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CNS Degenerative 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. - Wings of Fire: An Autobiography of Dr. APJ Abdul Kalam (1999)

Pathology of Neurodegenerative disorders

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

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Page 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.

- Wings of Fire: An Autobiography of Dr. APJ Abdul Kalam (1999)

Page 2: Pathology of Neurodegenerative disorders

CNS Degenerative disorders…

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…?

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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’

Page 4: Pathology of Neurodegenerative disorders

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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…

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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.’

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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. .?

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Brain: Functional areas.

Memory

Language

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Broca’s area - Cingulate and Parahippocampal gyri.

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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.

Limbic system: controls emotions and instinctive behavior (includes the hippocampus and parts of the cortex)

FunctionalNeuro Anatomy

Slide 8

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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)

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Cells / Structure Common Pathology Purkinje cells Alcoholism, carbon monoxide, Ischemia

Mammilaries, Purkinje cells

Wernicke's encephalopathy (alcoholism)

DM of thalamus Korsakoff's psychosis (alcoholism)

Hippocampus Alzheimer's, hypoxia, hypoglycemia

Retina Methanol toxicity

Anterior horn cells Polio, lower-ALS

Globus pallidus Carbon monoxide, Wilson's, Kernicterus.

Posterior columns B12 deficiency, syphilis (tabes)

Caudate nucleus Huntington's chorea

Fronto-temporal deg. Pick's disease

Deep brain stem Progressive supranuclear palsy

Substantia nigra Parkinson‘s

Upper motor neurons Upper-ALS (Amyotrophic Lateral Sclerosis)

Page 12: Pathology of Neurodegenerative disorders

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

Page 13: Pathology of Neurodegenerative disorders

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Pathology of C.N.S. Degenerative

Disorders

Dr. Venaktesh M. ShashidharA/Prof. & Head of Pathology

James Cook University

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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, Aβ Amyloid plaques. increase in number of astrocytes Athero & artero sclerosis.

Young

Old

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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 sclerosisDysmylinating disorders – Leukodystrophies.

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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)

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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 atrophysecondary ventricular enlargementNeurofibrillary tangles – Intracellular (Tau)Neuritic plaques (Aβ amyloid) – Extracellular.Amyloid angiopathy.

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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

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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.

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CNS Degenerative disorders…

20Cortical Atrophy

Neurofibrillary tangles & Extraneuronal Neuritic plaques

Alzheimers Disease:

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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.

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Generation of Amyloid (Aβ)

Plaque

Normal

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Cerebrum stained with polyclonal antibody against βA4 peptide showing amyloid deposits in plaques in brain substance (arrow A) and in blood vessel walls (arrow

Alzheimer’s - Amyloid Angiopathy

Amyloid core

Dystrophic neurite

s

Congo-red Amyloid stain

Silver stain

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Congo Red stain & Polarised Microscopy showing apple green” birefringence

Alzheimer’s - Amyloid Angiopathy

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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

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Neurofibrillary Tangles in AD:

C: Neurofibrillary (tau) tangles () within the neurons (H & E). D: Silver stain showing a neurofibrillary tangle within the neuronal cytoplasm

(Tau protein)

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Neuron degeneration- granulovcuolar.

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

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CNS Morphology in Alzheimer's:

A-Neuritic Plaque, B-Amyloid

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Morphology in AD:

Plaque around BV. NF Tangles-IntracellularAβ Amyloid tau protein

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Cerebral atrophy in Alzheimer's:

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• 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.

AD Morphology – Early / Preclinical

Slide 20

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• 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.

AD Morphology - Mild to Moderate

Slide 21

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• 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.

AD Morphology: Severe AD

Slide 22

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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

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CNS Degenerative disorders…

Fronto-Temporal Dementia Second common, Group of dementia,

affecting personality, behaviour & speech, Memory is not affected until late* Younger age.

Pick's DiseaseFrontotemporal Lobar DegenerationProgressive Aphasia (problems speaking)Semantic Dementia (understanding language)Corticobasal Degeneration (+ motor)

35

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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 intracytoplasmic Pick’s bodies (tau protein)

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Knife blade Fronto-temporal atrophy in Picks.

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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 sclerosisDysmylinating disorders – Leukodystrophies.

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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)

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Huntington’s Dementia, depression,

choreiform movement (Jerking dementia)

5th decade. Autosomal dom.

