Pathology of CNS Degenerations Lecture


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Pathology lecture on CNS degenerations to 4th year pre-clinical medical students.

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Pathology of CNS Degenerations Lecture

  1. 1. “Each individual creature on this beautifulplanet is here to fulfill a particular role. We are all born with a divine fire in us. Our efforts should be to give wings to this fire and fill the world with the glow of its goodness. - Wings of Fire: An Autobiography of Dr. APJ Abdul Kalam, President of India.
  2. 2. CNS Degenerative disorders…CPC11-3.4 – Mrs. J.G. 75 year old housewife. Husband Bob, aged 75, who is a retired accountant. I seem to be forgetting, can’t remember where she parked the car. couldn’t remember our friends’ names, she repeats things all the time.. I don‟t want to be a burden. Sleep disrupted, often up during early hours of morning. P/H: well known in the community, active, social, popular, intelligent … Kessler Psychological distress score K10: 36/50 * Mini mental state examination MMSE: 30/30 * Word list task : recall of 2 words after 20 minutes…? 2
  3. 3. CNS Degenerative disorders…2010: Helena, 65y Fem. Helena is a 65 year old married local GP. She is known as a „pillar of the community‟ and works full time as the senior partner at a GP surgery in Townsville. She is actively involved in many GP related educational activities. Her husband, Brad, is a local orthopedic surgeon. Although you have been their GP for sometime, they seldom consult you. Today they have booked a double appointment with you.  Brad : „I’ve come with Helena to discuss some memory problems she seems to be having‟  Helena : “I hope it’s nothing; Brad has always been a worrier’ 3
  4. 4. CNS Degenerative disorders…CPC 34: Clinical Not sleeping well, I think memmory is a bit worse- it’s stress and fatigue’ can’t remember where she parked the car She has forgotten social arrangements several times Couldn’t remember their names … she is struggling with organizing… 4
  5. 5. CNS Degenerative disorders…CPC34 – Clinical Duration of symptoms: ? about 6/12 Mood: low, quite tearful at times; not enjoying life much. Concentration: poor, struggling to read books/journal.. Sleep: disrupted, often up during early hours of morning. Appetite and weight: no change I am very tired. It’s probably time for me to retire.‟ Case presentation – YouTube 5
  6. 6. CNS Degenerative disorders…Differential diagnosis. Dementia: primary / secondary. (Alzheimer‟s Disease) Endocrine: e.g. hypothyroidism, drugs etc. Depression? – reactive – family events ? Ageing: Mild cognitive impairement * Investigations:  FBC, Liver FT & Thyroid FT normal,  HIV negative. ..?  CT scan: no space occupying lesion..? some loss of grey matter with increased ventricular space. .? 6
  7. 7. CNS Degenerative disorders… Brain Activity: PET Scan (language skills)Hearing Words Speaking Words Seeing Words Thinking about Words Different mental activities take place in different parts of the brain. Positron emission tomography (PET) scans can measure this activity. 7
  8. 8. CNS Degenerative disorders…Brain: Functional areas. Language Memory 8
  9. 9. Broca‟s area - Cingulate and Parahippocampal gyri. Hippocampus: where short-term memories are converted to long- term memories Thalamus: receives sensory and limbic information and sends to cerebral cortex (cognition) Limbic system: controls emotions and instinctive behavior (includes the hippocampus and parts of the cortex)
  10. 10. "I wasnt living my life. My life was living me. I realised I mademany of my decisions without thinking their consequences…“I realised all I really had to do to reclaim my life was to Startmaking decisions by considering their consequences in theimmediate present, near term and distant future.. i.e . In tenminutes, in ten months and in ten years”. -- Suzy Welch. The 10-10-10 rule. 10 – 10 – 10 minutes months years 10
  11. 11. Pathology ofC.N.S. Degenerative Disorders Dr. Venaktesh M. Shashidhar A/Prof. & Head of Pathology James Cook University 11
  12. 12. CNS Degenerative disorders…CNS Degenerations Increasing incidence – Ageing. Affect functional groups of neurons. Accumulate abnormal proteins. Primary & Secondary, Global & Local types. Dementia – Acquired defect in higher function: Memory, language, insight & planning.. “Human” > 45% of adults over 85y are demented…! (Starts >30y, rapid >70y…!) 12
