliferation at the ventricular zone).
54
What is asymmetrical division in terms of neuronal proliferation, differentiation and migration?
Asymmetrical division: two daughter cells produced with different cell fates.
- In this context: Can produce more progenitor cells of neuronal lineage or generate percursor cells that are astrocyte lineage or precursor cells that go onto become oligodendrocytes.
55
What can neural epithelial cells go onto form?
- Radial glial cells or intermediate progenitor cells that can then go onto form astrocytes, oligodendrocytes or neurones.
56
What is meant by the "inside out" way of cellular distribution in terms of neuronal proliferation, differentiation and migration?
- Cells that are born first are packed into the deeper layers of the cortex and those that are born last are packed to the dorsal surface of the brain. This is what happens to the excitatory neurons- to form the different layers of the cortex.
57
Are neuronal progenitors that are born first packed into the deeper layers or the surface?
- The cells that are born first are packed into the deeper layers of the cortex. This is known as the "inside out" way of cellular distribution.
58
Which type of neuronal cells undergo symmetric cell division and why ?
- NPCs (Neuroepithelial cells)
- This is to produce initial pool of cortical progenitors that will later be ventricular radial glia cells (vRGCs).
59
Which type of cells undergo asymetrical division?
- vRGCs (ventral radial glia cells)
- This is to generate another vRGC and nascent projection neuron. This will then migrate from VZ radially along the basal process of RGC into cortical plate.
60
As neurogenesis occurs, what form of cell division are diverse subtypes of neurons generated?
- Through successive asymmetric division of RGCs.
61
In which areas of the neocortex is tengential migration of interneurons observed?
- MZ (marginal zone), IZ (intermediate zone), SVZ (subventricular zone)
62
What does the radial scaffold do after the neurogenic stages in the neocortex?
- Radial scaffold detaches from apical surface and vRGCs become gliogenic
- This means they generate astrocytes, or transform into ependymal cells.
63
What is a reason for tangenial migration?
- There are no RGCs to help the new cells with migration so they migrate in a tangient direction
64
Does the cerebral cortex contain BOTH inhibitory and excitatory neurons?
- YES
65
Where are the excitatory neurons of the cerebral cortex born, and where do they end up?
- Born in Ventricular zone (VZ)
- Generate excitatory neurons which migrate to dorsal surface to then be packed down
66
Where are the inhibitory neurons of the cerebral cortex generated and where do they end up?
- Born in the ganglionic eminence (different migration pattern- migrate to L2 and L3 of cortex- they SWIM!)
- They move tangiently up the cortex from layers 2 and 3
67
Which type of neurons swim and move tangiently up the cortex from layers two and 3 (inhibitory or excitatory)?
- Inhibitory
68
Does brain development stop after birth?
- NO
69
When do synaptogenesis and synaptic pruning mainly occur (before or after birth)?
- Mainly after birth
70
What are the two main processes of neural development?
- Prenatal development
- Postnatal development
71
What are the two sub areas of prenatal development?
1. Embryonic
2. Fetal
72
What is characteristic of the embryonic stage of prenatal development in terms of:
- when in pregnancy it occurs
- what arises in that time?
- Occurs within the first 8 weeks of pregnancy
- The primordium of the CNS arises--> development of the neural tube and formation of 3 vesicles
- majority of the congenital abnormalities occur during this period
73
What is characteristic of the fetal phase of prenatal development?
- Characterised by growth (40x increase in brain weight)
- Appearance of sulci and gyri on cerebral surface
74
What are the two sub areas of postnatal development?
1. At birth
2. Infant
75
At birth, what does the gross anatomy of the CNS resemble?
- An adult
76
At birth, are the repertoire of neurons of the neocortex largely established?
- YES
77
Which three main events occur at the infant stage of postnatal development?
- Massive outgrowth of dendrites and axons
- Synaptogenesis, gliogenesis , myelination.
- Neurogenesis in cerebellum still occurring. I seriously
78
What are the structural changes that occur in the adolescent brain? (3 things)
- Reduction in grey matter of neocortex- pruning of synapses.
- Increases in white matter- increased myelination and connectivity.
- Axonal sprouting and growth in circuits in the amygdala and cortex.
79
What are the behavioural changes in the adolescent brain? (6 things)
- Increase social behaviour.
- Novelty in sensation seeking.
- Tendencies toward risk taking.
- Emotional instability
- Impulsivity
- Dominance of peer relationships.
80
What is the critical period in neural development defined as?
