Neurodegeneration and Alzheimer's Disease Flashcards
What is neurodegeneration?
The progressive loss of function/structure of neurons and neuronal death
What are the common factors of neurodegenerative diseases?
Involved with ageing, causes and pathogenic mechanisms largely unknown except Huntingtons and other rare familial conditions, they’re progressive diseases, there’s no cure (drugs only treat symptoms), characterised by common features eg accumulation and aggregation of specific proteins, mt damage, glial activation, etc
How are these diseases often classified?
On the basis of the location of the characteristic lesions ie. Amyotrophic Lateral Sclerosis aka. upper motor neuron disease (motor cortex) or lower (anterior horn of spinal cord or cranial nerve motor nuclei)
What is ataxia?
Ataxia is the loss of control and coordination of voluntary movement
Which diseases are often the result of neurodegeneration in the cerebellum?
Olivo-ponto-cerebellar degeneration and Freidrich’s ataxia
What are the characteristics of cerebellar neurodegeneration disorders?
Disturbances in gait, balance, speech, eye movements but no weakness. Also sufferers of ataxia may not be able to heel toe walk, stand on one leg, evaluate the right force direction and distance of movements
What is the cause of Freidrichs ataxia?
A recessive mutation in the mitochondrial protein frataxin. The cerebellar nuclei and sensory spinal structures have lesions which leads to the wide legged, unsteady, lurching walk
Which diseases involve neurodegeneration in the basal ganglia?
Parkinson’s and Huntington’s disease
Describe the region of the brain responsible for Parkinson’s disease and the pathology
Selective dopaminergic neuron loss in the substantia nigra pars compacta. This leads to slow stiff movements hindered by tremor which eventually cease
Describe the region of the brain responsible for Huntington’s disease and the pathology
Presents with involuntary, uncontrolled, exaggerated movements known as chorea. The cause is repeated CAGs (glutamine) in the Huntingtin gene which causes misfolding of protein that leads to GABAergic neuron death in the corpus striatum
How do neurons degenerate?
Acute injuries may lead to necrosis, where the cells can’t maintain their membrane integrity and ion gradients and release their contents -> inflammation. However, neurodegen. progresses slowly over the years with no evidence of necrosis. It’s thought that excessive PCD (apoptosis or autophagy) is the cause
What is dementia?
The progressive loss of memory and atleast one other cognitive domain, severe enough to interfere with everyday tasks. Many disorders are accompanied by dementia, which can be reversible (alcohol induced/medication) or irreversible (neurodegeneration)
What is dementia caused by and what does it effect?
Neurodegeneration in the cerebral cortex leading to impairment of higher cognitive functions eg. memory, spatial awareness, language, personality, judgement, emotions, abstract thought
What is mild cognitive impairment?
When complex (not simple) every day task performance is affected. Can be an early manifestation of dementia.
What is the most common cause of dementia?
Alzheimer’s disease, which is cortical neurodegeneration with a specific pattern of pathological features and accounts for 50-80% of dementia cases.
What are the other common types of dementia?
Vascular (multi infarct) - 2nd most common, typically caused by many small strokes
Dementia with lewy bodies (aggregated protein accumulation)
Frontotemporal neurodegeneration - characterised by loss of language and behavioural change in a relatively young population
Dementia associated with some cases of PD or HD
What are the pathological hallmarks distinguishing Alzheimer’s disease from other forms of dementia/
Microscopic deposits inside and outside the cortical neurons.
What are the first signs of demetia?
Often impairment of recent declarative memory, indicating pathological lesions in the medial temporal lobe. In the early stages, memories of the remote past are preserved
How does dementia progress?
Impairment of recent declarative memory. Then, other cognitive functions gradually decline, leading to becoming lost in familiar places, forgetting the meanings of words and uses of common objects, loss of language completely, forget family members, confused, agitated, aggressive
What is amyloid?
Amyloid is the protein constituting the neuritic (senile) plaques. Called amyloid beta as secondary structure is rich in B pleated sheets. They stick together to make fibrils, then causing large insoluble filaments
What is the mechanism of action of AB proteins causing senile plaques?
AB monomers turn into AB soluble oligomers, which are thought to be more harmful as they impair basic neuronal processes (communication) well before clinical presentation. It is thought that the plaques are a protective mechanism against the more harmful form of AB
What happens to the neurons surround AB plaques?
Neuronal dendrites and glial processes around the plaques appear abnormal and are surrounded by activated microglia - a sign of inflammation
How does Tau protein contribute to neurofibrilliary tangles?
They are intracellular inclusions caused by large aggregates of paired helical filaments made from tau protein. Normally, tau proteins bind to microtubules, stabilising them. When tau is abnormally hyperphosphorylated, microtubule affinity is decreased. Tangled clumps of tau protein impair neuronal function via obstructing axonal transport and intracellular transport mechanisms
How is Alzheimer’s disease diagnosed?
There is not a reliable non invasive marker of AD, so it is diagnosed on clinical symptoms, and confirmed by the presence of plaques and tangles on autopsy
