Pathology Of Neurodegenerative Diseases PDF

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http://pictures.directnews.co.uk/liveimages/a+study+could+pave+the+way+for+new+treatments+for+neurodegenerative+diseases_554_801569878_0_0_4002249_300.jpg PATHOLOGY OF NEURODEGENERATIVE DISEASES Prof. Dr. Süheyla Uyar Bozkurt  Neurodegenerative diseases characterized by; progressive loss of particular groups of neurons, which often have shared functions.  NEURODEGENERATIVE DISEASE Common point is accumulation of protein aggregates resistant to degradation ( “proteinopathy”) resistant to degradation and show aberrant localization within neurons. Aggregates recognized as inclusions Diagnostic hallmark of different disease  Prion Diseases rapidly progressive Humans; neurodegenerative Creutzfeldt-Jakob disorders disease (CJD) caused by Gerstmann- aggregation and Sträussler- intercellular spread Scheinker syndrome of a misfolded prion Fatal familial protein (PrP); insomnia, sporadic, familial, or Kuru transmitted Scrapie in sheep and goats; mink-transmissible encephalopathy  Prion Diseases “spongiform change” caused by intracellular vacuoles in neurons and glia, and clinically by a rapidly progressive dementia.  Pathogenesis caused by “spreading” of misfolded proteins, a pathogenic protein to acquire some of the characteristics of an infectious organism.  Pathogenesis Normal PrP is a 30-kD cytoplasmic protein of unknown function. Disease occurs when PrP undergoes a conformational change from its normal α- helix–containing isoform (PrPc) to an abnormal β-pleated sheet isoform, usually termed PrPsc (for scrapie) associated with this conformational change,  Pathogenesis of prion disease. α-helical PrPc may spontaneously shift to the β-sheet PrPsc α-helical PrPc β-sheet PrPsc PrPsc may also be acquired from exogenous sources (contaminated food, medical instrumentation, medicines) Once present, PrPsc converts additional molecules of PrPc into PrPsc through physical interaction, leading to the formation of pathogenic PrPsc aggregates.  Pathogenesis PrPsc acquires resistance to digestion with proteases (proteinase K) accumulation of PrPsc in neural tissue is the cause of the pathologic changes in these diseases, how this material induces the development of cytoplasmic vacuoles and eventual neuronal death is still unknown. Creutzfeldt-Jakob Disease (CJD) The most common prion disease, rare disorder clinically rapidly progressive dementia. Creutzfeldt-Jakob Disease (CJD) Sporadic %90 Familial (caused by mutations in PRNP, the gene that encodes PrP) iatrogenic transmission; corneal or dural transplantation deep implantation of electrodes in the brain administration of contaminated preparations of cadaveric human growth hormone. Creutzfeldt-Jakob Disease (CJD) changes in memory and behavior followed by a rapidly progressive dementia pronounced involuntary jerking muscle contractions on sudden stimulation uniformly fatal the average survival is only 7 months after the onset of symptoms.  Creutzfeldt-Jakob Disease (CJD) morphology The pathognomonic finding is a spongiform transformation of the cerebral cortex and deep gray matter structures (caudate, putamen) results in the uneven formation of small empty microscopic vacuoles of varying sizes within Creutzfeldt-Jakob Disease (CJD) morphology In advanced cases, severe neuronal loss reactive gliosis, and sometimes expansion of the vacuolated areas into cystlike spaces (“status spongiosus”). Inflammation is notably absent. Creutzfeldt-Jakob Disease (CJD) morphology Kuru plaques extracellular deposits of aggregated abnormal PrP. Congo red– and PAS-positive usually occur in the cerebellum In all forms of prion disease, immunohistochemical staining demonstrates the presence of proteinase K–resistant PrPsc in tissue. Prion disease. (A) Spongiform change in the cerebral cortex. Inset, High magnification of neuron with vacuoles. (B) Cerebellar cortex showing kuru plaques that consist of aggregated PrPsc. (C) Cortical kuru plaques surrounded by spongiform change in variant Creutzfeldt-Jakob disease.  