- A period in brain development when neural circuits responsible for a particular process can be sculpted or changed radically by experience or by the environment.
81
When do the critical periods for cortical regions devoted to vision and other senses open and close in?
- They open in infancy (technically birth but peaks at infancy) and close tightly in mid childhood
82
When do the critical periods for cortical regions devoted to language and higher concentration open and close?
- Open later than senses (late infancy) and never close entirely
83
What are the successive waves for sensitivity to learning ideal for?
- Aquiring increasingly complex skills
84
What is a good example of the critical period?
- If the child has a lazy eye, then you can patch the good eye and try to enhance the stimulation to the lazy eye. BUT once the critical period is over, then you can no longer do this. If children are exposed to new languages in infancy, then they are much more able to pick up languages easily (this closes in childhood). Cognitive function opens up much later in childhood.
85
What is the definition of NDD?
- Neurodevelopmental disorders
- A group of psychiatric illnesses that is the result of abnormal brain development.
86
What are the causes of NDDs?
- Deficits in neurogenesis, progenitor cell proliferation, migration, synapse formation and myelination during embryogenesis.
87
What do symptoms of an NDDs include?
- Disabilities in cognitive, social, motor and affective function.
88
When is impairment of an NDDs usually detected?
- At birth, during infancy and sometimes adolescence.
89
Is there both a genetic and environmental components NDDs?
- YES
90
Are most and NDDs highly heritable?
- YES
- Generally polygenic (de novo mutations of multiple genes)
91
What are two examples of monogenic NDDs?
- Angelman's (ubiquitin ligase UBE3A) and Fragile X syndromes (FMRP)
92
During embryonic and early postnatal development, What does GABA excite (depolarise) postsynaptic targets due to?
- This is due to the HIGH intracellular [Cl-] in the developing brain
93
What is the GABA induced current crucial for?
- Crucial for generating synchronised patterns of activity of developing networks that are fundamental to the maturation of neuronal circuits.
94
TRUE OR FALSE: The day synchronisation in spontaneous network activity coincides with increasing influence of sensory experience whereby external signals compete with internally generated activity to shape synaptic connectivity.
- TRUE
95
Doe GABAergic neurons switch from excitatory to inhibitory at birth, and if so, why is this thought to occur?
- YES
- Thought to PROTECT neurons from hypoxia and ischaemic damage during delivery
96
What may contribute to NDDs?
- Alterations in the ratio of excitatory to inhibitory cortical activity.
97
With current research, what is NDD defined as in terms of ASD and Schizophrenia?
- The failure of homeostatic mechanisms to 'regularise' activity
98
What is the esitmated prevalence of ASD worldwide?
- 1 in 100 people
99
Is ASD more prevalent in males or females?
- Males
100
At what age are the core symptoms of ASD detectable?
- before 3 yoa
101
What are the two core symptoms of ASD?
1. Persistent deficits in social communications
2. Restricted and fixated interests
- Also social impairment
102
What are some examples of behavioral symptoms of ASD?
- Anxiety
- Hyperactivity
- Agitation
- Impulsivity
- Aggressive behaviour
103
What are some examples of functional symptoms of ASD?
- Sensory hypersensitivity
- Seizures
- Gastrointestinal disorders
104
Which 3 conditions does autism spectrum disorder encompass under its umbrella?
- Aspergers syndrome
- Autistic disorder
- Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS)
105
What is aspergers syndrome characterised by?
- No delay in language and cognitive dev
- Difficulties in social interaction
- Development of restricted and repetitive patterns of behaviour, interest and activity
106
What is autistic disorder characterised by?
- Significant language delays
- Impairment in social interaction
- Restricted repetitive and stereotyped pattern of behaviour, interest, and activity.
107
What is PDD-NOS characterised by?
- Symptoms similar to Autistic disorder BUT the criteria for autistic disorders is NOT met due to LATE AGE ONSET
108
What do 95% of ASD patients with no intellectual disability have a phenotype of?
- Motor disorder
e.g. Posture and muscle tone dysfunction, problems with fine manipulation, dyscoordination
109
What are the two main diagnosis classifications for ASD?
1. Diagnostic & Statistical Manual of the American Psychiatry Association (DSM)
2. International Classification of Diseases of the World Health Organisation (ICD)
110
What are the two symptoms for the diagnosis of ASD via the Diagnostic & statistical Manual of the American Psychiatry Association (DSM)
1. Persistent deficits in social communication / social interaction.
2. Restricted, repetitive behaviours, interests and activities.
111
What are the two symptoms for the diagnosis of ASD via the . International Classification of Diseases of the World Health Organisation (ICD)?
