Pathology of CNS Degenerations Lecture
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Transcript of Pathology of CNS Degenerations Lecture
“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, President of India.
CNS Degenerative disorders…
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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’
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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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CPC34 – Clinical Duration of symptoms: ? about 6/12 Mood: low, quite tearful at times; not enjoying life
much. Concentration: poor, struggling to read
books/journal.. Sleep: disrupted, often up during early hours of
morning. Appetite and weight: no change I am very tired. It’s probably time for me to
retire.’Case presentation – YouTube
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Differential diagnosis. Dementia: primary / secondary.
(Alzheimer’s Disease) Endocrine: e.g. hypothyroidism, drugs etc. Depression? – reactive – family events ? Ageing: Mild cognitive impairement * Investigations:
FBC, Liver FT & Thyroid FT normal, HIV negative. ..?CT scan: no space occupying lesion..? some
loss of grey matter with increased ventricular space. .?
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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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Brain: Functional areas.
Memory
Language
Broca’s area - Cingulate and Parahippocampal gyri.
Hippocampus: where short-term memories are converted to long-term memories
Thalamus: receives sensory and limbic information and sends to cerebral cortex (cognition)
Limbic system: controls emotions and instinctive behavior (includes the hippocampus and parts of the cortex)
10 – 10 – 10minutes months years
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"I wasn't living my life. My life was living me. I realised I made many of my decisions without thinking their consequences…“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 minutes, in ten months and in ten years”.
-- Suzy Welch.The 10-10-10 rule.
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Pathology of C.N.S. Degenerative
Disorders
Dr. Venaktesh M. ShashidharA/Prof. & Head of Pathology
James Cook University
CNS Degenerative disorders…
CNS Degenerations Increasing incidence – Ageing. Affect functional groups of neurons. Accumulate abnormal proteins. Primary & Secondary, Global & Local types. Dementia – Acquired defect in higher function:
Memory, language, insight & planning.. “Human” > 45% of adults over 85y are demented…!
(Starts >30y, rapid >70y…!)
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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.
Myelin Degenerations:Demyelinating Disorders - Multiple sclerosisDysmylinating disorders – Leukodystrophies.
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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 disease: Commonest cause of dementia in elderly Sporadic common (>60y) familial ~10% early. insidious onset of impaired higher intellectual function,
altered mood and behavior, progress to disorientation, memory loss, aphasia disabled, immobile… ~25y.
Pathology: Significant cortical atrophy secondary ventricular enlargement Neurofibrillary tangles (Tau) – within neurons Neuritic plaques (Aβ amyloid) - Extracellular. Amyloid angiopathy around blood vessels.
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Alzheimer’s disease: Genetics Autosomal dominant genetic pattern – rare 10% 4 genes on chromosomes 1, 14, 19, and 21, influence
initiation and progression. Chromosome 21 generates the precursor protein for
the amyloid protein (APP). Trisomy 21 produces early Alzheimer's disease in persons with Down syndrome.
Chromosome 19 generates apolipoprotein (apo) some of them increase risk for Alzheimer's disease (ε4/ε4) by increasing Aβ amyloid deposition.
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Alzheimer’s – Pathogenesis: Amyloid Aβ is created when the transmembrane protein
amyloid precursor protein (APP) is cleaved by the enzymes β-amyloid converting enzyme (BACE) and γ-secretase (instead of α)
Deposition of neurotoxic Aβ around blood vessels (amyloid angiopathy) & interstitium neuritic plaques.(axonal tangles around)
Aβ also leads to hyperphosphorylation of the neuronal microtubule binding protein tau in neurons to form ‘neurofibrillary tangles’ within neurons.
Both are neurotoxic leading to Atrophy of neurons & reactive glial proliferation – gliosis.
CNS Degenerative disorders…
18• Cortical Atrophy
• Intraneuronal Neurofibrillary tangles
• Interstitial amyloid Neuritic plaques• Loss of neurons with gliosis.
Alzheimers Disease: MorphologyGross Microscopy
Neurofibrillary Tangles
Neurons have an internal support structure partly made up of microtubules. A protein called tau helps stabilize microtubules. In AD, tau breaks, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles.
Slide 18
Pathogenesis of
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Normal
Pathogenesis ofAmyloid Plaques
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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 B)
Alzheimer’s - Amyloid Angiopathy
Amyloid core
Dystrophic neurite
s
Silver stain
Congo Red stain
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Morphology in AD:
Plaques & around BV. NF Tangles-Intracellular Aβ Amyloid tau protein
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CNS Morphology in Alzheimer's:
A-Neuritic Plaque
, B-Amyloid
Atroph
y
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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
http://youtu.be/NjgBnx1jVIU (pathogenesis video)
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Age related / Senile degeneration: Age related Dementia: All spheres of
intellect affected. Decreasing mass - Slow 4th decade – rapid
7th decade. progressive neuronal loss Neuronophagia.
(hippocampus and cerebral cortex) reduction in size & numbers of dendritic
branches in surviving neurons Cortical atrophy, hydrocephalus. Thickening of leptomeninges. NF tangles, Aβ Amyloid plaques. increase in number of astrocytes Athero & artero sclerosis makes it worse.
Young
Old
Other CNS degenerations:
Local / Systems• Fronto-Temporal - Pick’s• Parkinson’s• Huntington’s
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Fronto-Temporal Dementia Second common, Group of dementia, affecting
personality, behaviour & speech. Younger*, Memory not affected until late* Many sub types.
Pick's Disease: FTLD-tau common. FTLD-TDP43 – next common.
Semantic Dementia (understanding language) Progressive language problems Aphasia
predominate. Dementia later.
