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Download Learning Objectives of Degenerative Diseases - By : Prof Dr
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Transcript
• Degenerative Diseases • Semester VIII • Prof Dr Syed Mehmood Hasan • Pathology Department SMC • Degenerative Diseases • Progressive and selective loss of functional neuronal system • They can be grouped using two approaches: • Symptomatic/anatomic: based on the anatomic regions of the CNS that are primarily affected, reflected in the clinical symptoms • Pathologic: based on the types of inclusions or abnormal structures observed • The pattern of neuronal loss is selective • One or more groups of neurons are affected while leaving others situated immediately adjacent to thios remains intact. Degenerative diseases affecting: • Cerebral cortex: Alzheimer’s disease Fronto-temporal dementias Pick disease Progressive supra nuclear palsy • Basal Ganglia and brainstem: Parkinson's disease Huntington's disease • Motor neurons: Amylotrophic lateral sclerosis Bulbospinal atrophy Spinal muscle atrophy • Alzheimer Disease • Most common cause of dementia in elderly • Impairment of high intellectual functions • Mood + behavior alteration • Memory loss • Aphasia • Progressive disorientation In 5 -10 years, the patient becomes: • Profoundly disabled • Mute • Immobile. • Patients rarely become symptomatic before 50 years of age • Clinical Features • The progression of AD is slow but persistent • A symptomatic course often running more than 10 years. Initial symptoms: 1. Forgetfulness 2. Memory disturbances 3. Language deficits 4. Loss of mathematical skills 5. Loss of learned motor skills. Final stages of AD: 1. Incontinent 2. Mute 3. Unable to walk. Intercurrent disease: • Morphology Gross: • Compensatory ventricular enlargement (hydrocephalus ex vacuo) secondary to loss of parenchyma • Reduced brain volume. • Structures of the medial temporal lobe, including hippocampus, entorhinal cortex and amygdala, are involved early in the course and are usually severely atrophied in the later stages. Microscopic Hallmarks: • The major microscopic abnormalities of AD, which form the basis of the histologic diagnosis – Neuritic plaques – Neurofibrillary tangles. • There is progressive and eventually severe neuronal loss • Reactive gliosis in the same regions that bear the burden of plaques and tangles Neuritic plaques : • Focal • Spherical collections of dilated, tortuous, neuritic processes • Around a central amyloid core • Surrounded by clear halo • Neuro-fibrillary tangles • These are bundles of filaments in neuronal cytoplasm that displace or encircle the neurons • These are visible as basophilic fibrillary structures in H & E stains and in silver stains • Seen in cortical neurons of hippocampus, amygdala, basal orebrain, raphe neuclei • Paired helical filaments are also found in the dystrophic neurites that form the outer portions of neuritic plaques and in axons coursing through the affected gray matter as neuropil threads. • Tangles are not specific to AD, being found in other diseases as well. • Pathogenesis • Alzheimer’s Disease is one of the most common neurodegenerative diseases worldwide. • In the normal state, • In the disease state Aβ40/42 aggregation results in: • Alzheimer’s Disease is also characterized by the presence of neurofibrillary tangles. • These tangles are the result of hyperphosphorylation of the microtubule associated protein Tau. • Hyperphosphorylation of Tau results in the dissociation of Tau from the microtubule, leading to microtubule destabilization and oligomerization of the Tau protein within the cell. • Neurofibrillary tangles form as a result of Tau oligomerization and lead to apoptosis of the neuron.