1. Abnormal development of receptive/expressive language.
2. Impaired development of selective social attachments/reciprocal social interaction.
3. Markedly restricted repertoire of activity and interest
112
Is the ICD set out to classify ALL neurological diseases?
- YES
113
What are the two main areas that biomarkers for ASD can be found?
1. Neuroimaging (brain)
2. Plasma
114
What are the three types of biomarker for ASD that can be found/measured via neuroimaging?
1. Volumetric analysis (regional, cortical volume- thickness or SA)
2. Connectivity (fibre tract measurements)
3. Functional- fMRI, eye tracking--> tend not to make eye contact with a lack of social connectivity
115
What are the three types of biomarker for ASD that can be found/measured via the plasma?
1. Abnormal levels of BDNF - brain derived neurotrophic factor in blood of ASD children.* (still no concrete evidence for this)
2. Decreased night time production of melatonin- as there is a high rate of sleep distrurbance
3. Altered components of metabolic (creatinine kinase, lactate dehydrogenase) and inflammatory (cytokines IL-1b, IL-4 levels) pathways
116
Are the ASD measurements for plasma biomarkers such as cytokine levels selective for ASD, and is this a good biomarker?
- NO
- could also be due to brain trauma or neurodegenerative diseases.
- Thus NOT a good biomarker for ASD
117
What are 5 possible regions as to why there is early brain enlargement in ASD children?
1. Increased number, size and myelin content of glial cells, increased neuronal dendrites and axons as a result of decreased pruning
2. Increased cortical thickness and folding in the parietal lobe.
3. Decreased GABAa receptor expression in superior frontal and parietal cortices.
4. Abnormal columnar structure in the neo cortex.
5. Hypometabolism in the frontal origins.
118
What are the 4 main neuropathologies that occur in ASD as time goes on?
1. Early brain enlargmeent in ASD children
2. Increased brain volume disappears around aged 6-8 due to abnormal slowness in brain growth.
3. Abnormalities in limbic structures in older individuals including hippocampus amygdala and cingulate cortex – reduction in volume and smaller neurons that are more densely packed.
4. Cerebellar abnormalities – decreased volume, reduced number and size of the perkinje cells.
119
Which three main areas of the brain does the cerebellum have very intricate connections with?
- Libmic areas
- sensorimotor corticies
- prefrontal and parietal association corticies
120
What is an example of a limbic area of the cerebellum in the brain and what is it responsible for in the context of ASD?
- POSTERIOR VERMIS:
- Affective dysregulation
- Social processing deficits
- Irritability
121
What is an example of the sensimotor corticies area of the cerebellum in the brain and what are they responsible for in the context of ASD?
1. Anterior lobe:
- stereotyped and repetitive behaviours
- Motor impairments
2. VIIIA & VIIIB:
- stereotyped and repetitive behaviours
122
What is an example of the prefrontal & parietal association cortices area of the cerebellum in the brain and what are they responsible for in the context of ASD?
Right Crus I & II:
- Language deficits
- Social cognition deficits.
- Theory of mind deficits.
- Face processing impairment.
- Imitation impairments
- Stereotyped and repetitive behaviours.
123
Cerebellum is initially known to be involved in fine motor control (balance), so why are we using it to detect abnormalities in measuring the decrease in volume, number and size of purkinje cells (major cells within the cerebellum)? (In terms of ASD)
- cerebellum has very intricate connections with different levels of the limbic system, sensory motor cortices, prefrontal and parietal association cortices
- This connectivity and neuronal circuitry from the cerebellum to limbic regions and to pre frontal and parietal cortex plays an important role in regulating social interaction and repetitive behaviour, as well as regulating language and social cognition.
124
Are columnar structures more packed in the control subjects or ASD subjects and what does this suggest?
- Columnar structures are MORE PACKED TOGETHER in the ASD subjects compared to controls (L3, III)
- Suggests that there are issues with the process of development of the brain such that it is haltered or slowed in the processes during early infancy (increase in synaptic connectivity and increase in brain volume, not sustained)
125
In the later stages of life, is the brain volume increased or decreased in kids with ASD?
- It is DECREASED in the later stages of life.
126
What do layers 2 and 3 of the neocortex have a lot of?
- Neuronal conenctivity
127
Which layers of the neocortex are GABAergic neurons that exert a tonic inhibitory tone on excitatory neurons present in?
- Layers 4, 5, and 6
128
Why are the neurons of the neocortex arranged in a columnar structure?