  13. 13. CNS Degenerative disorders…CNS Degenerations: Classification Neuronal Degenerations.  Primary Degenerations:  Global – Alzheimer, Lewy body, Fronto-temporal  Selective/System – Parkinsons, Huntingtons, MND  Secondary Degenerations:  Toxic, metabolic(storage), infections, nutritional.  Alcohol & B12 def. Myelin Degenerations:  Demyelinating Disorders - Multiple sclerosis  Dysmylinating disorders – Leukodystrophies. 13
  14. 14. CNS Degenerative disorders…Aloysius Alzheimer: German Psychiatrist. 1901 - Auguste Deter  51year male Patient.  Behavioural abnormality  Short term memory loss Colleague Franz Nissl  silver stain.  Observed amyloid plaques & NF tangles. Case Presented at Berlin Aloysius Alzheimer‟s first Patient 1906. International Brain Research Organization. 14
  15. 15. CNS Degenerative disorders…Alzheimer‟s disease: Commonest cause of dementia in elderly Sporadic common (>60y) familial ~10% early. insidious onset of impaired higher intellectual function, altered mood and behavior, progress to disorientation, memory loss, aphasia  disabled, immobile… ~25y. Pathology:  Significant cortical atrophy  secondary ventricular enlargement  Neurofibrillary tangles (Tau) – within neurons  Neuritic plaques (Aβ amyloid) - Extracellular.  Amyloid angiopathy around blood vessels. 15
  16. 16. CNS Degenerative disorders…Alzheimer‟s disease: Genetics Autosomal dominant genetic pattern – rare 10% 4 genes on chromosomes 1, 14, 19, and 21, influence initiation and progression. Chromosome 21 generates the precursor protein for the amyloid protein (APP). Trisomy 21 produces early Alzheimers disease in persons with Down syndrome. Chromosome 19 generates apolipoprotein (apo) some of them increase risk for Alzheimers disease (ε4/ε4) by increasing Aβ amyloid deposition. 16
  17. 17. CNS Degenerative disorders…Alzheimer‟s – Pathogenesis: Amyloid Aβ is created when the transmembrane protein amyloid precursor protein (APP) is cleaved by the enzymes β-amyloid converting enzyme (BACE) and γ- secretase (instead of α) Deposition of neurotoxic Aβ around blood vessels (amyloid angiopathy) & interstitium neuritic plaques.(axonal tangles around) Aβ also leads to hyperphosphorylation of the neuronal microtubule binding protein tau in neurons to form „neurofibrillary tangles‟ within neurons. Both are neurotoxic leading to Atrophy of neurons & reactive glial proliferation – gliosis. 17
  18. 18. CNS Degenerative disorders…Alzheimers Disease: Morphology Gross Microscopy • Intraneuronal Neurofibrillary tangles • Interstitial amyloid Neuritic plaques • Cortical Atrophy • Loss of neurons with gliosis. 18
  19. 19. Pathogenesis of Neurofibrillary TanglesNeurons have an internal support structure partly made up ofmicrotubules. A protein called tau helps stabilize microtubules. InAD, tau breaks, causing microtubules to collapse, and tauproteins clump together to form neurofibrillary tangles. Slide 18
  20. 20. CNS Degenerative disorders… NormalPathogenesis ofAmyloid Plaques 20
  21. 21. CNS Degenerative disorders…Alzheimer‟s - Amyloid Angiopathy Silver stain Congo Red stain Cerebrum stained with polyclonal antibody against βA4 peptide showing amyloid deposits in plaques in brain substance (arrow A) and in blood vessel walls (arrow B) 21
  22. 22. CNS Degenerative disorders… Morphology in AD:Plaques & around BV. NF Tangles-Intracellular Aβ Amyloid tau protein 22
  23. 23. CNS Degenerative disorders…CNS Morphology in Alzheimers: A-Neuritic Plaque , B-Amyloid 23
  24. 24. CNS Degenerative disorders… AD Morphology – Early / Preclinical • Degenration starts in the entorhinal cortex, then proceed to hippocampus. • Neuronal loss leads to shrinkage. • Changes can begin 10-20 years before symptoms appear. • Memory loss is the first sign of AD. 24 Slide 20
  25. 25. CNS Degenerative disorders… AD Morphology - Mild to Moderate • Involves cerebral cortex • Mild signs: Memory loss, confusion, trouble handling money, poor judgment, mood changes, and anxiety. • Moderate signs: increased memory loss and confusion, problems recognizing people, difficulty with language and thoughts, restlessness, agitation, wandering, and repetitive statements. 25 Slide 21
  26. 26. CNS Degenerative disorders… AD Morphology: Severe AD • Extreme shrinkage of brain. • Patients are completely dependent on others for care. • Symptoms: weight loss, seizures, skin infections, groaning, moaning, or grunting, loss of bladder and bowel control. • Death usually occurs from aspiration pneumonia or other infections. 26 Slide 22
