w11 - neurological disorders.

Tumours

Malignant -no capsule can metastasise

Metastasis - movement of cells either through vascular system - arteries and veins, lymphatic system.

Or throguh nervous system - perineural invasion

Benign - encapsulated so cause compression stops flow of cerebrospinal fluid.

Patient Mrs R suffered sudden onset of seizures due to tumour near primary motor cortex. Involuntary shaking

Uncapsulated tumour cells - glioma (glial cells).

Tumours often created from glial cells which surround and protect neurones. More malignant tumour initiating cells which orginate from stem cells. These cells rapidly proliferate. They are more resistant to chemotherapy and radiation so survival rate is low.

Treatment of tumours

Encapsulated = surgery.

Chemotherapy = attacks all rapidly dividing cells

Radiotherapy = more targeted stream of radiation. Alters DNA stopping replication.

Drug treatment =

drug that inhibits angiogenesis, the growth of new blood vessels. Cell growth requires higher blood supply.

Other drug binds with and deactivates growth factor which stops growth.

Seizure disorders.

2.5 mil people in US have seizure disorder

Seizure = period of sudden excessive activity if cerebral neurones. Sudden release of glutamate = neurotransmittpr from excitatory neurones

Partial seizure = localised in brain and acts in limited region.

Generalised seizure = widespread area of activation

If neurones make up motor system involved, seizure can cause convulsion which is uncontrolled activity of muscles.

Complex generalised seizure = lost consciousness

Can cause brain damage

50% of patients show evidence of damage to hippocampus. Damage to receptors because of large release of neurotransmitters.

Can be isolated to LHS = verbal learning and memory or RHS = spatial

Damage correlated to severity and number of seizures.

Significant hippocampal damage can be caused bya single episode of status epilepticus

Status epilepticus

Patient undergoes seizures without regaining consciousness

Caused by excessive release of excitatory neurotransmitters e.g. glutamate.

Temporal lobe epilepsy can also be associated with reduction in new cell development resulting in imparement in learning and memory.

Takes longer for Seizure patients with damage to RHS hippocampus to find platform in water. No learning of location.

Treatment for seizure

Drug. Increase effectiveness of inhibitory synapses or decrease effectiveness of excitatory. Can cause normal life in patients. Affects ion channels. Open chloride channels -ive. Inside becomes more negative through diffusion. Therefore higher stimulation needed for threshold to be reached. Resting becomes -90 mv. Anticonvulsant drugs.

Reduced neurogenesis can be reversed by fluoxetine (anti-depressant) with restorative effects on learning.

Few instances drug doesnt help. Therefore brain surgery to remove region of brain that is most effected.

Degenerative disorders - parkinson’s

Degeneration of nigrostriatal system - the dopamine-secreting neurones of the substantia nigra that sends axons to the basal ganglia and striatum.

Affects 1% of over 65yrs old.

Muscular rgidity, slowness of movement

Resting tremor - vibration movement im arms and hands that eases with purposeful movement.

Examination of brains of patients shows near dissapearence of nigrostriatal dopaminergic neurones.

Effect of loss of dopaminergic neurones = akinesia - difficulty initiating movement. Decreased activation pf the supplementary motor area and that tremors are assocaieted with abnormalities of neural systems including pons, cerebellum, midbrain and thalamus

Problems of initiating movement

Decreased release of dopamine into the caudate nucleus increases activity of globus pallidus. Output of the globus pallidus goes through the thalamus and to the motor cortex. Thus more activity in the gp makes it more difficult to initiate movement.

Globus pallidus - inhibit movements.

Lewy bodies

Consists of primarily of aggregation of misfolded proteins in dopaminergic neurones. Occurs due to a mutation in chromosome 4

α - synuclein = protein normally found in the presynaptic membrane, where it is apparently involved in synaptic plasticity: abnormal accumulations are cause of neural degeneration in Parkinson’s disease.

Removed via proteasome. Genes of chromosome 6 labels proteins and ferrying the misfolded proteins to the proteasomes. Mutation in c6 means labelling is missed and instead dopamine cells are destroyed.

95% have no family history of parkinsons. Seems to be triggered by toxins

Parkinson’s treatment

Increased level of L-DOPA (precursor to dopamine) in the brain cause patients remaining dopaminergic neurones to produce and secrete more dopamine and alleviate symptoms. Doesnt work indefinately: eventually number of nigrostriatal dopaminergic neurones declines to such a low level that symptoms worsen. L-DOPA activates DA neurones in the mesolimbic/ mesocortical system producing hallucination.

Neurosurgeons developed stereotaxic procedures designed to alleviate the symptoms that no longer respond to L-DOPA. removal of gp alleviates symptoms. Implanting electrodes in Subthalmic Nucleus and allowing patients to electricslly stimualte motor cortex themselves. Deep brain stimulation of subthalmic is as affective as brain regions in suppressing tremors and has fewer side effects. Prevents pg inhibiting thalamus and patients being able to activate thalamus.

Gene therapy - genetically modified virus into subthalamic nucleus of patients with parkinsons disease that delivered a gene for the enzyme which produces the inhibitory neurotransmittor GABA. - turns some excitatory neurones into inhibitory ones. Decreases activity of gp and thus increases motor cortex and symptoms improved.

Misfolded prion proteins may be toxic to brain cells becase…

Trigger apoptosis in a neuron

Alzheimer’s disease facts

50% of people over 85.