- Because progenitor neurons are produced in the VZ and climb up the glial cell surface and then get laid in the different layers
- so in short, due to the gial cells
129
What is an example of morphological changes in the ASD brain?
- the columnar structures
- These are more packed together in ASD kids than controls.
- Present in layer 3 (L3)
130
Is ASD a mono or polygenic disorder?
- Polygenic
131
Are ASDs highly heritable?
- YES around 90%
132
Has there been any success with identifying any chromosomal regions linked with ASDs?
- NO
133
What are examples of some ASD susceptibility genes?
- Scaffold proteins (SHANK2 &3)
- Adhesion molecules cadherins
- GABA receptor subunits
- Voltage gated cCa2+ channel subunits
- Regulators of chromatin remodeling (MSCP2, CHD8)
- Proteins involved in synapse formation (Neurexins and neuroligins)
134
Are any SNPs identified with ASD high or low risk?
- Large number identified but they are all low risk
135
What are CNVs and can they be linked to ASDs?
- de novo copy number variants (CNVs) are spontaneuous duplciation or deletion of genetic material
- functional gene sets involved in cellular proliferation, projection and motility
e.g. 15q11.13 deletion may be associated with autism (its duplication is Angelman syndrome)
136
What is the "Common disease-common variant" hypothesis in terms of ASD diagnosis?
- Many variants of small effect contribute to the tipping the person over the threshold to ASD diagnosis (basically there are many factors, that when combined, can pass the threshold required for ASD to develop)
137
What are the 4 major risk factors for ASD?
1. Infection/Immune dysfunction
2. Endocrine factors
3. Obstetric factors
4. environmental factors
138
What is involved in infection/immune dysfunction in terms of risk factors for ASD?
- CSF of ASD children contains atypical levels of autoantibodies to neural antigens and inflammatory cytokines
- Maternal infection during the critical period of early neuro-development possibly. (Fetus may have been exposed to some sort of maternal infection during development)
139
What is involved in endocrine factors contributing/being a risk factor for ASD?
- Maternal stress: intrauterine exposure to cortisol and thyroxine
140
What is involved in obstetric factors contributing/being a risk factor for ASD?
- Low birth weight, preterm/caesarean delivery, uterine bleeds possibly
141
What is involved in environmental factors contributing/being a risk factor for ASD?
- Maternal exposure to prescription medication, illicit drugs, heavy metals (mercury), environmental toxins (pollution), cigarette smoke
142
What are the three main theories of ASD?
1. Impeded plasticity
2. Excitation and inhibition dysregulation.
3. Theory of mind.
143
What is the impeded plasticity theory of ASD?
- Abnormal regulation of cell division and apoptosis.
- Early Overgrowth of brain structures e.g. the frontal cortex, amygdala and cerebellum.
- Hyper- followed by hypo- neuronal connectivity.
144
What is the excitation and inhibition dysregulation theory of ASD?
- Imbalance of glutamatergic and gabaergic synapses.
- ASD patients are susceptible to development of epileptic seizures.
145
What is the theory of mind theory of ASD?
- The capacity to understand subjective mental States including thoughts and desires is known as theory of mind (ToM)
- ToM develops early in children without disabilities but is delayed in children with ASD. (Kids with ASD have a disconnect with the thoughts of others)
146
What is the main role of oxytocin in pregnancy?
Inducing labour
147
What is the specific role of oxytocin in labour?
- Mediates sudden short lasting reduction in [Cl-] to facilitate the shift which protects neurons from anoxic episodes (so protects neurons from lack of O2)
148
What are the GABAergic signals like during development in terms of ASD?
- They shift from "depolarisation and excitation" to "hyperpolarisation and inhibition" as a result of reduction in intracellular [Cl-]
149
Does Oxytocin also play an important role in social behaviour?
- YES
150
Do ASD children have higher or lower baseline levels of oxytocin?
- Kids with ASD have lower than baseline levels of Oxytocin (OXY)
151
Has intranasal Oxytocin been trialed as a therapy for the core symptom of ASD?
- YES
152
What are the four types of ASD intervention models?
1. Discrete trial training.
2. Naturalistic interventions
3. Learning experiences: an alternative program.
4. Early start Denver model.
153
What is involved in the discrete trial training intervention model of ASD (behavioral treatment)?
- Breakdown of complex skills by teaching each subskill in a series of highly-structured teaching trials, also known as early intensive behavioral intervention if delivered before 5 years of age.