Huntington gene on 4p Excess CAG tandem

repeats = severity.

Atrophy of caudate & putamen (striatum) Compensatory hydrocephalus of lateral

ventricles*.

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Normal - Huntington’s

Striatum

Atrophy

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Parkinson’s: "shaking palsy" Parkinsonism: Clinical sy.

dopamine antagonists, post encephalitis. Toxins: MPTP(heroin),

Parkinson’s disease – Primary atrophy of substantia nigra. 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.

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Pathology of Parkinson’s disease: Gross: Loss of pigment in

substantia nigra. Neuronal loss,

degeneration, Loss of neurons replaced

by gliosis (microglia) Lewy bodies (α-synuclein)

in neurons.

L

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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 & substantia nigra (global)

Atrophy of cortex like AD.

cortical Lewy bodies (α-synuclein) special stain.

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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 infarctHypertensive lacunar lesions.Binswanger disese – subcortical

leukoencephalopathy - boxers, trauma.Mixed – AD+vascular.

Page 46: Pathology of Neurodegenerative disorders

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

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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 sclerosisDysmylinating disorders – Leukodystrophies.

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Demyelinating Disorders: Selective myelin damage - axon sparing. Defective transmission of impulse. Prognosis repair & axon damage. Types & Classification

Immune – Multiple sclerosisGenetic – Metabolic, Leukodystrophy.Vitamin deficiency – Vit B12 Infections – JC virus

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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.

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Multiple Sclerosis Plaque:

Section of fresh brain showing brown plaque around occipital horn of the lateral ventricle.

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Multiple Sclerosis: Demyelinated plaques

Microscopy showed loss of myelination with many lipid macrophages.

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Multiple Sclerosis - plaques

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Multiple Sclerosis - plaques

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MS – Periventricular plaque

MS

Like patches of grey matter within white matter…!

Normal

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MS- Plaques – Myelin stain.

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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.

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Metabolic CNS Disorders: Alcoholism induced CNS

disorders: Wernicke syndrome (vit B1

def.) Central pontine

myelinolysis Cortical atrophy Atrophy of vermis of the

cerebellum

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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

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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.

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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.

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Kernictirus – Neonatal hyperbilirubinemia

Kern+Ictirus – yellow nuclei. Complication of Neonatal

jaundice. Polycythemia, Hemolytic disease of new born. Hemolytic anemia.

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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.

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Pathology of CNS degenerations:Disease Lesion Components Location

Alzheimer disease

Plaques &NF tangles

β-Amyloid & tau Extracellular Intracytoplasmic

Frontotemporal dementias(eg. Picks)

NF tangles tau Intracytoplasmic

Dementia with Lewy bodies

Lewy bodies α-Synuclein Intracytoplasmic

Parkinson disease

Lewy bodies α-Synuclein Intracytoplasmic

Amyotrophic lateral sclerosis

Spheroids Neurofilament subunits/super-oxide dismutase (SOD-1)

Intracytoplasmic

Multi system atrophy

Glial inclusions

tau Intracytoplasmic

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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.

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…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

Page 66: Pathology of Neurodegenerative disorders

38y recurrent limb weakness 9m, MRI ? Diagnosis

1 2 3 4 5

0% 0%0%0%0%

1. Multiple sclerosis

2. Parkinsons

3. Alzheimer’s

4. Huntington’s

5. Pick’s disease

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38y depression, chorea ? Diagnosis

1 2 3 4 5

0% 0%0%0%0%

1. Multiple sclerosis

2. Parkinsons

3. Alzheimer’s

4. Huntington’s

5. Pick’s disease

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CNS Degenerative disorders…

A. B. C. D. E.

0% 0%0%0%0%

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?

A. Briefly discuss pathogenesis of this condition?

B. List 3 gross and Microscopic feature of this disease?

C. List 3 differentiating features of Alzheimers & this disease?.

A. Huntington’s disease.

B. Alzheimer’s disease.

C. Pick’s disease.

D. Parkinson’s disease

E. Multiinfarct dementia.

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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?

A. B. C. D. E.

0% 0%0%0%0%

A. Frontal lobes

B. Hippocampus

C. Hypothalamus

D. Occipital lobes

E. Thalamus

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CNS Degenerative disorders…

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 oligoclonal IgG bands and normal glucose. Image shows gross specimen of brain with lesions typical of this disease. What is the most likely diagnosis?