Characterised by loss of memory amd other mental factors. Resembles anterograde amnesia (recent events lost). Mostly STM and spatial memory.

Changes in brain structure in Alzheimers

Severe degeneration of hippocampus, entorhinal cortex, neocortex (especially the association cortex of frontal and temporal lobe).

Amyloid plaques - extracellular deposits. Dense core of a protein known as β-amyloid, surrounded by degenerating axons and dendrites along with cells that are involved in destruction of damaged cells

Neurofibrillary tangles consist of dying neurones that contain intracellular accumulations of twisted tau protein filaments that formerly served as cell’s internal skeleton providing transport.

During alzheimer’s disease excessive amounts of phosphate ions become attached to strands of tau protien thus changing molecular structure

Abnormal filaments seen in soma and proximal dendrites of pyramidal cells in the cerebral cortex which disrupts transport of substances so cell dies amd tangle of protein fillaments left.

Stages of tangles

Neurofibrillary tangles

Stage 1: perirhinal cortex and lateral portion of parahippocampal gyrus

2: CA1 layer of hippocampus and subiculum

3: higher levels lf CA1 but none seen in other areas of cortex.

4: CA1 layer densely filled with tangles.

5: all areas of hippocampus affected, also associated areas of cortex such as retrosplenial region and parietal lobe

6: hippocampul formation ‘infested’ with NFT’s

Early AD diagnosis and those at greater risk

• scans on patients with high risk of AD and found
  evidence of reduced brain volume, particularly in the hippocampus and
  parietal lobe, up to 5 years prior to AD diagnosis

• brains of mild AD patients there was a 32% loss of neurones in entorhinal cortex - relays info to hippocampus

• reduced levels of activity in the retrosplenial cortex in people with mild cognitive impairment

all areas play role in spatial learning.

Early Alzheimers symptoms - spatial abilities

54% have difficulty recognizing locations

30% of AD patients report difficulty in finding their way around their home

Spatial disorientation often first symptom seen by family

patients with early stage AD also made more mistakes on a newly learned route particularly when asked to travel route in reverse. They were also impaired on maintaining sense of direction.

Monacelli hospital route exp.

tested patients on their ability to recall a route through the hospital.

Hospital Lobby as test environment.

Subjects put into wheelchair and taken on specific route around lobby. AD patients became lost more than age matched controls and had more difficulty recognizing landmarks on route.

STM

patients also have difficulty identifying spatial scenes. Compared to controls made more error discriminating between similar scenes.

Cure?

Still no cure. Reduce anxiety to increase nostalgia which reduces symptoms

Amyloid plaque stages

A: in cortex near bottom of brain, none in hippocampus

B: throughout cortex, except motor, only small levels in hippocampus

C: all areas of cortex, higher levels in hippocampus.

What causes amyloid plaque

Production of defective form of β-amyloid

First a gene encodes the production of the b-amyloid precursor protein (APP),

An enzyme b secretase cuts the APP in two places leaving a normally short Abprotein.

However 5-10 percent are the long form but in Alzheimer’s patients that rises to 40%.

These long form fold over on themselves and form aggregations. Misfolded proteins are toxic to the cell.

•long-form Ab bind to receptors that normally responds to stress signals and stimulates apoptosis (Sotthibundhu et al., 2008).

•Basal forebrain Acetylcholinergic neurons contain high levels of these receptors; thus, once the level of long-form Ab reach a sufficiently high level, these neurons begin to die.

•ACh neurons in the basal forebrain are among the first cells to be affected in Alzheimer’s disease.

chromosome 21 contains the gene that produces APP. Since the discovery of the APP gene, several studies found specific mutations of this gene that produce familial Alzheimer’s disease. Abnormal APP genes cause the defective long form of Ab to be produced

Risk of alzheimers

•Traumatic brain injury is also a serious risk factor for Alzheimer’s disease.

•Examination of the brains of people who have sustained closed head injuries (including injuries to professional boxers) often reveals a widespread distribution of amyloid plaques.

Risk of Alzheimer’s disease following traumatic brain injury is especially high in people who possess the ApoE4 gene which interferes with the removal of the long form Ab

Obesity, hypertension, high cholesterol levels, and diabetes are also risk factors, and these factors, too, are exacerbated by the presence of the ApoE4 allele

Treatment alzheimers

•Pharmacological treatments for Alzheimer’s disease are acetylcholinesterase inhibitors

•Acetylcholinergic neurons are among the first to be damaged in Alzheimer’s disease, so drugs that inhibit the destruction of ACh and hence enhance its activity have been found to provide a modest increase in cognitive activity of patients.

•However, these drugs have no effect on the process of neural degeneration and do not prolong patients’ survival.

Immunisation of alzheimer

•attempted to sensitize the immune system against Ab. •They injected AD mice with a vaccine that, they hoped, would stimulate the immune system to destroy Ab. The treatment worked: The vaccine suppressed the development of amyloid plaques in the brains of mice that received the vaccine from an early age and halted or even reversed the development of plaques in mice that received the vaccine later in life.

•30 with mild-to-moderate Alzheimer’s disease were given injections of a portion of the Ab protein. •Twenty of these patients generated antibodies against Ab, which slowed the course of the disease—presumably because their immune systems began destroying Ab in their brain and reducing the neural destruction caused by the accumulation of this protein. compared the cognitive abilities of the patients who generated Ab antibodies to those who did not. Antibody production significantly reduced cognitive decline.