Pathology of CNS degenerations

1. Pathology of CNS degenerations “ Each individual creature on this beautiful planet 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 (1999)

2. CPC 4.3.5 – Helena, 65y Fem. <ul><li>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. </li></ul><ul><ul><li>Brad : ‘ I’ve come with Helena to discuss some memory problems she seems to be having ’ </li></ul></ul><ul><ul><li>Helena : “ I hope it’s nothing ; Brad has always been a worrier’ </li></ul></ul> CPC 4.3.5 – Helena, 65y Fem. <ul><li>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. </li></ul><ul><ul><li>Brad : ‘ I’ve come with Helena to discuss some memory problems she seems to be having ’ </li></ul></ul><ul><ul><li>Helena : “ I hope it’s nothing ; Brad has always been a worrier’ </li></ul></ul>

3. CPC 4.3.5 – Helena, 65y Fem. <ul><li>I haven’t been sleeping so well so I think my memory is a bit worse- it’s a combination of stress and fatigue’ </li></ul><ul><li>she can’t remember where she parked the car </li></ul><ul><li>She has forgotten social arrangements several times </li></ul><ul><li>Couldn’t remember their names … </li></ul><ul><li>she is struggling with organizing … </li></ul> CPC 4.3.5 – Helena, 65y Fem. <ul><li>I haven’t been sleeping so well so I think my memory is a bit worse- it’s a combination of stress and fatigue’ </li></ul><ul><li>she can’t remember where she parked the car </li></ul><ul><li>She has forgotten social arrangements several times </li></ul><ul><li>Couldn’t remember their names … </li></ul><ul><li>she is struggling with organizing … </li></ul>

4. CPC 4.3.5 – Helena, 65y Fem. <ul><li>Duration of symptoms: ? about 6/12 </li></ul><ul><li>Mood: low, quite tearful at times ; not enjoying life much </li></ul><ul><li>Concentration: poor , struggling to read books/journal.. </li></ul><ul><li>Sleep: disrupted , often up during early hours of morning. </li></ul><ul><li>Appetite and weight: no change </li></ul><ul><li>I am very tired . It’s probably time for me to retire .’ </li></ul> CPC 4.3.5 – Helena, 65y Fem. <ul><li>Duration of symptoms: ? about 6/12 </li></ul><ul><li>Mood: low, quite tearful at times ; not enjoying life much </li></ul><ul><li>Concentration: poor , struggling to read books/journal.. </li></ul><ul><li>Sleep: disrupted , often up during early hours of morning. </li></ul><ul><li>Appetite and weight: no change </li></ul><ul><li>I am very tired . It’s probably time for me to retire .’ </li></ul>

5. CPC 4.3.5 – Helena, 65y Fem. <ul><li>Physical Examination: NAD . </li></ul><ul><li>Cranial nerves, muscle power & tone, sensation & reflexes normal . </li></ul><ul><li>Co-ordination + proprioception normal bilaterally </li></ul><ul><li>MMSE : 30/30 ? , K10 : 36/50 ? </li></ul><ul><li>Word list task : recall of 2 words after 20 minutes …? </li></ul> CPC 4.3.5 – Helena, 65y Fem. <ul><li>Physical Examination: NAD . </li></ul><ul><li>Cranial nerves, muscle power & tone, sensation & reflexes normal . </li></ul><ul><li>Co-ordination + proprioception normal bilaterally </li></ul><ul><li>MMSE : 30/30 ? , K10 : 36/50 ? </li></ul><ul><li>Word list task : recall of 2 words after 20 minutes …? </li></ul>

6. CPC 4.3.5 – Helena, 65y Fem. <ul><li>Differential diagnoses: Dementia </li></ul><ul><ul><li>Depression – reactive? </li></ul></ul><ul><ul><li>Age related Mild cognitive impairement? </li></ul></ul><ul><ul><li>Hormonal e.g. hypothyroidism , drugs etc. </li></ul></ul><ul><ul><li>Alzheimer’s Disease ? </li></ul></ul><ul><li>Physical Examination… </li></ul><ul><li>Investigations: </li></ul><ul><ul><li>FBC, Liver FT & Thyroid FT normal, </li></ul></ul><ul><ul><li>HIV negative. (?) </li></ul></ul><ul><ul><li>CT scan : no space occupying lesion; ?some loss of grey matter with increased ventricular space. </li></ul></ul> CPC 4.3.5 – Helena, 65y Fem. <ul><li>Differential diagnoses: Dementia </li></ul><ul><ul><li>Depression – reactive? </li></ul></ul><ul><ul><li>Age related Mild cognitive impairement? </li></ul></ul><ul><ul><li>Hormonal e.g. hypothyroidism , drugs etc. </li></ul></ul><ul><ul><li>Alzheimer’s Disease ? </li></ul></ul><ul><li>Physical Examination… </li></ul><ul><li>Investigations: </li></ul><ul><ul><li>FBC, Liver FT & Thyroid FT normal, </li></ul></ul><ul><ul><li>HIV negative. (?) </li></ul></ul><ul><ul><li>CT scan : no space occupying lesion; ?some loss of grey matter with increased ventricular space. </li></ul></ul>

7. Brain: Functional areas. Memory

8. Brocas area (1878) consists primarily of cingulate and parahippocampal gyri. Brocas area (1878) consists primarily of cingulate and parahippocampal gyri.