154
What is involved in the Naturalistic interventions of ASD (behavioral treatment)?
- Embedding teaching into naturally occurring events. E.g. Play, meal time, can address communicated functions and peer interactions.
155
What is involved in the Learning experiences: an alternative program of ASD (behavioral treatment)?
- Integration of ASD preschoolers with typically developing peers but with individualized curriculum to incorporate ASD's idiosyncratic needs, promotion of social interactions and extensive parent training.
156
What is involved in the Early Start Denver Model of ASD (behavioral treatment)?
- Individualised interventions in consultation with caregiver, therapist, specialist and teaching occurs inside and outside family routines.
157
What are examples of skill based models for ASD?
- Functional communication training, positive behaviour support, self-management, speech generation.
158
What are examples of the most common ASD treatments?
- Antipsychotics to treat aggression/irritability e.g. Haloperidol
- Stimulants to treat hyperactivity/inattention
159
What are examples of some factors being trialed for the treatment of ASD?
- IGF-1 growth factor acting on IGF-1R to allow for Improved social and repetitive behaviour
- Oxytocin to improve social behaviour
- Small molecules
160
What are the three main attributes that are good animal model should possess in terms of ASD?
- Construct validity
- Face validity
- Predictive
161
What is predictive validity?
- A measure of how well an animal model can be used to predict unknown aspects of the disease.
162
What is construct validity?
- A measure of how well the mechanism used to induce the disease phenotype reflects the currently understood disease etiology.
163
What is face validity?
- A measure of how well the model is able to replicate the disease phenotype.
164
What are the three types of animal models for ASD (big picture)?
- Neonatal lesions
- Maternal intervention
- Genetic models
165
What do the neonatal lesion animal models include for ASD (i.e. which part of the brain and what the abnormality is)?
- Amygdala (dysfunction in amygdala linked to ASD behaviours)
- Cerebellum (Abnormalities (loss of Purkinje cells) detected in ASD patients)
- Medial prefrontal cortex – (social deficits, Overgrowth of mPFC pronounced in ASD patients.)
166
What do the maternal intervention animal models include for ASD (i.e. what is the effect)?
- Prenatal the poet acid exposure- mechanistically affect the epigenome at critical development stages.
- Prenatal exposure to infection – borna disease virus.
167
What do the genetic animal models include for ASD (i.e. what is the effect)?
- BNDF overexpression
- Fragile X mental retardation (FMR) 1 gene KO
- GABARb3 subunit KO
- MeCP2 (transcriptional repressor) KO
- Neuregulin (cell adhesion molecules) KO
- OXT, OXTR KO (Oxytocin, Oxytocin Receptor knock out)
168
What does BNDF overexpression result in, in terms of ASD genetic animal models?
- high seizure susceptibility, anxiety and depressive – like behaviour but no deficits in social behaviour.
169
What does Fragile X mental retardation (FMR) 1 gene KO result in, in terms of ASD genetic animal models?
- Decrease in social interaction, increased repetitive behaviours, anxiety, hyperactivity, decreased spatial learning.
170
What does GABARb3 subunit KO result in, in terms of ASD genetic animal models?
- Seizure susceptibility, hyperactivity, stereotyped behaviour, learning and memory deficits, impaired social interaction.
171
What does MeCP2 (transcriptional repressor) KO result in, in terms of ASD genetic animal models?
- Increased anxiety, decreased motor coordination, impaired social interactions and learning and memory.
172
What does Neuregulin (cell adhesion molecules) KO result in, in terms of ASD genetic animal models?
- Mutations in NLGN3 4 associated with ASD.
173
What does OXT, OXTR KO (Oxytocin, Oxytocin Receptor knock out) result in, in terms of ASD genetic animal models?
- Oxytocin has a key role in social interactions and recognition.
174
Is schizophrenia a disorder or a syndrome?
- Schizophrenia is a syndrome as it is a set of medical signs and symptoms that are associated with each other.
175
What do the positive symptoms of schizophrenia include?
- Paranoid delusions
- Hallucinations
- Thought disorder- disorganised speech and behaviour
176
What do negative symptoms of schizophrenia include?
- Diminished emotional expression and reaction.
- Diminished participation in interpersonal relationships.
- Loss of energy, drive and interests
- inertia and apathy
- Poverty of speech
177
Is there a single defining symptom or sign of schizophrenia or any diagnostic laboratory test?
- NO
- It is a heterogenous syndrome (no identifiable diagnostic test)
178
Which observable signs is schizophrenia defined by?
- Observable signs of psychosis.