A. Briefly discuss etiology & pathogenesis of this condition?

B. Describe the gross features shown in the image?

C. List other clinical features? What is the prognosis of this condition?

A. B. C. D. E.

23%

30%

17%17%

13%

A. Parkinson’s disease

B. MCA infarct.

C. Lacunar Infarcts.

D. Multiple sclerosis.

E. Viral encephalitis.

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38y female recurrent limb weakness. Image shows white mater stained for myelin.? Diagnosis

A. B. C. D. E.

23%

17%

20%

10%

30%

A. Multiple sclerosis

B. Parkinsons

C. Alzheimer’s

D. Huntington’s

E. Pick’s disease

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72y Male progressive severe dementia, Image shows amyloid stain of his brain. ? Diagnosis

1 2 3 4 5

27%

23%

13%

23%

13%

1. Pick’s disease.

2. Huntington’s disease.

3. Alzheimer’s disease.

4. Multi-infarct dementia.

5. Senile dementia.

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38y fem recurrent tremor & limb weakness progressive over 13 years. ? Diag

1 2 3 4 5

17%

23%

13%

23%23%

1. Multiple sclerosis

2. Hypertensive-stroke.

3. Alzheimer’s

4. Huntington’s

5. Pick’s disease

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CNS Degenerative disorders…

A. B. C. D. E.

20% 20%

10%

27%

23%

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?

A. Briefly discuss pathogenesis of this condition? (Trineucleotide repeat dis)

B. Describe the gross features shown in the image?

C. what other clinical features are expected in this disease?

A. Picks disease.

B. Lewy body disease.

C. Huntington’s disease.

D. Multiple sclerosis.

E. Amyotropic lateral sclerosis.

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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?

A. B. C. D. E.

23%

20%

17%

23%

17%

A. Autonomic neuropathy

B. Distal polyneuropathy

C. Inflammatory neuropathy

D. Mononeuropathy

E. Paraproteinemic polyneuropathy

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58y M, Progressive bradykinesia, dementia & Hallucinations ? Diagnosis

A. B. C. D. E.

20% 20%

27%

30%

3%

A. Alzheimer’s

B. Parkinson’s

C. Motor neurone disease

D. Syringomyelia

E. Lewy body disease

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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?

A. B. C. D. E.

17%

30%

13%

20%20%

A. AA amyloidosis

B. Lewy body dementia

C. Leukemic infiltrates

D. Neurofibrillary tangles

E. Old healed infarcts.

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CNS Degenerative disorders…

A. B. C. D. E.

17% 17%

23%

13%

30%

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?

A. Multiple Aspergilloma.

B. Cerebral TB lesions.

C. Multiple Abscesses.

D. Multiple sclerosis plaques.

E. Cerebral metastases.

A. What does “ring enhancing” lesion mean?

B. Briefly discuss etiology and pathogenesis?

C. List other pathologic findings expected in the brain of a AIDS patiets?.

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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?

1 2 3 4 5

0% 0%0%0%0%

1. Multiinfarct dementia.

2. Parkinsons disease.

3. Multiple sclerosis

4. Motor neurone disease.

5. Lacunar infarcts.

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52y male, dementia, depression with choreiform movements.

Image of his brain(B) compared with normal (A) ?Diagnosis

A B

A. B. C. D. E.

0% 0%0%0%0%

A. Binswanger disease

B. Parkinsons disease

C. Alzheimers disease

D. Pick’s disease

E. Huntington’s disease

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78y M, Dementia, memory loss and spacial disorientation. Cortical biopsy. ? Diagnosis

1 2 3 4 5

0% 0%0%0%0%

Cortical biopsy - β amyloid immunostain

1. Alzheimer’s

2. Parkinson’s

3. Lewy body disease

4. Huntington’s disease

5. Pick’s disease

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78y, Dementia, Aphasia, Image shows Hippocampus biopsy stained with anti tau stain. ? Diagnosis

A. B. C. D. E.

0% 0%0%0%0%

A. Multiple sclerosis

B. Parkinsons

C. Alzheimer’s

D. Multi-infarct dementia

E. Pick’s disease

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78y Male progressive severe dementia, Image shows amyloid stain of his brain.? Identify structure A

1 2 3 4 5

0% 0%0%0%0%

1. Neurofibrillary tangles.

2. Amyloid plaques.

3. Amyloid Angiopathy

4. Astrocytes - Gliosis.

5. Neuronophagia.

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58y female vocalist difficulty remembering songs, depression, dementia & gait abnormality. Image shows brain biopsy. What is the most likely diagnosis?