  27. 27. CNS Degenerative disorders…AD & Intelligence.…! In early life, higher skills in grammar and density of ideas are associated with protection against AD in late life. Mentally stimulating activity protects against AD. Use it or loose it…..! Coffee protects against Alzheimers Tea protects against Parkinsons (pathogenesis video) 27
  28. 28. CNS Degenerative disorders…Age related / Senile degeneration: Age related Dementia: All spheres of intellect affected. Decreasing mass - Slow 4th decade – rapid 7th decade. progressive neuronal loss Neuronophagia. (hippocampus and cerebral cortex) reduction in size & numbers of dendritic Young branches in surviving neurons Cortical atrophy, hydrocephalus. Thickening of leptomeninges. NF tangles, Aβ Amyloid plaques. increase in number of astrocytes Athero & artero sclerosis makes it worse. Old 28
  29. 29. Other CNSdegenerations: Local / Systems• Fronto-Temporal - Pick‟s• Parkinson‟s• Huntington‟s 29
  30. 30. CNS Degenerative disorders…Fronto-Temporal Dementia Second common, Group of dementia, affecting personality, behaviour & speech. Younger*, Memory not affected until late* Many sub types.  Picks Disease: FTLD-tau common.  FTLD-TDP43 – next common. Semantic Dementia (understanding language) Progressive language problems Aphasia predominate. Dementia later. 30
  31. 31. CNS Degenerative disorders… Pick‟s Disease: Severe, 40-65y, Rare. knife blade atrophy of Frontal & temporal lobe Progressive aphasia / language dysfunction Behaviour & personality change. Preserved memory. Micro: Neurons with round intracytoplasmic Pick‟s bodies (tau protein) 31
  32. 32. CNS Degenerative disorders…Knife blade Fronto-temporal atrophy in Picks. 32
  33. 33. CNS Degenerative disorders…Diffuse Lewy body Dementia: 10-15% of Parkinsons with dementia (Alzheimers) impaired memory of recent events, confusion, language problems. Dementia + visual Hallucinations. Lewy body (α-synuclein) in many part of cortex & cortical Lewy bodies (α- substantia nigra (global) synuclein) special stain. Atrophy of cortex like AD. 33
  34. 34. CNS Degenerative disorders…Vascular Dementia: (Multi-infarct) Second most common after AD. Different from senile dementia. Different pathophysiological types.  Mild vascular cognitive impairment – artereosclerosis.  Multi-infarct / single large infarct  Hypertensive lacunar lesions.  Binswanger disese – subcortical leukoencephalopathy - boxers, trauma.  Mixed – AD+vascular. 34
  35. 35. CNS Degenerative disorders… Dementia Pugilistica Punch drunk syndrome boxers – trauma. “chronic traumatic encephalopathy” Progressive dementia, tremor and focal neurological deficits. Degeneration in septum pellucidum, thinning of the corpus callosum, substantia nigra. Also cerebral neurofibrillary tangles & Aβ amyloid accumulation. (sec. alzheimer‟s) 35
  36. 36. CNS Degenerative disorders… Parkinson‟s: "shaking palsy" Parkinsonism: Clinical sy.  Drugs: dopamine antagonists  Toxins: MPTP(heroin),  Diseases: Multiple system atrophy, Post encephalitic. Parkinson‟s disease – Primary atrophy of substantia nigra. Dopaminergic nerves with α-synuclein - Lewy body. Clinical features:  Adults (45-60y), tremor, bradykinesia & rigidity  Diminished facial expressions, stooped posture,  Slow voluntary movements, festinating gait, & fine rolling resting tremors. Dementia in some cases.  When dementia arises within 1 year of the onset of motor symptoms, it is referred to Lewy body dementia (LBD). 36
  37. 37. CNS Degenerative disorders… Pathology of Parkinson‟s disease: Gross: Loss of pigment in substantia nigra. Parkinson Neuronal loss, degeneration, Loss of neurons replaced by gliosis (microglia) Normal Loss of neuromelanin. Neuronal degeneration Reactive gliosis. L Lewy bodies (α- synuclein) in neurons. 37
  38. 38. CNS Degenerative disorders… Huntington‟s Dementia, depression, choreiform movement (Jerking dementia) 5th decade. Autosomal dom. Huntington gene on 4p – Huntingtin. Excess CAG tandem repeats = severity. Atrophy of caudate & putamen (striatum) Compensatory hydrocephalus of lateral ventricles*. 38
  39. 39. CNS Degenerative disorders… Normal - Huntington’s Atrophy 39
  40. 40. Education without wisdom, Student without humility,Discourse that fails to inspire and knowledge without experience... are all futile!
