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Download 10_PG4700 Neurodegeneration general
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Neurodegenerative Disorders Neurodegenerative Diseases Chronic neurological disease characterised by selective loss of neurons in motor, sensory and cognitive systems Memory, cognition, language and personality Have sporadic and/or hereditary origins AD, PD, Huntington disease, Amyotropic Lateral Sclerosis and Ataxias Generally no cure and therapies produce minor and temporal improvement No biochemical diagnoses before onset of symptoms Neurodegenerative Diseases Common Chronic and progressive brain degeneration resulting in death Generally the frequency increases with age Sporadic and/or inherited Accumulation of misfolded protein aggregates in brain areas damaged in disease Different Clinical manifestation and incidence Brain area damaged Genes involved in inherited forms Proteins deposited in brain Ageing Cohort effect White matter atrophy ~2ml/yr No neuronal loss -hippocampus -entorhinal cortex ↑Plaques and tangles Causes Neurotransmitter Hypothesis Inflammatory Hypothesis Oxidation Hypothesis Protein Misfolding Hypothesis Misfolded protein aggregates Protein aggregates in neurodegenerative diseases Mutations in the gene of the protein undergoing misfolding produces inherited forms of the disease Transgenic animals overexpressing mutant forms of the misfolded protein develop some typical features of the disease, including protein deposits Protein aggregate quantity and localization correlates with extent of damage Prion disorders – aggregated protein is component of infectious agent Cell culture – aggregated protein induces apoptosis Parkinson disease Define parkinsonism and Parkinson disease Age is the biggest risk factor Consequences of decreased nigrostriatal dopamine Subtypes Treatment Parkinsonism is synonymous with Parkinson syndrome and Parkinsonian State – characterised by 6 specific motor features Parkinson disease is a specific entity within the parkinsonism syndrome, ie one of the parkinsonian states Six cardinal features of parkinsonism Tremor at rest Bradykinesia/hypokinesia/akinesia Rigidity Flexed posture of neck, trunk and limbs Loss of postural reflexes Freezing phenomenon Features of PD “Shaking palsy” – Parkinson - 1817 Full clinical description - Charcot- 1879 Substantia nigra involvement – Brissaud - 1895 Cytoplasmic inclusions – Lewy - 1914 Hornykiewicz – Nigrostriatal dopamine loss - 1960 Cotzias – Levodopa therapy - 1967 Definition of PD Clinical Pathological Biochemical Imaging (PET/SPECT) Clincal definition of PD Slowly progressive parkinsonian syndrome Begins insidiously, usually asymmetrically No known etiology (other than genetic factors) Responds to levodopa for at least 7 years Freezing of gait, flexed posture and loss of postural reflexes are not early signs Pathological and biochemical definition of PD Depigmentation (loss of neuromelanin) in substantia nigra pars compacta (SNpc) and locus ceruleus (LC). Neuromelanin is dervied from oxidized dopamine. Within SNpc and LC: loss of monoamine neurons, usually presence of Lewy bodies (intracytoplasmic eosinophilic inclusion bodies), increase in glial cells Imaging and defining PD Fluorodopa, dopamine transporter (DAT) ligand and VMAT2 ligand -reveal decreased nirgostriatal dopamine nerve terminals FDG/PET – reveal increased metabolism in globus pallidus Fluorodopa PET Parkinson disease Define parkinsonism and Parkinson disease Age is the biggest risk factor Consequences of decreased nigrostriatal dopamine Subtypes Treatment Parkinson disease – age-specific relevance Age-specific prevalence of Lewy bodies Sex- and age-specific incidence Prevalence – 187/100,000 rises to 347/100,000 over 40yrs Parkinson disease Define parkinsonism and Parkinson disease Age is the biggest risk factor Consequences of decreased nigrostriatal dopamine Subtypes Treatment Consequence of putaminal DA loss Consequences on physiology of: Subthalamic neurons Globus pallidus Thalamus Cerebral cortex Clinical features: Rigidity Bradykinesis Tremor at rest Parkinson disease Define parkinsonism and Parkinson disease Age is the biggest risk factor Consequences of decreased nigrostriatal domamine Subtypes Treatment Rate of clinical progression Gene locations “Benign” Parkinsonian patient Parkinson disease Define parkinsonism and Parkinson disease Age is the biggest risk factor Consequences of decreased nigrostriatal domamine Subtypes Treatment Treatments Dopamine and non-dopamine Dopaminergic Levodopa Dopamine agonist Peripheral decarboxylase inhibitor Catechol-O-methyltransferase inhibitors Dopamine releaser MAO type 2 inhibitor Dopamine production and Levodopa Non-dopaminergic Anticholinergics Antihistaminics Glutamate antagonists Muscle relaxants Adenosine A2A antagonists Neurotrophins eg GDNF Treatment complications Frequency of Motor response complications Etiology
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