Pathology of Neurodegenerative disorders

1. Pathology of Neurodegenerative disorders “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.<br />- Wings of Fire: An Autobiography of Dr. APJ Abdul Kalam (1999) <br />

2. 2<br />CPC11-3.4 – Mrs. J.G.<br />75 year old housewife. <br />Husband Bob, aged 75, who is a retired accountant.<br />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.. <br />I don‟t want to be a burden. <br />Sleep disrupted, often up during early hours of morning.<br />P/H: well known in the community, active, social, popular, intelligent …<br />Kessler Psychological distress score K10: 36/50 *<br />Mini mental state examination MMSE: 30/30 *<br />Word list task : recall of 2 words after 20 minutes…?<br /> 2<br />CPC11-3.4 – Mrs. J.G.<br />75 year old housewife. <br />Husband Bob, aged 75, who is a retired accountant.<br />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.. <br />I don‟t want to be a burden. <br />Sleep disrupted, often up during early hours of morning.<br />P/H: well known in the community, active, social, popular, intelligent …<br />Kessler Psychological distress score K10: 36/50 *<br />Mini mental state examination MMSE: 30/30 *<br />Word list task : recall of 2 words after 20 minutes…?<br />

3. 3<br />2010: Helena, 65y Fem.<br />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.<br />Brad : ‘I’ve come with Helena to discuss some memory problems she seems to be having’<br />Helena : “I hope it’s nothing; Brad has always been a worrier’<br /> 3<br />2010: Helena, 65y Fem.<br />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.<br />Brad : ‘I’ve come with Helena to discuss some memory problems she seems to be having’<br />Helena : “I hope it’s nothing; Brad has always been a worrier’<br />

4. 4<br />CPC 34: Clinical<br />Not sleeping well, I think memmory is a bit worse- it’s stress and fatigue’<br />can’t remember where she parked the car<br />She has forgotten social arrangements several times<br />Couldn’t remember their names …<br />she is struggling with organizing…<br /> 4<br />CPC 34: Clinical<br />Not sleeping well, I think memmory is a bit worse- it’s stress and fatigue’<br />can’t remember where she parked the car<br />She has forgotten social arrangements several times<br />Couldn’t remember their names …<br />she is struggling with organizing…<br />

5. 5<br />CPC34– Clinical<br />Duration of symptoms: ? about 6/12<br />Mood: low, quite tearful at times; not enjoying life much.<br />Concentration: poor, struggling to read books/journal..<br />Sleep: disrupted, often up during early hours of morning.<br />Appetite and weight: no change <br />I am very tired. It’s probably time for me to retire.’<br /> 5<br />CPC34– Clinical<br />Duration of symptoms: ? about 6/12<br />Mood: low, quite tearful at times; not enjoying life much.<br />Concentration: poor, struggling to read books/journal..<br />Sleep: disrupted, often up during early hours of morning.<br />Appetite and weight: no change <br />I am very tired. It’s probably time for me to retire.’<br />

6. 6<br />Differential diagnosis.<br />Dementia: primary / secondary, vascular. <br />(Alzheimer’s Disease)<br />Endocrine: e.g. hypothyroidism, drugs etc.<br />Depression? – reactive – family events ?<br />Ageing: Mild cognitive impairement *<br />Investigations:<br />FBC, Liver FT & Thyroid FT normal, <br />HIV negative. ..?<br />CT scan: no space occupying lesion..? some loss of grey matter with increased ventricular space. .?<br /> 6<br />Differential diagnosis.<br />Dementia: primary / secondary, vascular. <br />(Alzheimer’s Disease)<br />Endocrine: e.g. hypothyroidism, drugs etc.<br />Depression? – reactive – family events ?<br />Ageing: Mild cognitive impairement *<br />Investigations:<br />FBC, Liver FT & Thyroid FT normal, <br />HIV negative. ..?<br />CT scan: no space occupying lesion..? some loss of grey matter with increased ventricular space. .?<br />

7. 7<br />Brain: Functional areas.<br />Language<br />Memory<br /> 7<br />Brain: Functional areas.<br />Language<br />Memory<br />

8. Broca’s area - Cingulate and Parahippocampal gyri. <br /> Broca’s area - Cingulate and Parahippocampal gyri. <br />

9. FunctionalNeuro Anatomy<br />Hippocampus:where short-term memories are converted to long-term memories<br />Thalamus: receives sensory and limbic information and sends to cerebral cortex (cognition)<br />Hypothalamus: monitors and controls internal clock & other activities.<br />Limbicsystem: controls emotions and instinctive behavior (includes the hippocampus and parts of the cortex)<br />Slide 8<br /> FunctionalNeuro Anatomy<br />Hippocampus:where short-term memories are converted to long-term memories<br />Thalamus: receives sensory and limbic information and sends to cerebral cortex (cognition)<br />Hypothalamus: monitors and controls internal clock & other activities.<br />Limbicsystem: controls emotions and instinctive behavior (includes the hippocampus and parts of the cortex)<br />Slide 8<br />

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

11. .