9. Hippocampus: where short-term memories are converted to long-term memories Thalamus : receives sensory and limbic information and sends to cerebral cortex Hypothalamus : monitors and controls internal clock & other activities. Limbic system : controls emotions and instinctive behavior (includes the hippocampus and parts of the cortex) Functional Neuro Anatomy Slide 8 Hippocampus: where short-term memories are converted to long-term memories Thalamus : receives sensory and limbic information and sends to cerebral cortex Hypothalamus : monitors and controls internal clock & other activities. Limbic system : controls emotions and instinctive behavior (includes the hippocampus and parts of the cortex) Functional Neuro Anatomy Slide 8

10. . Dendritic tree - vs - Intelligence Rat CA1 pyramidal cell labeled with EGFP (Two photon laser scanning microscopy) Synaptic bouton in rat CA1 stratum radiatum (Electron microscopy)

11. . What is Success? &quot;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

12. . Pathology of C.N.S. Degenerative Disorders Dr. Venaktesh M. Shashidhar A/Prof. & Head of Pathology James Cook University

13. . Age related / Senile degeneration: <ul><li>Dementia: All spheres of intellect affected. </li></ul><ul><li>Decreasing mass - Slow 4th decade – rapid 7th decade. </li></ul><ul><li>progressive neuronal loss Neuronophagia . (hippocampus and cerebral cortex) </li></ul><ul><li>reduction in size & numbers of dendritic branches in surviving neurones </li></ul><ul><li>Cortical atrophy, hydrocephalus. </li></ul><ul><li>Thickening of leptomeninges. </li></ul><ul><li>NF tangles, A β Amyloid plaques. </li></ul><ul><li>increase in number of astrocytes </li></ul><ul><li>Athero & artero sclerosis. </li></ul>

14. . CNS Degenerations: Classification <ul><li>Neuronal Degenerations. </li></ul><ul><ul><li>Primary Degenerations: </li></ul></ul><ul><ul><ul><li>Global – Alzheimer & Lewibody </li></ul></ul></ul><ul><ul><ul><li>Selective/System – Parkinsons , Huntingtons , MND </li></ul></ul></ul><ul><ul><li>Secondary Degenerations: </li></ul></ul><ul><ul><ul><li>Toxic, metabolic(storage), infections, nutritional. </li></ul></ul></ul><ul><ul><ul><li>Alcohol & B12 def. </li></ul></ul></ul><ul><li>Disorders of Myelin: </li></ul><ul><ul><li>Demyelinating Disorders - Multiple sclerosis </li></ul></ul><ul><ul><li>Dysmylinating disorders – Leukodystrophies. </li></ul></ul>

15. . Dementia: <ul><li>Acquired global impairment of intellect-intact consciousness </li></ul><ul><li>> 15% of adults over 80 are demented…! (>30y, >70y…!) </li></ul><ul><li>Primary & secondary dementias </li></ul><ul><li>Primary: </li></ul><ul><ul><li>Alzheimer's disease </li></ul></ul><ul><ul><li>Diffuse Lewy body disease, Huntington's Dis, Pick's, </li></ul></ul><ul><li>Secondary: </li></ul><ul><ul><li>Cerebrovascular disease – stroke. </li></ul></ul><ul><ul><li>Infections (e.g. Creutzfeldt-Jakob, syphilis, HIV) </li></ul></ul><ul><ul><li>Neoplasms, haematoma, hydrocephalus. </li></ul></ul><ul><ul><li>drugs and toxins (barbiturates, digoxin , alcohol, heavy metals) </li></ul></ul><ul><ul><li>metabolic disorders (e.g. hypothyroidism, hypoparathyroidism, uraemia, hepatic failure) </li></ul></ul><ul><ul><li>vitamin deficiencies (e.g. B1-Wernicke-Korsakoff sy., B2, B12) </li></ul></ul>