  41. 41. CNS Degenerative disorders…CNS Degenerations: Classification Neuronal Degenerations.  Primary Degenerations:  Global – Alzheimer, Lewy body, Fronto-temporal  Selective/System – Parkinsons, Huntingtons, MND  Secondary Degenerations:  Toxic, metabolic(storage), infections, nutritional. Disorders of Myelin:  Demyelinating Disorders - Multiple sclerosis  Dysmylinating disorders – Leukodystrophies. 41
  42. 42. CNS Degenerative disorders…Metabolic CNS Disorders: Alcoholism induced CNS disorders:  Wernicke syndrome (vit B1 thiamine def.) – ataxia, confusion.  Korsakoff syndrome (memory)  Central pontine myelinolysis  Cortical atrophy  Atrophy of vermis of the cerebellum. 42
  43. 43. CNS Degenerative disorders…Wernickes encephalopathy:Recurrent petechial hemorrhages in the hypothalamus, mamillary bodieswith atrophy.Wernicke‟s Sy: Altered Thermal regulation & consciousness,ophthalmoplegia, nystagmus.Korsokoff Psychosis: Loss of recent memory compensated byconfabulation. 43
  44. 44. CNS Degenerative disorders…Korsakoffs disease: Korsakoffs disease. Central pontine myelinolysis. Demyelination of the center of the pons. Shrunken, brown mammillary bodies (indicating chronic stage). Cause is unknown but usually seen in chronic alcoholics and associated with rapid over-correction of hyponatremia. Alcoholic cerebellar atrophy. Shrunken folia and widened fissures of the anterior, superior vermis of the cerebellum. Another change which may be found in chronic alcoholics. 44
  45. 45. CNS Degenerative disorders…Vitamin Def & Neuropathy: A - Benign intracranial hypertension (rare) B1 Wernicke-Korsakoff syndrome B2 Peripheral neuropathy, ataxia,dementia B6 Convulsions in infants B12 Weakness and paraesthesiae in the lower limbs (1 & 3) C Scurvy E Weakness, sensory loss, ataxia, nystagmus 45
  46. 46. CNS Degenerative disorders…CNS Degenerations: Classification Neuronal Degenerations.  Primary Degenerations:  Global – Alzheimer, Lewy body, Fronto-temporal  Selective/System – Parkinsons, Huntingtons, MND  Secondary Degenerations:  Toxic, metabolic(storage), infections, nutritional. Disorders of Myelin:  Demyelinating Disorders - Multiple sclerosis  Dysmylinating disorders – Leukodystrophies. 46
  47. 47. CNS Degenerative disorders…Demyelinating Disorders: Selective myelin damage  axon damage. Defective transmission of impulse. Morphology: Myelin loss, inflammation, gliosis, secondary axon damage. Types & Classification  Immune – Multiple sclerosis  Vitamin deficiency – Vit B12.  Metabolic: Central pontine myelinolysis – alcohol  Infections – JC virus  PML in immunosuppressed.  Genetic – Leukodystrophy* (Dysmyelinating) 47
  48. 48. CNS Degenerative disorders…Multiple Sclerosis: Common 1:1000, adults, females 2:1, HLA DR2, <50y. Autoimmune (Gen+Env+AI) Episodes of Limb Weakness, paraesthesia. Relapsing & remitting. Progressive  death in years. Multiple soft pink plaques of demyelination- periventricular. Inflammation, perivascular T lymphocytes & plasma cells. CSF - oligoclonal IgG. Reactive gliosis. 48
  49. 49. CNS Degenerative disorders…Multiple Sclerosis: Demyelinated plaques Microscopy showed loss of myelination with many lipid  macrophages around BV. 49
  50. 50. CNS Degenerative disorders…Multiple Sclerosis - plaques MRI Gross Specimen 50
  51. 51. CNS Degenerative disorders… MS – Periventricular plaque Like patches of grey matter within white matter…! 51
