Lecture 18 - Neurodegeneration 1 PDF

Neurodegeneration Overview The Biggest Challenge of Current Research  What is neurodegeneration? Progressive loss (death) of neurons beyond that of the normal aging process. However, for most of the “common” neurodegnerative diseases AGE is the most important risk factor...

Neurodegeneration Overview The Biggest Challenge of Current Research  What is neurodegeneration? Progressive loss (death) of neurons beyond that of the normal aging process. However, for most of the “common” neurodegnerative diseases AGE is the most important risk factor. It is a problem because neurons cannot be replaced.  Where is it found? Neurodegenerative diseases Other diseases of the nervous system that may cause neuronal loss: Cancer Trauma (head/spine injury) Viral diseases/Infections Vascular/Circulatory disorders. Developmental disorders Vascular and Circulatory Disorders Ischemia/Infarction Transient Ischemic Attacks Hemorrhage  Stroke: Ischemia/Infarct Atherosclerosis: Narrowing Thrombosis: Damages vessel, infarcts are non-hemorrhagic Embolism: Heart valves, plaques (frequently hemorrhagic) Vasospasm: Rare, but common after subarachnoid hemorrhage Hypertensive vasculopathy: Lacunar infarcts  Risk Factors atherosclerosis Two Major Types of Stroke  Venous Infarction Venous infarction usually results from venous sinus thrombosis Risk factors include a number of states that result in hyperviscosity or increased coagulability Grossly they are very hemorrhagic  Pathophysiology of Ischemic Brain Injury Topography of focal ischemia Flow gradient: heterogeneous regional cerebral blood flow (CBF) reduction after focal ischemia Densely ischemia region surrounded by areas of less severe CBF reduction Ischemic penumbra: an area of reduced perfusion sufficient to cause potentially reversible clinical deficits but insufficient to cause disrupted ionic homeostasis Pathogenesis of Ischaemic Stroke Penumbra Infarction Ischemic Penumbra: Current Concept  Infections Meningitis Cerebral abscess –Bacterial Subdural –Tuberculous empyema –Fungal Cerebritis –Viral Viral encephalitis  Polio Poliomyelitus is caused by an RNA virus, the poliovirus In 3% of cases it enters the CNS In 1% of cases this leads to Focal loss of motoneurons in the spinal cord  Neuroscience findings from Polio Study of spinal motoneuron loss and comparison to the resulting loss of muscle control allowed mapping of motoneuron foci in the spinal cord to the innervated muscle demonstrating a rostra- caudal/medio-lateral topographical map. Sharrard, W. 1955 Neurodegenerative Diseases Includes most Dementias but also non-dementias  What makes them special? Often the cause is unknown No cure Progressive Sporadic and/or Inherited forms Often age dependent.  A List of Diseases Alexander disease Machado-Joseph disease Alper's disease Menke’s disease Alzheimer’s disease Motorneuron disease Amyotrophic lateral sclerosis Multiple sclerosis Ataxia Telangiectasia Multiple System Atrophy Canavan disease Parkinson’s disease Cockayne syndrome Pelizaeus-Merzbacher Disease Corticobasal Degeneration Pick's disease Creutzfeldt-Jakob disease Primary lateral sclerosis Dementia with Lewy bodies Fatal Familial Insomnia Progressive supranuclear palsy, Frederick’s Ataxia Refsum's disease Frontotemporal dementia Sandhoff disease Gerstmann-Straussler-Scheinker Syndrome Schilder's disease Huntington disease Spinocerebellar ataxia, Kennedy's disease Steele-Richardson-Olszewski disease Krabbe disease Tabes dorsalis Kuru Wilson’s Disease Lewy body dementia  Types of Neurodegenerative diseases Dementia – Alzheimer’s disease: common, amyloid hypothesis, plaques and tangles, gross brain atrophy – Prion disease: rare, “transmissible” protein, rapidly progressive, vacuolar changes Movement disorders – Parkinson’s disease: hypokinetic, loss of dopaminergic cells substantia nigra, Lewy bodies – Huntington’s disease: choreiform movements, caudate atrophy, nuclear inclusions Motor neuron disease (ALS): Loss of upper and lower motor neurons, progressive over 2-5 years  Amyloidogenic Diseases Neurodegenerative diseases where there is deposition of an abnormal protein isoform Alzheimer’s Disease, Parkinson’s disease, prion diseases.  Alzheimer’s Disease The most common neurodegenerative disease and the most common cause of dementia. Likelihood increases with age. Those over 85 have a 47% chance to develop the disease.  Theories of the cause. Deposition of beta-amyloid - the amyloid cascade hypothesis Deposition of phosphorylated tau in the form of paired helical filaments or tangles. Metal hypothesis Amyloid cascade Formation of Tangles  Parkinson’s Disease 2nd Most common neurodegenerative disease but not a dementia 1 in 200 over the age of 50. Due to loss of dopaminergic neurons In the Substantia nigra. Changes in movement and posture Resting temour Difficulty in starting movement Location of the Substantia nigra Substantia Nigra Early Onset (before 50) and late onset forms Analysis of large nuclear families with many affected individuals have revealed several single gene mutations/locus replications that cause PD – α-synuclein (PARK1) – Parkin (PARK2) – DJ-1 (PARK7) – PINK-1 (PARK6) – LRRK2 (PARK8) – UCHL1 (PARK5) Parkinsons’s Disease  Prion Diseases Very rare Transmissible (experimentally) Human and Animal diseases CJD, vCJD, GSS, FFI, Kuru, iCJD, fCJD BSE, Scrapie, CWD  Characteristics Long incubation period – 10-40 years in humans. Deposition of large amounts of abnormal prion protein Rapid neuronal loss Gliosis Vacuoles Short symptomatic period (6-18 months) vCJD Prion Protein Misfolding  Metal Hypothesis AD, PD and Prion disease are all linked to a protein that occurs normally in the brain In each case the protein binds copper. In each case there is a suggestion that metals play some role in the cause (either iron or copper).  Diseases of MYELIN DEMYELINATING DISEASES: Acquired disorders of myelin, such as multiple sclerosis. DYSMYELINATING DISEASES: Genetic disorders of myelin and its turnover, such as leukodystrophies  Multiple Sclerosis Multiple sclerosis is the most common disease of CNS myelin; prevalence of 1:1000. – Central nervous system myelin is selectively destroyed (axons are relatively preserved) – Onset is frequently in 30 and 40 year old age groups. – The disease is typically progressive with relapsing and remitting accumulations of focal neurologic deficits. – The etiology is thought to be autoimmune in nature  MS Symptoms - muscle weakness - Difficulty moving – ataxia - Difficulty with speech or swallowing - Pain - Depression - Cognitive disturbances Immune Cell Invasion