Pathology lectures for 4th year medical students on neurodegenerative disorders, Alzheimers, dementia etc.

1. “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. 2 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…?

3. 3 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’

4. 4 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…

5. 5 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.’

6. 6 Differential diagnosis. Dementia: primary / secondary, vascular. (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. .?

7. 7 Brain: Functional areas. Language Memory

8. Broca’s area - Cingulate and Parahippocampal gyri.

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

10. 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)

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

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

14. 14 Age related / Senile degeneration: 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 branches in surviving neurones Cortical atrophy, hydrocephalus. Thickening of leptomeninges. NF tangles, AβAmyloid plaques. increase in number of astrocytes Athero & artero sclerosis. Young Old

15. 15 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. Disorders of Myelin: Demyelinating Disorders - Multiple sclerosis Dysmylinating disorders – Leukodystrophies.

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

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

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

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

20. 20 Neurofibrillary tangles & Extraneuronal Neuritic plaques Cortical Atrophy Alzheimers Disease:

21. 21 Alzheimer’s disease: Genetics Autosomal dominant genetic pattern – rare. 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 Alzheimer's disease in persons with Down syndrome. 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.

22. 22 Normal Generation of Amyloid (Aβ) Plaque

23. 23 Alzheimer’s - Amyloid Angiopathy Congo-red Amyloid stain Amyloid core Dystrophic neurites Silver 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

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

25. Neurofibrillary Tangles 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

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

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

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

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

30. 30 Cerebral atrophy in Alzheimer's:

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.Slide 20

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.Slide 21

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. Slide 22

42. 34 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

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

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

45. 37 Knife blade Fronto-temporal atrophy in Picks.

46. 38 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.

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

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

51. 43 Pathology of Parkinson’s disease: Gross: Loss of pigment in substantianigra. Neuronal loss, degeneration, Loss of neurons replaced by gliosis (microglia) Lewy bodies (α-synuclein) in neurons. L

52. 44 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 & substantianigra(global) Atrophy of cortex like AD. cortical Lewy bodies (α-synuclein) special stain.

53. 45 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.

54. Anybody who thinks money will make you happy, hasn't got it….!

55. 47 CNS Degenerations: Classification Neuronal Degenerations. Primary Degenerations: Global – Alzheimer, Lewybody, Fronto-temporal Selective/System – Parkinsons, Huntingtons, MND Secondary Degenerations: Toxic, metabolic(storage), infections, nutritional. Disorders of Myelin: Demyelinating Disorders - Multiple sclerosis Dysmylinating disorders – Leukodystrophies.

56. 48 Demyelinating Disorders: Selective myelin damage - axon sparing. Defective transmission of impulse. Prognosis  repair & axon damage. Types & Classification Immune – Multiple sclerosis Genetic – Metabolic, Leukodystrophy. Vitamin deficiency – Vit B12 Infections – JC virus

57. 49 Multiple Sclerosis Commonest. CNS only. Autoimmune (Gen+Env+AI) 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.

58. 50 Multiple Sclerosis Plaque: Section of fresh brain showing brown plaque around occipital horn of the lateral ventricle.

59. 51 Multiple Sclerosis: Demyelinated plaques Microscopy showed loss of myelination with many lipid macrophages.

60. 52 Multiple Sclerosis - plaques

61. 53 Multiple Sclerosis - plaques

62. 54 MS – Periventricular plaque MS Normal Like patches of grey matter within white matter…!

63. 55 MS- Plaques – Myelin stain.

64. 56 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.

65. 57 Metabolic CNS Disorders: Alcoholism induced CNS disorders: Wernicke syndrome (vit B1 def.) Central pontine myelinolysis Cortical atrophy Atrophy of vermis of the cerebellum

66. 58 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) CScurvy EWeakness, sensory loss, ataxia, nystagmus

67. 59 Wernicke's encephalopathy: Recurrent petechial hemorrhages in the hypothalamus, mamillary bodies with atrophy. Wernicke’s Sy: Altered Thermal regulation & consciousness, ophthalmoplegia, nystagmus. Korsokoff Psychosis: Loss of recent memory compensated by confabulation.

68. 60 Korsakoff's disease: Note: Shrunken, bodies brown mammillary bodies indicating chronic stage or Korsakoff's disease. Central pontine myelinolysis. Demyelination of the center of the basis pontis. Cause is unknown but is usually in chronic alcoholics and is often 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.

69. 61 Kernictirus – Neonatal hyperbilirubinemia Kern+Ictirus – yellow nuclei. Complication of Neonatal jaundice. Polycythemia, Hemolytic disease of new born. Hemolytic anemia.