179
Is schizophrenia a disorder of the mind or an imbalance of the brain chemistry?
- It was initially thought of as a dopamine imbalance (dopamine hypothesis). Use of neuroleptic drugs, chlorpromazine and haloperidol with DA2 receptor antagonist activity (blocking the dopamine receptor).
180
In what age range does schizophrenia peak in?
- Peeks around the age of 18 to 25 years (2nd to 3rd decade of life)
181
Like ASD, is schizophrenia a highly heritable disorder?
- Yes
182
In children with early onset schizophrenia, what changes are seen in the brain?
- Excessive loss of grey matter and cortical thinning detected by neuroimaging.
183
Do people have schizophrenia have a shorter Lifespan, and why is this/this not the case?
- Yes they do have a shorter lifespan, with the main cause being due to suicide early on and CVD later in life
184
Is schizophrenia slightly more frequently in males or females?
- Schizophrenia is slightly more frequently in males and females with a 4:1 ratio
185
is Schizophrenia more severe in males or females?
- More severe in males
186
What are the four main categories of symptoms in schizophrenia?
1. Positive symptoms (fluctuates)
2. Negative symptoms (fluctuates)
3. Cognitive symptoms (stable)
4. Mood symptoms
187
Do positive symptoms of schizophrenia fluctuate or they stable?
- They fluctuate
188
Do negative symptoms of schizophrenia fluctuate or are they stable?
- They fluctuate
189
Do cognitive symptoms of schizophrenia fluctuate or are they stable?
- They are stable
190
What do the cognitive symptoms of schizophrenia include?
Deficits in working memory/attention/executive function.
- Difficulty in understanding subtle interpersonal cues.
191
What do mood symptoms of schizophrenia include?
- Depression is common, off and cheerful/without reason.
192
What is the schizophrenia diagnosis according to the diagnostic and statistical manual of the American psychiatry Association (DSM)?
At least two of the following symptoms of:
- Delusions
- Hallucinations
-Disorganised speech
- Catatonic behaviour
- Negative symptoms
At least one of the symptoms must be delusions/hallucinations/disorgansied speech and signs of disturbance must persist for at least 6 months and ACTIVE SYMPTOMS must be experienced for at least 1 month. The problems must not be caused by other conditions.
193
What is the schizophrenia diagnosis according to the International Classification of Diseases of the World Health Organisation (ICD)?
- Abnormality in perception/expression of reality – difficulties in distinguishing real/unreal experiences, logical thoughts and normal emotional responses.
- Retreat from reality with the delusion formation, emotional disharmony and regressive behaviour
- Disturbance in cognition and psychomotor function
194
Are children born in the winter at an increased risk of developing schizophrenia?
- Yes
195
What is the two-hit hypothesis in terms of schizophrenia?
- Person who goes onto develop schizophrenia has two waves of environmental factors/trauma that lead onto them developing schozophrenia.
- A lot of the occurrences of symptoms can occur through adverse events.
- Just when you think you have handled something well, you can undergo some adverse psychological event which can bring on symptoms again ('booster hits')
196
What are some examples of first wave hits in the two-hit hypothesis for schizophrenia?
- Infections and/or trauma.
- Malnutrition
- These can occur in utero and infancy
197
What are some examples of second wave hits in the two-hit hypothesis of schizophrenia?
- Urban rearing
- Migration (these first two occur during childhood)
- Social isolation
- Drug abuse
- Stress (these three occur in adolescence)
198
What are some examples of booster hits in the two-hit hypothesis of schizophrenia?
- These are types of adverse events
e.g.
- Psychomotor and mood disruption.
- Impaired neural recognition/social cognition.
- Positive and negative symptoms.
- Disorganisation of speech, thought and behaviour.
199
Why is schizophrenia a neurodevelopmental disorder?
- Because during the first wave (no early signs or symptoms), the brain is still developing. Neurogenesis is occurring, formation of synapses etc. So it is not surprising that we can classify it as a neurodev disorder. Later on the second hit (higher risk stage, prodormal stage) and you see the brain is still undergoing development, circuit development, synaptic pruning still occurring. Hence since the brain is still undergoing differenet processes, we can identify schizophrenia as neurodevelopmental.
200
What are the three different stages of schizophrenia?
- Latent- pre morbid stage
- High-risk, prodome stage
- Chronic, fluctuating, non linear stage
201
What are some events occurring in terms of brain formation as part of the latent, pre-morbid stage of development of schizophrenia?
- Neurogenesis
- Neuronal proliferation, migration and differentiation.