12. . What is Success?"To laugh often and much; to win the respect of intelligent people andthe 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<br />

13. . 13<br />Pathology of C.N.S. Degenerative Disorders<br />Dr. Venaktesh M. Shashidhar<br />A/Prof. & Head of Pathology<br />James Cook University<br />

14. . 14<br />Age related / Senile degeneration:<br />Dementia: All spheres of intellect affected.<br />Decreasing mass - Slow 4th decade – rapid 7th decade.<br />progressive neuronal loss Neuronophagia. (hippocampus and cerebral cortex)<br />reduction in size & numbers of dendritic branches in surviving neurones<br />Cortical atrophy, hydrocephalus. <br />Thickening of leptomeninges.<br />NF tangles, AβAmyloid plaques.<br />increase in number of astrocytes <br />Athero & artero sclerosis.<br />Young<br />Old<br />

15. . 15<br />CNS Degenerations: Classification<br />Neuronal Degenerations.<br />Primary Degenerations:<br />Global – Alzheimer, Lewy body, Fronto-temporal<br />Selective/System – Parkinsons, Huntingtons, MND<br />Secondary Degenerations:<br />Toxic, metabolic(storage), infections, nutritional.<br />Alcohol & B12 def.<br />Disorders of Myelin:<br />Demyelinating Disorders - Multiple sclerosis<br />Dysmylinating disorders – Leukodystrophies.<br />

16. . 16<br />Dementia:<br />Acquired global impairment of intellect-intact consciousness<br />> 15% of adults over 80 are demented…! (>30y, >70y…!)<br />Primary & secondary dementias <br />Primary: <br />Alzheimer's disease<br />Diffuse Lewy body disease, Huntington's Dis, Pick's,<br />Secondary: <br />Cerebrovascular disease – stroke.<br />Infections (e.g. Creutzfeldt-Jakob (CJD), syphilis, HIV) <br />Neoplasms, haematoma, hydrocephalus.<br />drugs and toxins (barbiturates, digoxin, alcohol, heavy metals) <br />metabolic disorders (e.g. hypothyroidism, hypoparathyroidism, uraemia, hepatic failure) <br />vitamin deficiencies (e.g. B1-Wernicke-Korsakoff sy., B2, B12) <br />

17. . 17<br />Alzheimer’s disease:<br />Commonest cause of dementia in elderly<br />insidious with mood and behavior change.<br />Prevalence 1% in 6th to >40% 8th decade. <br />Pathology: <br />Significant cortical atrophy<br />secondary ventricular enlargement<br />Neurofibrillary tangles – Intracellular (Tau)<br />Neuritic plaques (Aβamyloid) – Extracellular.<br />Amyloid angiopathy.<br />

18. . 18<br />Aloysius Alzheimer: <br />German Psychiatrist.<br />1901 - Auguste Deter<br />51 year male Patient.<br />Behavioural abnormality<br />Short term memory loss<br />Colleague Franz Nissl <br />silver stain.<br />Observed amyloid plaques & NF tangles.<br />Case Presented at Berlin 1906. <br />International Brain Research Organization.<br />Aloysius Alzheimer’s first Patient<br />

19. . 19<br />Alzheimer’s – Pathogenesis:<br />Deposition of neurotoxic amyloid protein (peptide Aβ derived from APP) around blood vessels & neurons – extracellular plaques<br />Abnormal forms of axonal microtubule protein (protein tau) in neurons ‘neurofibrillary intracellular tangles’<br />Leading to Atrophy of neurons, gliosis.<br />

20. . 20<br />Neurofibrillary tangles & <br />Extraneuronal Neuritic plaques<br />Cortical Atrophy<br />Alzheimers Disease:<br />

21. . 21<br />Alzheimer’s disease: Genetics<br />Autosomal dominant genetic pattern – rare. <br />4 genes on chromosomes 1, 14, 19, and 21, influence initiation and progression. <br />Chromosome 21 generates the precursor protein for the amyloid protein (APP). Trisomy 21 produces early Alzheimer's disease in persons with Down syndrome.<br />Chromosome 19 generates apolipoprotein (apo) 3 allelic forms ε2, ε3, and ε4, resulting in six combinations, of these risk for Alzheimer's disease is high with ε4/ ε4 & low with ε2/ε2. <br />

22. . 22<br />Normal<br />Generation of Amyloid (Aβ) Plaque<br />

23. . 23<br />Alzheimer’s - Amyloid Angiopathy<br />Congo-red Amyloid stain<br />Amyloid core<br />Dystrophic neurites<br />Silver stain<br />Cerebrum stained with polyclonal antibody against βA4 peptide showing amyloid deposits in plaques in brain substance (arrow A) and in blood vessel walls (arrow <br />

24. . 24<br />Congo Red stain & Polarised Microscopy showing apple green” birefringence <br />Alzheimer’s - Amyloid Angiopathy<br />

25. . Neurofibrillary Tangles<br />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.<br />Slide 18<br />

