Brain Disease Flashcards
Diseases generally divide into 2 categories
1) neurological (physical) signs and symptoms
2) Psychiatric (mental) disorders
BUT
research has shown the brain is also functionally/ anatomically abnormal in psychiatric disorders = cross-over/ overlap in definition
Neurological assessment of patient includes:
state of consciousness gait mental state/attitude/ insight cognitive function coordination and fine movements cranial nerves sensory system motor system
Psychiatric assessment includes:
appearance and behaviour mood and affect speech -disorders of thought cognitive state insight abnormal beliefs(delusions) and perceptions(hallucinations)
Parkinsons Disease symptoms pathology incidence Treatment (Deep brain stimulation = experimental)
-decrease in spontaneous movements, gait difficulty, postural inability, rigidity and tremor (initiation and termination of movement difficult)
-degeneration of the pigmented neurons of the substantia nigra of the brain, resulting in decreased dopamine activity
- 1-2% freq increases exponentially >60yrs; mortality between 45 + 100 = 7%men and women equally affected
developed countries there is a higher incidence
- L-Dopa, stem cells,
-deep brain stimulation( STN=most effective site, frequences >60Hz = effectively alleviate symptoms; <30Hz make symptoms worse, mechanisms underlying its efficacy are controversial… hypothesis: stimulation of >60Hz prevents low frequency rhythm generation and desynchronises the extrastriatal basal ganglia and cortex
Why do substantia nigra dopamine neurons die in parkinsons? (5 reasons)
1- idiopathic in most cases (disease arises spontaneously)
2- genetic forms associated with mutations (BUT identical mutations in families can be associated with different onsets
3- Aberrant proteostasis, mitochondrial funciton
4- Environmental factors - those that disrupt mitochondrial function may be important eg.pesticides
5- dopamine
Do substantia nigra have a unique Ca++ burden?
neurons express low voltage-dependent Ca++ channels –> the energy burden for Ca++ homeostasis may be high
- energy demand for Ca++ homeostasis may lead to impaired oxidative phosphorylation, improper Ca++ homeostasis, aberrant protein folding and production om ER and release of pro-apoptotic factors
- genetic and envrionmental factor may increase the burden
- Calbindin expressing DA neurons are relatively resistant
- Resistant VTA dopamine neurons = less reliance on Ca++ channels for excitability
21st century treatment for Parkinsons?
1) protection - Ca voltage channel blockers help reduce overexcitation and slow down disease (SN cells have high energy Ca++ burden?) , glial derived neurotrophic factor Amgen=treatment
2) Regeneration - transplantation, stem cells
3) stimulation - smart stimulators (know when to stimulate), optogenetics
Huntington's Disease symptoms pathology incidence cause
Symptoms: progressive hyper(too much)/dykinesias(too little movement) followed by akinesia dystania and dementia/ psychosis
Pathology: - striato-GPe neurons die first, followed by striato- GPi neurons and finally more widespread neurodegeneration - associated with nuclear and cytoplasmic inclusions containing mutant huntingtin and other proteins
(huntingtin is important in: synaptic vesicles dynamics and transmitter release)
-pathological changes caused due to widespread expression of mutant huntingtin
-pathology due to aberrant circuit activity
Incidence: rare, 0.04-0.1%
Causes:
autosomal hereditary disease
abnormal number of CAG repeats in exon 1 of huntington gene
no. of CAG repeats related to gene expression
< 35 no disease
35-39 enhanced risk, variable onset 40-75 years
> 40-50 disease onset 30-40 years
> 50 early onset disease
Animal models suggest that cortical dysfunction is the initial trigger in Huntingtons disease
what often precedes abnormalities of movement?
What is initially reduced and intitally enhanced?
Release of what increases?
Uptake of what decreases?
cog, emotional, behavioural changes often precede
- cortical inhibition initially reduced, corticostriatal excitation initially enhanced
- release of corticostriatal glutamate increased
- uptake of synaptically released glutamate decreased due to downregulation of GLT1(glutamate transporter1)
- MSNs lose spines, input resistance increases, K+ channels down regulated, sensitivity to NMDA increased, increased expression of extrasynaptic NMDARs(voltage dependence decreases tho)
- homeostatic compensatory changes cortico-striatal de
- afferentation, increased inhibition in striatum, which may lead to reduced BDNF
Treatment for Huntingtons?
Deep brain stimulation Memantine (NMDAR antagonist) Tetrabenazine (VMAT inhibitor), v serious side effects RNA interference Stem cell transplantation
2 pathways exist in the basal ganglia circuit
1) direct
2) indirect
1- outflow from striatum
-directly inhibits GPi and SNr
-striatal neurons containing D1 receptors constitute the direct pathway and project to the GPi/SNr
2 - comprises inhibitory connections between the striatum and the GPe and between
What do these stand for: GPe GPi SNr STN
Globus Pallidus Externus
Globus Pallidus Internus
Substantia Pars reticulata
subthalamic nucleus
What happens in Parkinsons?
increased inhibition of the thalamocortical pathway which suppresses movement
- -> via direct pathway: decreased striatal DA stimulation causes decreased inhibition of the GPi/SNr
- ->via indirect pathway: decreased DA inhibition causes increased inhibition of GPe resulting in disinhibition of the STN, increased STN output increases GPi/SNr output to thalamus
So, parkinsons -striatal DA increase of decrease? effect?
p disease = decrease striatal DA = increase inhibitory output from GPi/SNr
pathology of disease= characterised by accumulation of protein ‘alpha-synuclein’ into inclusions called ‘Lewy bodies’ in neurons, and from insufficient formation + activity of DA produced in certain neurons of part of midbrain