16. . Alzheimer’s disease: <ul><li>Commonest cause of dementia in elderly </li></ul><ul><li>insidious with mood and behavior change. </li></ul><ul><li>Prevalence 1% in 6 th to >40% 8 th decade. </li></ul><ul><li>Pathology: </li></ul><ul><ul><li>Significant cortical atrophy </li></ul></ul><ul><ul><li>secondary ventricular enlargement </li></ul></ul><ul><ul><li>Neurofibrillary tangles – Intracellular ( Tau ) </li></ul></ul><ul><ul><li>Neuritic plaques ( A β amyloid ) – Extracellular. </li></ul></ul><ul><ul><li>Amyloid angiopathy. </li></ul></ul>

17. . Aloysius Alzheimer: <ul><li>German Psychiatrist. </li></ul><ul><li>1901 - Auguste Deter </li></ul><ul><ul><li>51 year male Patient. </li></ul></ul><ul><ul><li>Behavioural abnormality </li></ul></ul><ul><ul><li>Short term memory loss </li></ul></ul><ul><li>Colleague Franz Nissl </li></ul><ul><ul><li>silver stain. </li></ul></ul><ul><ul><li>Observed amyloid plaques & NF tangles. </li></ul></ul><ul><li>Case Presented at Berlin 1906. </li></ul><ul><li>International Brain Research Organization. </li></ul>Aloysius Alzheimer’s first Patient

18. . Alzheimer’s – Pathogenesis: <ul><li>Deposition of neurotoxic amyloid protein (peptide Aβ derived from APP) around blood vessels & neurons – extracellular plaques </li></ul><ul><li>Abnormal forms of axonal microtubule protein (protein tau) in neurons ‘neurofibrillary intracellular tangles ’ </li></ul><ul><li>Leading to Atrophy of neurons, gliosis. </li></ul>

19. . Alzheimers Disease: Cortical Atrophy Neurofibrillary tangles & Extraneuronal Neuritic plaques

20. . Alzheimer’s disease: Genetics <ul><li>Autosomal dominant genetic pattern – rare. </li></ul><ul><li>4 genes on chromosomes 1, 14, 19, and 21, influence initiation and progression. </li></ul><ul><li>Chromosome 21 generates the precursor protein for the amyloid protein (APP). Trisomy 21 produces early Alzheimer's disease in persons with Down syndrome. </li></ul><ul><li>Chromosome 19 generates apolipoprotein (apo) 3 allelic forms ε 2, ε 3, and ε 4, resulting in six combinations, of these risk for Alzheimer's disease is high with ε 4/ ε 4 & low with ε 2/ ε 2. </li></ul>

21. . Generation of Amyloid ( Aβ) Plaque Normal

22. . Alzheimer’s - Amyloid Angiopathy Cerebrum stained with polyclonal antibody against βA4 peptide showing amyloid deposits in plaques in brain substance (arrow A) and in blood vessel walls (arrow Amyloid core Dystrophic neurites

23. . <ul><ul><li>Neurofibrillary Tangles </li></ul></ul>Neurons have an internal support structure partly made up of microtubules. A protein called tau helps stabilize microtubules. In AD, tau changes, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles. Slide 18

24. . Neurofibrillary Tangles in AD: C: Neurofibrillary tangles (arrowheads) are present within the neurons (H & E). D: Silver stain showing a neurofibrillary tangle within the neuronal cytoplasm

25. . Alzheimer’s - Amyloid Angiopathy Congo Red stain & Polarised Microscopy showing apple green” birefringence

26. . Neuron degeneration- granulovcuolar. Several neurons display granulovacuolar degeneration of the cytoplasm. B. A neuron (center) contains an eosinophilic Hirano body (arrow).

27. . Cerebral atrophy in Alzheimer's: A-Neuritic Plaque, B-Amyloid

28. . Cerebral atrophy in Alzheimer's:

29. . Knife blade Fronto-temporal atrophy in Picks.

30. . Cerebral atrophy in Alzheimer's:

31. . Cerebral atrophy in Alzheimer's:

32. . Cerebral atrophy in Alzheimer's: Severe cortical atrophy, narrow gyri, wider sulci. White matter loss leading to dilated ventricles (compensatory hydrocephalus). Hippocampus Atrophy

33. . <ul><li>Degenration starts in the entorhinal cortex, then proceed to hippocampus. </li></ul><ul><li>Neuronal loss leads to shrinkage. </li></ul><ul><li>Changes can begin 10-20 years before symptoms appear. </li></ul><ul><li>Memory loss is the first sign of AD. </li></ul>AD Morphology – Early / Preclinical Slide 20

34. . <ul><li>Involves cerebral cortex </li></ul><ul><li>Mild signs: M emory loss, confusion, trouble handling money, poor judgment, mood changes, and anxiety. </li></ul><ul><li>Moderate signs: increased memory loss and confusion, problems recognizing people, difficulty with language and thoughts, restlessness, agitation, wandering, and repetitive statements. </li></ul>AD Morphology - Mild to Moderate Slide 21

35. . <ul><li>Extreme shrinkage of brain. </li></ul><ul><li>Patients are completely dependent on others for care. </li></ul><ul><li>Symptoms: weight loss, seizures, skin infections, groaning, moaning, or grunting, loss of bladder and bowel control. </li></ul><ul><li>Death usually occurs from aspiration pneumonia or other infections. </li></ul>AD Morphology: Severe AD Slide 22

36. . Neurofibrillary Tangles in AD: Plaque around Blood Vessels. Neurofibrillary Tangles -Intracellular A β Protein Amyloid tau protein – Microtubule.