- Synaptogenesis
- Gliogenesis
- Sub – cortical myelination.
202
What are some events occurring in terms of brain reorganisation as part of the High-risk, prodome stage of development of schizophrenia?
- Cortical myelination
- Dendritic arborization
- Circuit plasticity
- Synaptic pruning
- Sexual maturation
203
What are some events occurring in terms of Brain upkeep as part of the chronic, fluctuating, non-linear stage of development of schizophrenia?
- Cerebral housekeeping
- Glial support
- Neuroprotection and/or neuro restoration.
- Myelin repair
204
In terms of the shcizophrenia timeline and three main stages for neuronal development, where is the window of opportunity to try and decrease transition and impede progession of schizophrenia?
- Age 15-27
- This is During the High risk, prodome stage and falls slightly into the chronic fluctuating stage (but mainly high risk prodome)
205
Is the cortex in people who go onto develop schizophrenia thinner or thicker?
- It is thinner, particularly the prefrontal cortex area
206
In which stage of schizophrenia risk and development (altered excitation-inhibitory balance) does cortical thinning occur?
- Stage I: At risk, people who are <12 years of age
207
What are the two main stages involved in altered excitatory-inhibitory balance in terms of Schizophrenia?
- Stage I: At risk (<12 years)
- Stage II: Psychosis (18-24 years)
208
What occurs in stage III: psychosis in the brain, regarding the altered excitatory-inhibitory balance graph of schizophrenia?
- Decrease in interneuron activity
209
What three main things are thought to contribute to the development of Schizophrenia in terms of brain changes?
1. Decrease in excitation
2. Decrease in inhibition (reduction in interneuron activity)
3. Reduction in cortical thickness
210
Neurodevelopmental disorders such as Schizophrenia are from an imbalance of _____ and _____ in the ______.
- Neurodevelopmental disorders such as schizophrenia from an imbalance of EXCITATION and INHIBITION in the CORTICAL REGION.
211
What can the reduction in cortical thickness be attributed to in Schizophrenia?
- Decreases in excitatory synapse due to excessive excitatory pruning.
212
What are three main neurochemical changes that occur in Schizophrenia as the person ages?
1. Neuroinflammation/immune dysregulation
2. Aberrant subcortical and/or cortical myelination (oligodendrocyte dysfunction)
3. Anomalous epigenetic programming
213
In terms of the neurochemical changes in Schizophrenia graph, what is thought to contribute to the increased susceptibility in developing schizophrenia?
- The differences in glutaminergic neurotransmission as well as GABAergic neurotransmission which leads to the disruption in the excitatory/inhibitory (E-I) balance, that in the prefrontal cortex as well as in the hippocampus
214
Which proteins are associated with synapse formation, and circuitry formation (in context of Schizophrenia)?
- DISC1 (more detail later in at risk genes)
- Reelin (structural protein)
- SHANK3 (structural protein)
- Neurexin and neuregulin (synapse formation)
215
Which protein networks are dysregulated in Schizophrenia?
- DISC1 (more detail later in at risk genes)
- Reelin (structural protein)
- SHANK3 (structural protein)
- Neurexin and neuregulin (synapse formation)
216
What are three of the main neuropathologies found in schizophrenia?
- Reductions in total grey and white matter and overall whole brain volume.
- Abnormalities in striatal connectivity to the prefrontal cortex linked to the positive and negative symptoms.
- Executive dysfunction associated with abnormalities in the dorsolateral prefrontal cortex, anterior cingulate cortex and inferior parietal lobe.
217
What are the 2 stages of the risk factors for schizophrenia?
1. Prenatal/perinatal events
2. Premorbid risks
218
What are 4 things that the prenatal/perinatal events for schizophrenia (in terms of risk factors) includes?
- Maternal nutrition – increased incidence following famine.
- Maternal infections – Increased incidence following influenza epidemic.
- Maternal adverse life events.
- Labour-delivery complications.
219
What are 4 things that the premorbid risks for schizophrenia (in terms of risk factors) includes?
- Social adversities- physical and sexual abuse, neglect, bullying.
- Drug abuse – amphetamine, cocaine use.
- Urban environment
- Migrant status (detachment, neglect- migrants more likely to have schizophrenia)
220
What is the lifetime risk of schizophrenia for monozygotic twins?
- 50%`
221
What is the lifetime risk of schizophrenia for children of two affected parents?
- Just under 30%.
222
At least how many genes have a strong genetic linkage and a highly polygenic in terms of schizophrenia?
- At least 20 genes, with a heritability of 64-81%
223
What are 4 out of 108 examples of chromosomal loci identified through GWAS studies that may be linked to Schizophrenia?
- Neuregulin, chromosome 8
- MHC region, chromosome 6p21.3-22.1
- ZNF804A, chromosome 2q32.1
- TCF4, chromosome 18q21.2
224
Candidate gene studies for Schizophrenia identified 43 genes that confer an increased risk - SNPs and CNVs. What are three examples of genes that were identified?
- DISC1 (Disruption in Schizophrenia Copy)
- Neurexin
- Dopamine D2R, Glutamate R components
225
Which is the best supported candidate gene for an increased risk of Schizophrenia and what is the abnormality in the gene?
- DISC1
- Chromosomal 1:11 translocation, rare variant that confers very HIGH risk
226
What is the normal function of DISC1?
- Neurodevelopmental roles in regulating neuronal migration, neurite outgrowth and neuronal maturation, adults roles in modulation of cytoskeletal function, synaptic transmission and plasticity.
227
What are the two types of pharmacological treatment for schizophrenia?
- Neuroleptic
- Atypical Anti-psychotic
228
What are two pharmacological treatments for schizophrenia that are neuroleptic?
- Chloropromazine and Haloperidol
- DA2R antagonistic activity but not very selective
229
What is a downside of neuroleptic pharmacological treatment for schizophrenia?
- Can cause extrapyramidal motor disabilities such as rigidity and involuntary tremors
230
What do the atypical anti-psychotic medications include and what is the mechanism of action? (Schizophrenia)
- Second generatoin antipsychotics
- e.g. clozapine, risperidone, paliperidone
- They are thought to antagonise the DA2 receptors
- The exact mechanism of action is UNKNOWN
- Equally potent in blocking the 5HT2A receptors
231
Do the atypical anti-psychotics for schizophrenia have an increased incidence of extrapyramidal side effects such as rigidity like the Neuroleptics?
- NO, they have a DECREASED incidence of these side effects
232
What are the two main behavioural therapies used to treat Schizophrenia?
- Cognitive behavioural therapy
- Supportive psychotherapy
233
What is the primary aim of CBT for the treatment of Schizophrenia?
- To reduce the impact of positive symptoms
- BUT not effective for all patients
234
Should CBT be seen as a replacement for those on anti-psychotics for Schizophrenia?
- NO this should be seen as an additive treatment alongside antipsychotics
235
What is the main aim of supportive psychotherapy in the treatment of schizophrenia?
- The aim is to help patients deal with loss, disability and stigma of living with schizophrenia.
236
Where is the window of opportunity for Schizophrenia intervention to try and stop the progression and what is this known as?
- Teenagers and adults
- 'hybrid' strategy is a combination of symptom relief with reduced conversion to and progression of schizophrenia (and other psychiatric disorders)
237
What are the three different broad categories for animal models for schizophrenia?
1. Pharmacological
2. Lesion
3. Genetic
238
What are the limitations in the pharmacological animal models of schizophrenia?
-Suppression of neuroexcitatory receptors could lead to a whole range of differing symptoms that aren't associated with schizophrenia.
239
What are the limitations in the lesion animal models of schizophrenia?
- You can NOT model positive symptoms e.g. Hallucination and delusions because you can't ask animals if they are hallucinating
240
What are the limitations in the genetic animal models of schizophrenia?
- Limitations with the hallucinations and delusions and animals- can't ask them if hallucinating etc.
241
What is an example of the pharmacologocial animal model for Schizophrenia and what types of symptoms do they cause?
- NMDA R antagonist- PCP/ketamine
- Causes symptoms such as hyperlocomotion, enhanced stereotype behavior, cognitive and sensorimotor gating deficits, impaired social interactions.
242
What is an example of the lesion animal model for Schizophrenia and what types of symptoms do they cause?
Neonatal lesion of the ventral hippocampus – hyperlocomotion, social and working memory deficits.
243
What are 6 examples of the genetic models for Schizophrenia and what types of symptoms do they cause?
1. DISC 1 mutant mice (N/C terminal truncation)- some but not all symptoms including increased aggression, social deficits, contextual associative learning and short term memory deficits
- Neureulin KO/knockdown- Some but not all symptoms including hyperactivity, impairment of contextual associative learning, increased aggression, social deficits.
- NMDAR (NR1) knockdown
- alpha7-Nicotinic R knockdown
- Fisher344 rat
- N-CAM 180 depletion