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Pick’s Disease: Severe, 40-65y, Rare. knife blade atrophy of
Frontal & temporal lobe Progressive aphasia / language dysfunction
Behaviour & personality change.
Preserved memory. Micro: Neurons with
round intracytoplasmic Pick’s bodies (tau protein)
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Knife blade Fronto-temporal atrophy in Picks.
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Diffuse Lewy body Dementia: 10-15% of Parkinsons with
dementia (Alzheimers) impaired memory of recent
events, confusion, language problems.
Dementia + visual Hallucinations.
Lewy body (α-synuclein) in many part of cortex & 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.
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Dementia Pugilistica
Punch drunk syndromeboxers – trauma.
“chronic traumatic encephalopathy” Progressive dementia, tremor and focal
neurological deficits. Degeneration in septum pellucidum,
thinning of the corpus callosum, substantia nigra.
Also cerebral neurofibrillary tangles & Aβ amyloid accumulation. (sec. alzheimer’s)
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Parkinson’s: "shaking palsy" Parkinsonism: Clinical sy.
Drugs: dopamine antagonists Toxins: MPTP(heroin), Diseases: Multiple system atrophy, Post encephalitic.
Parkinson’s disease – Primary atrophy of substantia nigra. Dopaminergic nerves with α-synuclein - Lewy body.
Clinical features: Adults (45-60y), tremor, bradykinesia & rigidity Diminished facial expressions, stooped posture, Slow voluntary movements, festinating gait, & fine rolling resting
tremors. Dementia in some cases. When dementia arises within 1 year of the onset of motor
symptoms, it is referred to Lewy body dementia (LBD).
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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)
Loss of neuromelanin. Neuronal
degeneration Reactive gliosis. Lewy bodies (α-
synuclein) in neurons.
Parkinson
Normal
L
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Huntington’s
Dementia, depression, choreiform movement (Jerking dementia)
5th decade. Autosomal dom. Huntington gene on 4p –
Huntingtin. Excess CAG tandem
repeats = severity.
Striatal atrophy
Atrophy of caudate & putamen (striatum) Compensatory hydrocephalus of lateral ventricles*.
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Normal - Huntington’s
Striatum
Atrophy
Education without wisdom, Student without humility,
Discourse that fails to inspire and knowledge without experience...
are all futile!
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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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Metabolic CNS Disorders: Alcoholism induced CNS
disorders: Wernicke syndrome (vit B1
thiamine def.) – ataxia, confusion.
Korsakoff syndrome (memory)
Central pontine myelinolysis
Cortical atrophy Atrophy of vermis of the
cerebellum.
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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: Korsakoff's disease.Central pontine myelinolysis. Demyelination of the center of the pons. Shrunken, brown mammillary bodies (indicating chronic stage).Cause is unknown but usually seen in chronic alcoholics and associated with rapid over-correction of hyponatremia.
Alcoholic cerebellar atrophy. Shrunken folia and widened fissures of the anterior, superior vermis of the cerebellum. Another change which may be found in chronic alcoholics.
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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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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 damage. Defective transmission of impulse. Morphology: Myelin loss, inflammation,
gliosis, secondary axon damage. Types & Classification
Immune – Multiple sclerosisVitamin deficiency – Vit B12.Metabolic: Central pontine myelinolysis –
alcohol Infections – JC virus PML in
immunosuppressed.Genetic – Leukodystrophy* (Dysmyelinating)
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Multiple Sclerosis: Common 1:1000, adults,
females 2:1, HLA DR2, <50y. Autoimmune (Gen+Env+AI) Episodes of Limb Weakness,
paraesthesia. Relapsing & remitting. Progressive death in years. Multiple soft pink plaques of
demyelination- periventricular. Inflammation, perivascular T
lymphocytes & plasma cells. CSF - oligoclonal IgG. Reactive gliosis.
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Multiple Sclerosis: Demyelinated plaques
Microscopy showed loss of myelination with many lipid macrophages around BV.
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Multiple Sclerosis - plaques
MRI
Gross Specimen
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MS – Periventricular plaque
MS
Like patches of grey matter within white matter…!
Normal
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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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ALS: Amyotrophic Lateral Sclerosis Also known as Lou Gehrig's disease,
is the most common type of Motor Neurone Disease (MND).
Genetic: Mutations in SOD1 gene on Chromosome 21.
Progressive neuron loss. Middle age, men, sporadic common,
Familial 10% Muscle weakness, fasciculations,
spasticity, Sensation normal. Degeneration of LMN tracts in the
lateral portion of the spinal cord ("lateral sclerosis"). and of UMN - Betz cells in the motor cortex.
Degeneration of lateral and ventral corticospinal tracts (myelin stain).
MND subtypes:• Amyotrophic Lateral Sclerosis*• Progressive muscle atrophy (LMN) • Primary lateral sclerosis (UMN)• Progressive bulbar palsy
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
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)
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CPC-3.6– CNS –Degenerations Pathology – Major Learning Issues:
Common Dementias & system degenerations. Dementia diagnosis & Laboratory investigations. Alzheimer’s disease, Pick’s & Parkinson’s. Huntington’s, Multiple Sclerosis, MNDs.
Pathology – Minor Learning Issues: Senile, Vascular dementia, Infections – Prions(MCD),
syphilis, HIV Toxins and vitamin def. Vit B12/thiamine def. Manganese, lead poisoning.
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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
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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,
The only real mistake is the one from which we learn nothing!
JOHN POWELL:
Pathogenesis: YouTube
Anyone who thinks money will make you happy, hasn't got it….!
"Education is for ‘life’.. not for merely for ‘living’
"The end of education is character" -
BABA
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