ALZHEIMER DISEASE Most common cause of dementia in elderly Insidious impairment of intellectual function Alteration in mood-behaviour Progressive disorientation Memory loss  ALZHEIMER DISEASE Symptoms >50 years Etiplogy: Mostly sporadic Genetic defect %5-10 familial disease of elderly Systemic metabolic defect Slow or latent virus disorders Toxins Combination viruses  ALZHEIMER DISEASE Morphology Cortical atrophy-widening of cerebral sulcus-frontal,temporal, parietal lobes Compensatory ventricular enlargement Medial temporal lobe; hipocampus, amygdala involved  pathogenesis Accumulation of two proteins (Aβ and tau) in specific brain regions, as a result of excessive production and defective removal two pathologic hallmarks of AD; amyloid plaques and neurofibrillary tangles.  Alzheimer Disease normal patient Amyloid plaq Tau protein AND Auguste Deter Aloïs Alzheimer (1864-1915) Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie und Psychisch-gerichtliche Medizin. 1907 Jan ; 64:146-8.  Pathogenesis of AD Amyloid Plaques are APP- cell surface deposits of protein receptor aggregated Aβ Deposition of Aβ peptides in the peptides derived from neuropil; abnormal cleavage of APP Aβ peptides aggregate-directly neurotoxic elicit inflammatory response from microglia and astrocyte Pathogenesis of AD  Pathogenesis of AD Neurofibrillary tangles are aggregates of the microtubule binding protein Tau is a microtubule- tau, associated protein present in axons in – develop association with the intracellularly microtubular network. – persist With the development of tangles in AD, extracellularly after becomes neuronal death. hyperphosphorylated, and loses the ability to bind to microtubules. Tau is a microtubule-associated protein present in axons in association with the microtubular network. With the development of tangles in AD, becomes hyperphosphorylated, and loses the ability to bind to microtubules.  How tangles injure neurons? remains poorly understood, but two possible pathways have been suggested (1) the aggregates of tau protein elicit a stress response; (2) the loss of tau protein destabilizes microtubules http://www.nature.com/nrn/journal/v3/n4/images/nrn785-i1.jpg  ALZHEIMER DISEASE Microscopy Neuritic plaques(senile) Neurofibrillary tangles Cerebral amyloid angiopathy Severe neuronal loss Reactive gliosis Neuritic plaques Focal-spherical collections of neuritic process (dystrophic neurites) In central area amyloid core; abnormal proteins (Aβ) Dystrophic neurites contain tau aggregates that are biochemically similar to neurofibrillary tangles Microglial cells and reactive astrocytes at periphery  Neuritic plaques Aβ40/Aβ42 TAU Component proteins Pro-inflammatory cytokines Apolipoproteins Alpha--antichemotrypsin Neuritic plaques  Neurofibrillary tangles Composed of paired helical filament Abnormally hyperphosphorylated TAU protein, MAP2,ubiquitin in neuronal cytoplasm http://1.bp.blogspot.com/-zmw15DAYqxA/UGkTuC6NzOI/AAAAAAAAKdU/9GNwYLILCcI/s1600/alz.jpg Globose neutofibrillary tangle  Alzheimer disease Cerebral amyloid angiopathy Amyloid accumulation in vessel wall  A, Plaques with dystrophic neurites surrounding amyloid cores B, Plaque core and surrounding neuropil are immunoreactive for Aβ. C, Neurofibrillary tangle is present within one neuron D, Silver stain showing a neurofibrillary tangle within the neuronal cytoplasm. E, Tangle and neurites around a plaque contain tau, demonstrated by immunohistochemistry  DEGENERATIVE DISEASES OF BASAL GANGLIA AND BRAINSTEM Ass. with movement disorders Rigidity, abnormal posture, chorea Reduction in voluntary movement Abundance of involuntary movement Basal ganglia esp.nigrostrial ptw imp role in (+) (-) regulatory ptw Parkinson Disease Huntington Disease  PARKINSON DISEASE neurodegenerative disease marked by a hypokinetic movement disorder caused by loss of dopaminergic neurons from the substantia nigra Damage to nigrostrial dopaminergic system  PARKINSON DISEASE Parkinsonism: characterized by diminished facial expression,slowness of voluntary movement, short accelerated steps, rigidity, ‘pill-rolling tremor’ http://t1.gstatic.com/images?q=tbn:ANd9GcR4uXfkfnxlzdUwLeZ_5FUdjcigqcfOHxsjQ3BZl0g4QUplWE29  http://kin450-neurophysiology.wikispaces.com/file/view/BW_JanFeb07_basal_ganglia_spot.jpg/394063532/349x334/BW_JanFeb07_basal_ganglia_spot.jpg