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

http://youtu.be/q1BkfV2h09g


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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

http://www.strokecenter.org/education/ais_images/ais046-lg.jpg

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 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

http://upload.wikimedia.org/wikipedia/commons/1/1d/Auguste_D_aus_Marktbreit.jpg


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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.


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)

http://youtu.be/NjgBnx1jVIU




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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.


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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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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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

pathology of cns degenerations lecture

Health & Medicine

classification

mnd secondary

temporal selectivesystem

primary degenerations

lewy body

blood vessels

nf tangles

substantia