37. . AD & Intelligence.… <ul><li>In early life, higher skills in grammar and density of ideas are associated with protection against AD in late life. </li></ul><ul><li>Mentally stimulating activity protects against AD. </li></ul><ul><li>Use it or loose it…..! </li></ul>

38. . Pick’s Disease: <ul><li>Severe, 40-65y. Rare. </li></ul><ul><li>Frontal & temporal lobes. </li></ul><ul><li>Progressive aphasia, personality change. </li></ul><ul><li>Relatively preserved memory. </li></ul>

39. . Picks Disease: Knife blade Fronto-temporal atrophy

40. . Pick’s Disease: <ul><li>Gross: Gyral atrophy of frontal and parietal lobes. </li></ul><ul><li>Micro: Hippocampus stained with anti-tau antibody. Many neuronal cell bodies contain sharply circumscribed, spherical cytoplasmic inclusion bodies (Pick bodies) </li></ul>

41. . CNS Degenerations: Classification <ul><li>Neuronal Degenerations. </li></ul><ul><ul><li>Primary Degenerations: </li></ul></ul><ul><ul><ul><li>Global – Alzheimer & Lewibody </li></ul></ul></ul><ul><ul><ul><li>Selective/System – Parkinsons , Huntingtons , MND </li></ul></ul></ul><ul><ul><li>Secondary Degenerations: </li></ul></ul><ul><ul><ul><li>Toxic, metabolic(storage), infections, nutritional. </li></ul></ul></ul><ul><li>Disorders of Myelin: </li></ul><ul><ul><li>Demyelinating Disorders - Multiple sclerosis </li></ul></ul><ul><ul><li>Dysmylinating disorders – Leukodystrophies. </li></ul></ul>

42. . Systemic Degenerations: <ul><li>Degeneration in functionally related areas of the CNS </li></ul><ul><li>Neuronal death  neuronophagia  fibrillary gliosis </li></ul><ul><li>Dementia: Intellectual disability. </li></ul><ul><li>Several types with overlapping features: </li></ul><ul><li>Many show neurotransmitter abnormalities (Parkinsons, Alzheimers ) </li></ul><ul><li>Mostly unknown Aetiology , some genetic (Friedreich‘s) </li></ul>

43. . Huntington’s <ul><li>Dementia, depression, choreiform movement ( Jerking dementia ) </li></ul><ul><li>5 th decade. Autosomal dom. </li></ul><ul><li>Huntington gene on 4p </li></ul><ul><li>Excess CAG tandem repeats = severity. </li></ul><ul><li>Atrophy of caudate & putamen with compensatory hydrocephalus of lateral ventricles. </li></ul>

44. . Huntington’s

45. . Normal - Huntington’s Striatum Atrophy

46. . Huntington’s

47. . Huntington’s

48. . Parkinson’s disease <ul><li>&quot;shaking palsy&quot; </li></ul><ul><li>Disease of substantia nigra - dopaminergic system in the and corpus striatum </li></ul><ul><li>Clinical features: </li></ul><ul><ul><li>tremor, bradykinesia and rigidity (45-60 years) </li></ul></ul><ul><ul><li>inhibition of movement & dementia in some cases. </li></ul></ul><ul><ul><li>Diminished facial expressions, stooped posture, decreased voluntary movements, festinating gait, rigidity & fine rolling tremors. </li></ul></ul>

49. . Parkinson’s disease <ul><li>Common Causes: </li></ul><ul><ul><li>Idiopathic (? free radical-induced oxidative damage) </li></ul></ul><ul><ul><li>Post-encephalitic </li></ul></ul><ul><ul><li>Post-traumatic </li></ul></ul><ul><ul><li>Ischaemia </li></ul></ul><ul><ul><li>Drug-induced (heroin) </li></ul></ul><ul><ul><li>Toxic damage (CO, manganese poisoning) </li></ul></ul>

50. . Pathology <ul><li>Pallor of the substantia nigra </li></ul><ul><li>Decrease in number of pigmented neurones </li></ul><ul><li>Other neurones in the same region show shrinkage and vacuolation </li></ul><ul><li>Loss of neurons replaced by macrophage </li></ul><ul><li>Marked degree of astrocyte gliosis. </li></ul><ul><li>Lewy bodies (hyaline bodies) </li></ul>