26. . 26<br />Neurofibrillary Tangles in AD:<br />(Tau protein)<br />C: Neurofibrillary (tau) tangles () within the neurons (H & E). D: Silver stain showing a neurofibrillary tangle within the neuronal cytoplasm <br />

27. . 27<br />Neuron degeneration- granulovcuolar.<br />Several neurons display granulovacuolar degeneration of the cytoplasm. B. A neuron (center) contains an eosinophilic Hirano body (arrow). <br />

28. . 28<br />CNS Morphology in Alzheimer's:<br />A-Neuritic Plaque, B-Amyloid<br />

29. . 29<br />Morphology in AD:<br />Plaque around BV. NF Tangles-Intracellular<br /> Aβ Amyloid tau protein<br />

30. . 30<br />Cerebral atrophy in Alzheimer's:<br />

31. . 31<br />AD Morphology – Early / Preclinical<br /><ul><li>Degenration starts in the entorhinal cortex, then proceed to hippocampus.

32. . Neuronal loss leads to shrinkage.

33. . Changes can begin 10-20 years before symptoms appear.

34. . Memory loss is the first sign of AD.</li></ul>Slide 20<br />

35. . 32<br />AD Morphology - Mild to Moderate<br /><ul><li>Involves cerebral cortex

36. . Mild signs: Memory loss, confusion, trouble handling money, poor judgment, mood changes, and anxiety.

37. . Moderate signs:increased memory loss and confusion, problems recognizing people, difficulty with language and thoughts, restlessness, agitation, wandering, and repetitive statements.</li></ul>Slide 21<br />

38. . 33<br />AD Morphology: Severe AD<br /><ul><li>Extreme shrinkage of brain.

39. . Patients are completely dependent on others for care.

40. . Symptoms: weight loss, seizures, skin infections, groaning, moaning, or grunting, loss of bladder and bowel control.

41. . Death usually occurs from aspiration pneumonia or other infections. </li></ul>Slide 22<br />

42. . 34<br />AD & Intelligence.…!<br />In early life, higher skills in grammar and density of ideas are associated with protection against AD in late life.<br />Mentally stimulating activity protects against AD.<br />Use it or loose it…..!<br />Coffee protects against Alzheimers<br />Tea protects against Parkinsons<br />

43. . Fronto-Temporal Dementia<br />Second common, Group of dementia, affecting personality, behaviour & speech, <br />Memory is not affected until late*<br />Younger age.<br />Pick's Disease<br />Frontotemporal Lobar Degeneration<br />Progressive Aphasia (problems speaking)<br />Semantic Dementia (understanding language)<br />Corticobasal Degeneration (+ motor)<br />35<br />

44. . 36<br />Pick’s Disease:<br />Severe, 40-65y, Rare. <br />Selective Frontal & temporal lobe atrophy.<br />Progressive aphasia / language dysfunction<br />Behaviour & personality change.<br />Preserved memory.<br />Micro: Neurons with round intracytoplasmicPick’s bodies (tau protein)<br />

45. . 37<br />Knife blade Fronto-temporal atrophy in Picks.<br />

46. . 38<br />CNS Degenerations: Classification<br />Neuronal Degenerations.<br />Primary Degenerations:<br />Global – Alzheimer, , Lewy body, Fronto-temporal<br />Selective/System – Parkinsons, Huntingtons, MND<br />Secondary Degenerations:<br />Toxic, metabolic(storage), infections, nutritional.<br />Disorders of Myelin:<br />Demyelinating Disorders - Multiple sclerosis<br />Dysmylinating disorders – Leukodystrophies.<br />

47. . 39<br />Systemic Degenerations:<br />Degeneration in functionally related areas of the CNS <br />Neuronal death  neuronophagia  fibrillary gliosis <br />Dementia: Intellectual disability.<br />Several types with overlapping features: <br />Many show neurotransmitter abnormalities (Parkinsons, Alzheimers )<br />Mostly unknown Aetiology , some genetic (Friedreich‘s)<br />

48. . 40<br />Huntington’s<br />Dementia, depression, choreiform movement (Jerking dementia)<br />5th decade. Autosomal dom.<br />Huntington gene on 4p<br />Excess CAG tandem repeats = severity.<br /><ul><li>Atrophy of caudate & putamen (striatum)

49. . Compensatory hydrocephalus of lateral ventricles*.</li></li></ul><li>41<br />Normal - Huntington’s<br />Atrophy<br />Striatum<br />

50. . 42<br />Parkinson’s:<br />"shaking palsy" <br />Parkinsonism: Clinical sy.<br />dopamine antagonists, post encephalitis.<br />Toxins: MPTP(heroin), <br />Parkinson’s disease – Primary atrophy of substantianigra. Dopaminergic system.<br />Clinical features: <br />Diminished facial expressions, stooped posture, <br />Slow voluntary movements, festinating gait, rigidity & fine rolling tremors.<br />tremor, bradykinesia and rigidity (45-60 years)<br />Inhibition of movement & dementia in some cases.<br />