70. 62 ALS_Amyotrophic lateral sclerosis Progressive motor weakness leading to death. Degeneration of upper motor neurons (spastic paralysis). Middle age, men more, Familial & geographic (Guam, PNG, Japan.. ) Loss of motor neurons in lateral and ventral corticospinal tracts. Degeneration of lateral and ventral corticospinal tracts (myelin stain). Degeneration of upper motor neurons and causes spasticity, brisk reflexes, and up-going plantar responses. Lower motor neurons and their axons are not involved. Therefore, there is no muscle atrophy.

71. Pathology of CNS degenerations:

72. 64 CPC-3.6– CNS –Degenerations Pathology - Core Learning Issues: Pathology & Pathogenesis of common Dementias/CNS degenerations. Overview of rare forms of degenerative CNS disorders. Dementia diagnosis & Laboratory investigations. Basic science - Core Learning Issues: Structure and function of brain Areas of brain dealing with higher cognitive function Age related changes in structure & function of brain. Senile dementia.

73. 65 …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

74. 38y recurrent limb weakness 9m, MRI ? Diagnosis Multiple sclerosis Parkinsons Alzheimer’s Huntington’s Pick’s disease

75. 38y depression, chorea ? Diagnosis Multiple sclerosis Parkinsons Alzheimer’s Huntington’s Pick’s disease

76. A 65 year old woman with 3y history of emotional disturbances, irritability, irresponsible and difficulty with activities of daily living. Now she has difficulty talking. Image shows appearance of her brain. What is the most likely diagnosis? Huntington’s disease. Alzheimer’s disease. Pick’s disease. Parkinson’s disease Multiinfarct dementia. Briefly discuss pathogenesis of this condition? List 3 gross and Microscopic feature of this disease? List 3 differentiating features of Alzheimers & this disease?.

77. A 56-year-old man is rushed to the emergency room after collapsing while shoveling snow. The patient has no pulse on admission but is resuscitated. Laboratory studies show elevated serum levels of cardiac-specific proteins, and ECG confirms a transmural infarct of the left ventricle. The patient expires 2 weeks later of cardiac tamponade. Examination of the patient's brain at autopsy would most likely reveal necrosis of Purkinje cells and selective loss of neurons in which of the following regions? Frontal lobes Hippocampus Hypothalamus Occipital lobes Thalamus

78. A 28 year old woman with ataxia, diplopia on lateral gaze and flashes of light on eye movement. CSF analysis shows increased proteins, lymphocytes and oligoclonalIgG bands and normal glucose. Image shows gross specimen of brain with lesions typical of this disease. What is the most likely diagnosis? Parkinson’s disease MCA infarct. Lacunar Infarcts. Multiple sclerosis. Viral encephalitis. Briefly discuss etiology & pathogenesis of this condition? Describe the gross features shown in the image? List other clinical features? What is the prognosis of this condition?

79. 38y female recurrent limb weakness. Image shows white mater stained for myelin.? Diagnosis Multiple sclerosis Parkinsons Alzheimer’s Huntington’s Pick’s disease

80. 72y Male progressive severe dementia, Image shows amyloid stain of his brain. ? Diagnosis Pick’s disease. Huntington’s disease. Alzheimer’s disease. Multi-infarct dementia. Senile dementia.

81. 38y fem recurrent tremor & limb weakness progressive over 13 years. ? Diag Multiple sclerosis Hypertensive-stroke. Alzheimer’s Huntington’s Pick’s disease

82. A 48 year old man with a year long history of worsening jerky, choreo-athetoid movements of all limbs, bradykinesia and rigidity. Image shows coronal section of a brain specimen showing typical features of his disease. What is the most likely diagnosis? Picks disease. Lewy body disease. Huntington’s disease. Multiple sclerosis. Amyotropic lateral sclerosis. Briefly discuss pathogenesis of this condition? (Trineucleotide repeat dis) Describe the gross features shown in the image? what other clinical features are expected in this disease?

83. A 60-year-old man with a 15-year history of diabetes mellitus type II complains of deep burning pain and sensitivity to touch over his hands and fingers. Nerve conduction studies show slow transmission of impulses and diminished muscle stretch reflexes in both ankles and knees. Sensations to vibrations and light touch are also markedly diminished. Laboratory analysis of CSF shows no biochemical abnormalities. Which of the following is the most likely type of peripheral nerve disease in this patient? Autonomic neuropathy Distal polyneuropathy Inflammatory neuropathy Mononeuropathy Paraproteinemic polyneuropathy

84. 58y M, Progressive bradykinesia, dementia & Hallucinations ? Diagnosis Alzheimer’s Parkinson’s Motor neurone disease Syringomyelia Lewy body disease

85. A 35-year-old man with Down syndrome dies of acute lympho-blastic leukemia. Gross examination of the patient's brain at autopsy shows mild microcephaly and underdevelopment of the superior temporal gyri. Histologic examination would most likely show which of the following neuropathologic changes? AA amyloidosis Lewy body dementia Leukemic infiltrates Neurofibrillary tangles Old healed infarcts.