  52. 52. CNS Degenerative disorders…Multiple Sclerosis – Chronic plaque Sharp area of myelin loss (white area in this blue myelin stain) Plaque contain fibrillary astrocytes. A few lymphocytes and macrophages are present around blood vessels (V) Normal myelinated white matter appears blue. 52
  53. 53. CNS Degenerative disorders… ALS: Amyotrophic Lateral Sclerosis Also known as Lou Gehrigs disease, is the most common type of Motor Neurone Disease (MND). Genetic: Mutations in SOD1 gene on Chromosome 21. Progressive neuron loss. Middle age, men, sporadic common, Familial 10% Muscle weakness, fasciculations, Degeneration of lateral and ventral spasticity, Sensation normal. corticospinal tracts (myelin stain). Degeneration of LMN tracts in the lateral portion of the spinal cord MND subtypes: ("lateral sclerosis"). and of UMN - • Amyotrophic Lateral Sclerosis* Betz cells in the motor cortex. • Progressive muscle atrophy (LMN) • Primary lateral sclerosis (UMN) • Progressive bulbar palsy 53
  54. 54. Pathology of CNS degenerations: Disease Lesion Components LocationAlzheimer Plaques & β-Amyloid & Extracellulardisease NF tangles tau IntracytoplasmicFrontotempor NF tangles tau Intracytoplasmical dementias(eg. Picks)Dementia with Lewy bodies α-Synuclein IntracytoplasmicLewy bodiesParkinson Lewy bodies α-Synuclein IntracytoplasmicdiseaseAmyotrophic Spheroids Neurofilament Intracytoplasmiclateral subunits/super-oxidesclerosis dismutase (SOD-1)Multi system Glial tau Intracytoplasmicatrophy inclusions
  55. 55. Cells / Structure Common PathologyPurkinje cells Alcoholism, carbon monoxide, IschemiaMammilaries, Purkinje Wernickes encephalopathy (alcoholism)cellsDM of thalamus Korsakoffs psychosis (alcoholism)Hippocampus Alzheimers, hypoxia, hypoglycemiaRetina Methanol toxicityAnterior horn cells Polio, lower-ALSGlobus pallidus Carbon monoxide, Wilsons, Kernicterus.Posterior columns B12 deficiency, syphilis (tabes)Caudate nucleus Huntingtons choreaFronto-temporal deg. Picks diseaseDeep brain stem Progressive supranuclear palsySubstantia nigra Parkinson„sUpper motor neurons Upper-ALS (Amyotrophic Lateral Sclerosis)
  56. 56. CNS Degenerative disorders…CPC-3.6– CNS –Degenerations Pathology – Major Learning Issues:  Common Dementias & system degenerations.  Dementia diagnosis & Laboratory investigations.  Alzheimer‟s disease, Pick‟s & Parkinson‟s.  Huntington‟s, Multiple Sclerosis, MNDs. Pathology – Minor Learning Issues:  Senile, Vascular dementia, Infections – Prions(MCD), syphilis, HIV  Toxins and vitamin def. Vit B12/thiamine def.  Manganese, lead poisoning. 56
  57. 57. CNS Degenerative disorders……To leave the world a better place. To know even one life hasbreathed easier because you have lived… that is success..!-- Ralph Waldo Emerson 57
  58. 58. CNS Degenerative disorders…CPC-3.6– KFP Questions: Dementia – definition, classification. Primary:  Alzheimers, Picks, Huntingtons & Diffuse Lewy body disease. Secondary:  CVD, Infections, Neoplasms, haematoma, hydrocephalus.drugs and toxins metabolic, vitamin def. (e.g. B1, B2, B12). Demyelinating disorders:  Multiple sclerosis, MND, 58
  59. 59. Pathogenesis: YouTubeThe only real mistake is the one from which we learn nothing! JOHN POWELL:
  60. 60. Anyone who thinks money will make you happy, hasnt got it….!
  61. 61. "Education is for ‘life’.. not for merely for ‘living’"The end of education is character" - BABA
  62. 62. What is Success?"To laugh often and much; to win the respect of intelligent people and the affection of children. To leave the world a better place. To know even one life has breathed easier because you have lived… that is success..! -- Ralph Waldo Emerson