https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcTJpVsLTJmVTe9ujJBg-BNo85imyO_tcoH8G8XiQPrFlsUL-UdvJA dopaminergic neurons of the substantia nigra project to the striatum (caudate and putamen), and their degeneration in PD is associated with a reduction in striatal dopamine content. http://chen2820.pbworks.com/f/substantia%20nigra%20b.jpg  PARKINSON DISEASE Pallor in substancia nigra  Pathogenesis of PD Protein α-synuclein accumulation and accumulation an abundant lipid-binding aggregation, protein normally mitochondrial localized to synapses. abnormalities, This protein is a major component of the and neuronal loss Lewy body, (diagnostic in the substantia hallmark of PD). nigra and elsewhere in the brain.  PARKINSON DISEASE Microscopy: Loss of pigmented, catecholaminergic neurons Lewy bodies; eosinophilic inclusions in neurons are single or multiple, cytoplasmic, eosinophilic, round to elongated inclusions that often have a dense core surrounded by a pale halo. Composed of α-synuclein Areas of neuronal loss also typically show gliosis  HUNTINGTON DISEASE Autosomal dominant disease Progressive movement disorders&dementia Degeneration of strial neurons;dysregulation of basal ganglia(normally dampen motor activity)  HUNTINGTON DISEASE Abnormal basal ganglia function Reduction in neurotransmitter GABA, metenkephalin due to loss of neuron in striatum; Cause relatively higher dopamin concentration Excessive excitation of thalamocortical ptw Choreaform movements increased motor output Jerky, hyperkinetic, dystonic movement(chorea)  HUNTINGTON DISEASE Small brain Enlarged ventricle Degeneration in cortex-cerebellum Neuronal death ;Atrophy of – caudate nucleus+putamen=ST RIATUM Frontal-parietal lobe atrophy Atrophy of caudate nucleus+putamen=STRIATUM Atrophy of the striatum and ventricular dilatation  HUNTINGTON DISEASE Microscopy: Loss of strial neurons esp. in caudate nucleus and putamen GABA’nergic neuronal loss Fibrillary gliosis Protein aggreagation in neurons-huntingtin Spinocerebellar Degenerations Affect cerebellum, spinal cord, peripheral nerves… Clinically cause cerebellar and sensory ataxia, spasticity, Spinocerebellar Degenerations Spinocerebellar Neuronal loss in Ataxia: affected area group of disease Secondary Caharac. by degeneration in symptoms related white matter tracts with cerebellum, brainstem,s.c Spinocerebellar Degenerations Friedreich Ataxia: Distinctive spinocerebellar degeneration 1th decade of life Gait ataxia, Joint position, vibratory sense impaired  Friedreich Ataxia: Morphology: Spinal cord; loss of axons and gliosis in posterior column Degeneration of neuron&brain stem, cerebellum Hypertrophic cardiomyopathy Spinocerebellar Degenerations Ataxia-Telengectasia: Ataxic-dyskinetic syndrome ATM gene mutated-imp.DNA repair mechanism Early childhood Telengectasia in conjunctiva and skin İmmunodeficiency Morphology: cerebellum:Loss of purkinje & granuler cell Degeneration of dorsal column LN, gonad, thymus hypoplastic.  Degenerative Disease affecting motor neurons Anterior horn of s.c Brainstem motor nuclei Upper motor neurons in cortex Denervation of muscles from loss of lower motor neurons results in muscular atrophy  Degenerative Disease affecting motor neurons Amyotropic Lateral Sclerosis (ALS): Progresssive loss of lower motor neurons in s.c&brain stem&upper motor neurons ?  ALS Both sporadic and familial ALS are associated with degeneration of upper and lower motor neurons, often in association with toxic protein accumulation.  etiology SOD(Superoxide dismutase) mutations cause reduced detoxification of free radicals….neuronal death?? Mutated SOD1 protein misfolded- triggers disease?  Amyotropic Lateral Sclerosis (ALS): Microscopy: Decrease ant. Horn neurons Reactive gliosis Pas (+) inclusions:Bunina body; remnants of autophagic vacuoles Skeletal muscles: neurogenic atrophy Segment of spinal cord viewed from anterior (upper) and posterior (lower) surfaces showing attenuation of anterior (motor) roots compared with posterior (sensory) roots. Spinal cord showing loss of myelinated fibers (lack of stain) in corticospinal tracts (best seen on the right side of this specimen; arrow) as well as degeneration of anterior roots (arrowhead). ALS