86. A 35 year old HIV +ve man with Kaposisarcoma has a 3 day history of headache and confusion followed by seizures and hemiparesis. CT scan showed multiple ring-enhancing lesions. Image shows Gross appearance and MRI of a brain typical of this disorder. What is the most likely diagnosis? Multiple Aspergilloma. Cerebral TB lesions. Multiple Abscesses. Multiple sclerosis plaques. Cerebral metastases. What does “ring enhancing” lesion mean? Briefly discuss etiology and pathogenesis? List other pathologic findings expected in the brain of a AIDS patiets?.

87. 38y fem, recurrent attacks of limb weakness, paraesthesia worsened over 7 years resulting in death due to respiratory failure. Image shows her brain specimen. What is the most likely Diagnosis? Multiinfarct dementia. Parkinsons disease. Multiple sclerosis Motor neurone disease. Lacunar infarcts.

88. 52y male, dementia, depression with choreiform movements. Image of his brain(B) compared with normal (A) ?Diagnosis Binswanger disease Parkinsons disease Alzheimers disease Pick’s disease Huntington’s disease A B

89. 78y M, Dementia, memory loss and spacial disorientation. Cortical biopsy. ? Diagnosis Alzheimer’s Parkinson’s Lewy body disease Huntington’s disease Pick’s disease Cortical biopsy - βamyloidimmunostain

90. 78y, Dementia, Aphasia, Image shows Hippocampus biopsy stained with anti tau stain. ? Diagnosis Multiple sclerosis Parkinsons Alzheimer’s Multi-infarct dementia Pick’s disease

91. 78y Male progressive severe dementia, Image shows amyloid stain of his brain.? Identify structure A Neurofibrillary tangles. Amyloid plaques. Amyloid Angiopathy Astrocytes - Gliosis. Neuronophagia.

92. 58y female vocalist difficulty remembering songs, depression, dementia & gait abnormality. Image shows brain biopsy. What is the most likely diagnosis? Alzheimer’s disease. Pick’s disease. Huntington’s disease. Lewy body disease. Creutzfeldt-Jakob disease. CJD: Spongiform degeneration (vacuoles) no inflammation - Slowly progressive ataxia and dementia. Prion protein (APrPamyloid) – form template to make more abnormal protein (not a living being) Infection  From contaminated brain of infected animal. Prion diseases: Kuru, CJD, Scrapie, and bovine spongiform encephalopathy (mad cow disease).

93. 38y progressive weakness, spasticity, dysphagia and loss of muscle mass. Image shows section of spinal cord stained for myelin. Diagnosis? Multiple sclerosis Parkinsons Motor neurone disease Syringomyelia Spinal cord infarction.

94. 30y F, 7 day history of mild tremor in her arms and impaired balance when walking. Vital signs are normal. Her symptoms disappear the following week, but recures several times over next 4 years gradually developed weakness requiring assistance when walking. Neurologic examination reveals ataxia, dysarthria, decreased vibratory sensation, absent abdominal reflexes, increased deep tendon reflexes, and a Babinski sign on the left. Fifteen years after the onset of symptoms, the patient becomes bedridden and dies. A coronal section of the patient's brain at autopsy is stained for myelin (shown). Which of the following histopathologic findings would be expected in the lesions seen in the patient's brain? Astrogliosis Lewy bodies Myelin loss. Neuritic plaques Neuronophagia.

95. What is the best clinical description for the image? 83y man – dementia, memory loss and disorientation. 43y man -abnormal movements who committed suicide 56y woman -progressive paralysis 60y man -tremor, rigidity and dementia 73y woman –Dementia aphasia but intact memory.

96. What is the best clinical description for the image? AD HD ALS PD Pick 83y man – dementia, memory loss and disorientation. 43y man -abnormal movements who committed suicide 56y woman -progressive paralysis 60y man -tremor, rigidity and dementia 73y woman –Dementia aphasia intact memory.

97. 89 CPC-3.6– KFP Questions: Dementia – definition, classification. Primary: Alzheimer's, Pick's, Huntington's & 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,

98. The only real mistake is the one from which we learn nothing!JOHN POWELL:

99. 10 – 10 – 10minutes months years 91 The 10-10-10 rule. "I wasn't living my life. My life was living me. I realised I made many of my decisions as if I was watching from a moving car. (decisions for instant pleasure…) “I realised all I really had to do to reclaim my life was to Start making decisions by considering their consequences in the immediate present, near term and distant future.. i.e . In ten months, in ten minutes and in ten years”. -- Suzy Welch.