1 2 3 4 5

0% 0%0%0%0%

1. Alzheimer’s disease.

2. Pick’s disease.

3. Huntington’s disease.

4. Lewy body disease.

5. Creutzfeldt-Jakob disease.

CJD: Spongiform degeneration (vacuoles) no inflammation - Slowly progressive ataxia and dementia.Prion protein (APrP amyloid) – 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).

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38y progressive weakness, spasticity, dysphagia and loss of muscle mass. Image shows section of spinal cord stained for myelin. Diagnosis?

1 2 3 4 5

0% 0%0%0%0%

1. Multiple sclerosis2. Parkinsons3. Motor neurone disease4. Syringomyelia5. Spinal cord infarction.

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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?

A. B. C. D. E.

0% 0%0%0%0%

A. Astrogliosis

B. Lewy bodies

C. Myelin loss.

D. Neuritic plaques

E. Neuronophagia.

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What is the best clinical description for the image?

1 2 3 4 5

0% 0%0%0%0%

1. 83y man – dementia, memory loss and disorientation.

2. 43y man -abnormal movements who committed suicide

3. 56y woman -progressive paralysis

4. 60y man -tremor, rigidity and dementia

5. 73y woman –Dementia aphasia but intact memory.

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What is the best clinical description for the image?

1 2 3 4 5

0% 0%0%0%0%

1. 83y man – dementia, memory loss and disorientation.

2. 43y man -abnormal movements who committed suicide

3. 56y woman -progressive paralysis

4. 60y man -tremor, rigidity and dementia

5. 73y woman –Dementia aphasia intact memory.

ADHDALSPDPick

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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,

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The only real mistake is the one from which we learn nothing!

JOHN POWELL:

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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.

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"Education is for ‘life’.. not for mere ‘living’

"The end of education is character"                                                               -

BABA

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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.

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MND: Atrophy of anterior nerve roots.

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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.“

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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.

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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.

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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.

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Neuropathies And Myopathies Neuronal / Muscular damage: Causes:

Hereditary Motor & Sensory neuropathies Inflammatory - Diphtheria, Infectious: HZV, HIV, LeprosyAcquired/ Metabolic: Diabetes, UraemiaVitamin B12 defToxins: Alcohol, Lead toxicity, Drugs

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Diabetic Neuropathy Types:

Distal symmetric sensory neuropathy: tingling numbness, loss of pain in toes, hands, legs.

Autonomic neuropathyFocal asymmetric neuropathy: cranial/

peripheral nerve involvement Pathogenesis:

Microangiopathy, ischemia, Hyperosmolar cell damage by polyols, myelin loss in sensory nerves.

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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. Intranuclear inclusions are generally not

found in the peripheral nerve lesions.

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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

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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.

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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.

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Cerebral atrophy in Alzheimer's:

Severe cortical atrophy, narrow gyri, wider sulci. White matter loss leading to dilated ventricles (compensatory hydrocephalus).

Hippocampus Atrophy

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Disease Sites affected Clinical features Genetic basisFriedreich's ataxia Spinal cord

Sensory nucleiCerebellum

AtaxiaSensory lossDeafnessAutosomal recessive inheritance

CAA triplet expansion in frataxin gene on 9q

Autosomal dominant cerebellar ataxia type 1

Purkinje cellsGranular neuronesInferior olivary nuclei

AtaxiaNystagmusAutosomal dominant inheritance

CAG triplet expansion in ataxin-1 gene on 6p

Dentatorubro-pallidoluysial atrophy (DRPLA)

Dentate nucleusGlobus pallidusSubthalamusRed nucleus

ChoreaMyoclonic epilepsyDementiaAutosomal dominant inheritance

CAG triplet expansion in gene on 12p

Multiple system atrophy (Shy-Drager syndrome)

Substantia nigraPurkinje cellsPontine nucleiSpinal autonomic nuclei

AtaxiaSensory lossTremorOrthostatic hypotension

Unknown

System Degenrations: