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…

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…?

2


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’

3


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…

4


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

5


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. .?

6


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.

7


Brain: Functional areas.

Language

Memory

8

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)

"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.

10 – 10 – 10
minutes months years
10

Pathology of
C.N.S. Degenerative
Disorders

Dr. Venaktesh M. Shashidhar
A/Prof. & Head of Pathology
James Cook University

11


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…!)

12


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 sclerosis
 Dysmylinating disorders – Leukodystrophies.

13


Aloysius Alzheimer:
 German Psychiatrist.
 1901 - Auguste Deter
 51year male Patient.
 Behavioural abnormality
 Short term memory loss
 Colleague Franz Nissl
 silver
stain.
 Observed amyloid
plaques & NF tangles.
 Case Presented at Berlin Aloysius Alzheimer‟s first Patient
1906.
 International Brain
Research Organization.
14


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.

15


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.

16


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.

17


Alzheimers Disease: Morphology
Gross Microscopy

• Intraneuronal Neurofibrillary tangles
• Interstitial amyloid Neuritic plaques
• Cortical Atrophy • Loss of neurons with gliosis.
18

Pathogenesis of
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


Normal

Pathogenesis of
Amyloid Plaques
20


Alzheimer‟s - Amyloid Angiopathy

Silver stain

Congo Red 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 B)
21


Morphology in AD:

Plaques & around BV. NF Tangles-Intracellular
Aβ Amyloid tau protein
22


CNS Morphology in Alzheimer's:

A-Neuritic Plaque

, B-Amyloid

23


AD Morphology – Early / Preclinical

• 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.

24
Slide 20


AD Morphology - Mild to Moderate

• 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.
25
Slide 21


AD Morphology: Severe AD

• 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.
26
Slide 22


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)

27


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 Young
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. Old
28

Other CNS
degenerations:
Local / Systems
• Fronto-Temporal - Pick‟s
• Parkinson‟s
• Huntington‟s

29


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.

30


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)
31


Knife blade Fronto-temporal atrophy in Picks.

32


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 & cortical Lewy bodies (α-
substantia nigra (global) synuclein) special stain.

 Atrophy of cortex like AD.

33


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.

34


Dementia Pugilistica
 Punch drunk syndrome
boxers – 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)

35


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).
36


Pathology of Parkinson‟s disease:
 Gross: Loss of
pigment in substantia
nigra.
Parkinson
 Neuronal loss,
degeneration,
 Loss of neurons
replaced by gliosis
(microglia) Normal
 Loss of neuromelanin.
 Neuronal
degeneration
 Reactive gliosis. L
 Lewy bodies (α-
synuclein) in neurons.

37


Huntington‟s
 Dementia, depression,
choreiform movement
(Jerking dementia)
 5th decade. Autosomal dom.
 Huntington gene on 4p –
Huntingtin.
 Excess CAG tandem
repeats = severity.
 Atrophy of caudate & putamen (striatum)
 Compensatory hydrocephalus of lateral ventricles*.

38


Normal - Huntington’s

Atrophy

39

Education without wisdom,
Student without humility,
Discourse that fails to inspire and
knowledge without experience...
are all futile!


 Disorders of Myelin:

41


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.

42


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.
43


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.

44


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

45


 Disorders of Myelin:

46


Demyelinating Disorders:
 Selective myelin damage  axon damage.
 Defective transmission of impulse.
 Morphology: Myelin loss, inflammation, gliosis,
secondary axon damage.
 Types & Classification
 Immune – Multiple sclerosis
 Vitamin deficiency – Vit B12.
 Metabolic: Central pontine myelinolysis – alcohol
 Infections – JC virus  PML in immunosuppressed.
 Genetic – Leukodystrophy* (Dysmyelinating)

47


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.
48


Multiple Sclerosis: Demyelinated plaques

Microscopy showed loss of
myelination with many lipid 
macrophages around BV.

49


Multiple Sclerosis - plaques
MRI

Gross Specimen

50


MS – Periventricular plaque

Like patches of grey matter within white matter…! 51


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.

52


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, Degeneration of lateral and ventral
spasticity, Sensation normal. corticospinal tracts (myelin stain).
 Degeneration of LMN tracts in the
lateral portion of the spinal cord MND subtypes:
("lateral sclerosis"). and of UMN - • Amyotrophic Lateral Sclerosis*
Betz cells in the motor cortex. • Progressive muscle atrophy (LMN)
• Primary lateral sclerosis (UMN)
• Progressive bulbar palsy

53

Pathology of CNS degenerations:
Disease Lesion Components Location
Alzheimer Plaques & β-Amyloid & Extracellular
disease NF tangles tau Intracytoplasmic
Frontotempor NF tangles tau Intracytoplasmic
al dementias
(eg. Picks)
Dementia with Lewy bodies α-Synuclein Intracytoplasmic
Lewy bodies

Parkinson Lewy bodies α-Synuclein Intracytoplasmic
disease
Amyotrophic Spheroids Neurofilament Intracytoplasmic
lateral subunits/super-oxide
sclerosis dismutase (SOD-1)
Multi system Glial tau Intracytoplasmic
atrophy inclusions

Cells / Structure Common Pathology
Purkinje cells Alcoholism, carbon monoxide, Ischemia
Mammilaries, Purkinje Wernicke's encephalopathy (alcoholism)
cells
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)


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.

56


…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 57


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,

58

Pathogenesis: YouTube

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

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

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