100. "Education is for ‘life’.. not for mere ‘living’ "The end of education is character" - BABA

101. 93 MND: Case study: A 25 year old woman developed progressive weakness of the left arm during the second trimester of her first pregnancy.Over the next few months she developed progressive weakness of the arms and later the legs and respiratory muscles. On examination she had reduced limb reflexes, with grade 1 power in the arms and grade 1 - 2 in the legs. Wasting and fasciculation were not seen. Sensation was normal. Nerve conduction studies showed evidence of axonal degeneration in motor nerves only. Normal investigations included MRI of the brain, cervical spine and brachial plexus, sural nerve biopsy, antiganglioside antibodies, CSF examination, lyme, syphilis and HIV serology, heavy metal levels, hexosaminidase levels, SOD-1 gene and mitochondrial DNA analyses. 10 months after the onset of her symptoms she required ventilation. Despite treatment with intravenous gammaglobulin, methyl prednisolone and plasma exchange her condition deteriorated and she became globally weak and areflexic, with involvement of bulbar muscles. Ocular movements were preserved until shortly before death. At times she appeared inappropriately cheerful, but cognition was normal. Sensation and autonomic function remained normal throughout the disease duration. She was ventilated for 27 months prior to death.

102. 94 MND: Atrophy of anterior nerve roots.

103. 95 Case study 1 62-year-old minister is having trouble composing his sermons. wife tells that members of the church have complained that the pastor is making many mistakes. (Patient denies) "I can't grasp the profounder thoughts.“

104. 96 Case study 2 A 73y widow, brought by daughter. She lives alone, and continues to drive. The daughter reports that her mother has become more disoriented during telephone conversations. Discussions with the mother's friends reveal memory lapses and inappropriate decisions.

105. 97 Case study 3 A 62-year-old tool-and-die maker, accompanied by his wife, appears for an office visit. He has no physical complaints, but his wife reports a progressive decline in his short-term memory.

106. 98 Case study 4 64y male, 2-year history severe depression. insomnia and early morning wakening. The patient typically woke feeling "unrefreshed", and the collateral history from the spouse suggested that the patient was "less active" during sleep, with reduced turning, and a tendency to sleep on his back throughout the night. attention and concentration were impaired, experiencing "slowing" and "difficulty getting going" with tasks. The patient reported feeling suspicious of others, and had concerns that people intended him harm. However, the patient did not describe any hallucinations. When questioned further, the patient reported that he was slower in his day-to-day activities, gait change, uncontrolled walking gait.. with a reduction in spontaneity and physical activity. He also reported a relatively recent onset of anxiety and irritability with associated tremor, which he thought was perhaps more marked on the left side. His appetite and weight were unchanged.

107. 99 Neuropathies And Myopathies Neuronal / Muscular damage: Causes: Hereditary Motor & Sensory neuropathies Inflammatory - Diphtheria, Infectious: HZV, HIV, Leprosy Acquired/ Metabolic: Diabetes, Uraemia Vitamin B12 def Toxins: Alcohol, Lead toxicity, Drugs

108. 100 Diabetic Neuropathy Types: Distal symmetric sensory neuropathy: tingling numbness, loss of pain in toes, hands, legs. Autonomic neuropathy Focal asymmetric neuropathy: cranial/ peripheral nerve involvement Pathogenesis: Microangiopathy, ischemia, Hyperosmolar cell damage by polyols, myelin loss in sensory nerves.

109. 101 Herpetic Neuralgia (HZ infection) Sensory ganglia of spinal cord & brain stem. Reactivation of latent infection following decrease in cell mediated immunity. Painful vesicular lesions in the distribution of sensory dermatome, trigeminal nerve. Intranuclearinclusions are generally not found in the peripheral nerve lesions.

110. 102 Inflammatory/ Immune Neuropathy (Guillain-Barre Syndrome): Life threatening spinal neuropathy following an acute viral illness: Clinical Features: Distal limb weakness & paraesthesia which progresses to affect proximal muscles (Ascending Paralysis) Death usually due to respiratory paralysis Pathogenesis: T-cell mediated response, inflammation of peripheral nerves & segmental demyelination Pathology: CSF: Albumino-Cytological dissociation

111. 103 Myopathies: Muscular degeneration, weakness & wasting. 3 main groups Muscular dystrophies – Abnormal structure. Myositis – Inflammation / immune. Myopathy- Degeneration. Usually sec to systemic disease: eg.Thyrotoxicosis or Neurogenic muscular atrophy.

112. 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. 104

113. 105 Cerebral atrophy in Alzheimer's: Hippocampus Atrophy Severe cortical atrophy, narrow gyri, wider sulci. White matter loss leading to dilated ventricles (compensatory hydrocephalus).

114. 106 System Degenrations: