PATHOLOGY 

OF 
DEMYELINATING AND 
DEGENERATIVE DISEASES 
OF THE CNS

AP DR ANANI AILA MAT ZIN,
MD, MPATH (USM), FIAC
DEPARTMENT OF PATHOLOGY
SCHOOL OF MEDICAL SCIENCE, USM
NORMAL NERVE
BASIC HISTOLOGY
NEURON

• A neuron is the basic functional unit of the 
nervous system.
 -collecting information, processing and then 
generating response
The basic structures :
-body or perikaryon,dendrites
axon’ which transmits signals to
other neurons.
-a large nucleus with a prominent
nucleolus.

The cytoplasm contain rough

endoplasmic reticulum termed
‘Nissl substance
The ‘axon hillock’ from where
action potentials are generated.
How to Identify a Neuron

• Large cell and cell body
• Large nucleus
• Single prominent 
nucleolus
• Nissl substance (purplish 
granules on H&E)
 Oligodendrocytes

• are the myelin producing cells
• The process of myelination is complex and relies on 
neuronal and axonal signals
• forms myelin segments on multiple axons. 
• Mainly present within the white matter along bundles 
of axons which they myelinate. 
• cells appear as naked dark round nuclei with 
‘perinuclear halo’ or ‘ fried egg’ appearance 
 ROUND NUCLEUS AND 
PERINUCLEAR HALO IN WHITE 
MATTER (H&E STAIN)

How to Identify an Oligodendrocyte

Small to medium-size cell
Dark round nucleus
Cytoplasmic clearing or ‘perinuclear halo’
or ‘fried egg’ appearance
 DEMYELINATING DISEASES

• Preferential damage to myelin, with 
relative preservation of the axons

• Limited regenerative capacity of 
myelin
• Secondary damage to axon
DEMYELINATING DISEASES
• Autoimmune 
• Multiple sclerosis
• Acute disseminated encephalomyelitis (ADEM)
• Viral infection
• Progressive multifocal leukoencephalopathy (PML)
• Subacute sclerosing panencephalitis (SSPE) 
• Genetic metabolic disorder
• Leukodystrophies
• Krabbe disease (galactosylceramidase def.)
• Metachromatic leukodystrophy (arylsulfatase A def)
MULTIPLE SCLEROSIS
• Commonest demyelinating disease CNS
• Age of onset = 20 -30 years old
• Slightly > women
• Progressive
• Relapsing & 
   remitting episodes 
   of neurological 
   deficits
 MULTIPLE SCLEROSIS
• Autoimmune
• Attack against component of myelin sheath
• by CD4+, CD8+ & activated macrophages (via 
interferon gamma)

• Influenced by genetic & environmental factors
• In monozygotic twins
• HLA DW2 & DR2 (European)
• DR6 & BW22 (Japanese)
 MULTIPLE SCLEROSIS
• MS PLAQUE
• Sharply defined grey/translucent areas
• Sites
• Borders of ventricles
• Optic nerves, chiasm & optic tracts
• Cerebellum
• Cerebral white matter
• Brain stem and spinal cord
• Spare PNS
 CLINICAL MANIFESTATIONS OF 
MS
Manifestations Causes
Early clinical symptoms
• Blurring of vision • Optic nerve disease
• Incoordination • Cerebellar peduncle ds
• Abnormal sensation • Disease of long
ascending
sensory tracts
Late stages
• Blindness, paraplegia & • Spinal tract involvement
incontinence • Spinal & cerebellar
• Ataxia involvement
• Intellectual dysfunction • Loss of hemispheric
white matter
• Diagnosis
• Clinical evaluation
• CT & MRI scans 
   – areas of demyelination
   - perpendicular to ventricle
     surface
• CSF 
   – lymphocytosis 
   – oligoclonal bands of IgG
• Biopsy (rarely indicated)
BRAIN OF A PATIENT WHO DIED 
OF MS

MS plaques
=
discoloured
areas
in white
matter
HPE OF A PATIENT WHO DIED WITH MS

Blue : Myelinated area

(LFB stain)
Green: MS plaques

Red : ‘Shadow plaques’

= remyelination
 HPE OF MS PLAQUES
• Areas of myelin loss

• Sharply circumscribed
• Active plaques
• Lipid laden macrophages
• Perivascular lymphocytic cuffing
• Inactive plaques
• Less inflammatory cells, less/no myelin
• Astrocytic proliferation & gliosis
• Shadow plaques
• Less circumscribed
• Abnormally thinned-out myelin sheath
• Disease progression
• Variable 
• 5% rapidly progressive and fatal within 5 
years
• Others may survive > 20 years with minor 
disability

• Treatment – steroids / beta-interferon
ACUTE DISSEMINATED 
ENCEPHALOMYELITIS (ADEM)
• = Post-infectious encephalomyelitis
• Following viral infection (EBV,CMV, HSV) or rarely 
viral immunization
• Abrupt onset, brief but intense attack of 
inflammation in the brain and spinal cord and 
occasionally the optic nerves
• Symptoms – fever, lethargy, headache, blur vision, 
nausea, vomiting, seizure & coma
• 20% fatal; the rest complete recovery
 ADEM MS

Occurrence Once Repeated

Time of Seasonal – more in No seasonal variation

occurrence spring and winter
Sex predilection Males Females

Age Children Adults

Symptoms Fever, headache and  More of neurological

confusion, vomiting, and  deficits
seizures 
Medications Nil Usually on
medication to prevent
relapse
MRI pattern Acute lesions. No new New scars on
 ACUTE DISSEMINATED 
ENCEPHALOMYELITIS

• Gross
• Grayish discoloration of 
  white matter

• HPE
• Diffuse myelin loss
• Acute inflammation  
   lipid-laden macrophages
Fatal case of ADEM involving the
brainstem in a 13-month-old.
FULMINATING ADEM SHOWING MANY LESIONS. MARGINS NOT 
WELL DEFINED. LESIONS NOT PERPENDICULAR TO VENTRICLES. 
THE PATIENT SURVIVED, BUT REMAINED IN A PERSISTENT 
VEGETATIVE STATE
 PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY 

• Multifocal destruction of oligodendrocytes ᾆ 
demyelination, with minimal inflammation & 
damage to axons
• Etiological agent : JC polyomavirus
• Associated conditions: AIDS, CLL, Ca & SLE
• SnSm: progressive dementia
 PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY 
• Gross: irregular areas of granularity in white matter;  
some resemblance to MS plaques
• HPE of PML:
• Demyelinated areas as seen by LFB stain
• HPE of PML:
•   Lipid-laden macrophages
•  Intranuclear glassy amphophilic viral inclusions 
in oligodendrogliocytes
• reactive astrocytes that may mimic astrocytoma
• Minimal
   inflammation
NEURODEGENERATI
VE DISEASE
• Diseases of the gray matter
• Progressive loss of neurons with associated 
secondary changes in white matter tracts
• Hallmark: presence of protein aggregates that are 
resistant to degradation
• Divided based on symptomatic/anatomic regions 
involved – cortex, basal ganglia etc
DEGENERATIVE DISEASES
• Cerebral cortex
• Alzheimer disease
• Pick disease
• Corticobasal degeneration
• Basal ganglia and brainstem
• Parkinson disease
• Huntington disease
• Spinocerebellar degeneration
• Friedreich ataxia
• Ataxia-telangiectasia
• Motor neuron degeneration
• Amyotrophic lateral sclerosis
 ALZHEIMER DISEASE
• Progressive loss of neurons in the entire cerebral 
cortex
• Frontal lobe is involved preferentially 
• Commonest cause of dementia in the elderly (> 
50% of cases)
• Age > 50 
• Rarely symptomatic before age of 50
• Risk factor: Trisomy 21
• Diagnosis - combined clinical assessment and 
radiologic methods (80-90% accuracy)
ALZHEIMER DISEASE
• Clinical
• Insidious impairment of higher function 
~ loss ability to solve problems 
~ decreased agility of thought processes 
~ mild emotional lability
• Later:  progressive disorientation, memory loss 
and aphasia
• Much later: Profound disability, mute and 
immobile

• Definitive diagnosis is by pathological 
examination of the brain tissue
 ALZHEIMER DISEASE: 
PATHOGENESIS
• Defective copy of ß-amyloid gene at Chromosome 
21
• Down syndr at 3rd – 4th decade of life
• ß-amyloid protein in neuritic plaque
• Abnormal ApoE gene at Chromosome 19
• Apoprotein E4 in the neurofibrillary tangles
• ApoE4 less effective than ApoE2 in stabilizing 
microtubules
• Reduction of choline acetyltransferase in cerebral 
cortex
• Amyloid precursor 
protein (APP) is 
membrane protein 
that sits in the 
membrane and 
extends outward. It 
is thought to be 
important for 
neuronal growth, 
survival, and repair.
• With Alzheimer’s, 
enzymes come 
along and cut the 
APP into 
fragments, with 
the most 
important 
fragment being 
the beta-amyloid
• Beta-amyloid is “sticky” 
so the fragments cling 
together along with other 
material outside of the 
cell, forming the plaques, 
causing neuronal death, 
and leading to 
Alzheimer’s

• Aβ is neurotoxic, resistant 
to degradation and elicits 
response from microglial 
 AD : PATHOLOGY
• Gross
• Variable degree of cortical atrophy
• Fronto-parietal and medial temporal lobes
• Thinning of the gyri & widening of the sulci
• Compensatory dilatation of the ventricles

• HPE
• Neuronal loss 
• Neuritic plaques
• Cellular processes around a central ß-amyloid 
mass 
• Neurofibrillary tangles
• Abnormal microtubule protein tau and 
• HPE (AD)
• Neuropil threads
• Paired helical filaments at outer part of neuritic 
plaques and in the axons
• Amyloid angiopathy
• Granulovacuolar degeneration
• Increased cytoplasmic vacuoles containing 
argrophilic granules in the hippocampus and 
olfactory bulb
• Hirano bodies
• Elongated, glassy eosinophilic 
bodies esp. in hippocampus and   
     pyramidal cells 
This is cerebral atrophy in a patient with Alzheimer disease.
The gyri are narrowed and the intervening sulci widened, particularly
pronounced toward the frontal lobe region. Sparing the occipital lobes.
The cortical atrophy leads to compensatory dilation of the cerebral
ventricles known as "hydrocephalus ex vacuo".
Alzheimer Disease: Senile plaques with astrocytes and microglia. (silver stain)
Alzheimer disease: Neuritic plaques having an amyloid core (amyloid
angiopathy) seen in glial tissue and small peripheral cerebral arteries.
Neurofibrillary tangles in neurons of a patient with Alzheimer's disease.
The cytoskeletal filaments are grouped together in the elongated pink tangles.
Neurofibrillary tangles of Alzheimer's disease are also seen best with a silver
stain.
PICK DISEASE
• Rare autosomal dominant disease
• Age : 40 – 65
• Clinical course similar to AD
• Gross
• Severe focal atrophy of the frontal and 
temporal lobes – (localized/lobar atrophy)
• Sparing of the posterior 2/3 of the superior 
temporal gyrus
• HPE
• Neuron loss with reactive gliosis
• Pick cells (neuron w argyrophilic NF)
• Pick bodies (collection of argyrophilic NF)
Very marked frontotemporal atrophy of the brain.
The marked atrophy of Pick's disease, a senile dementia, produces "knife-like" thinning
of the gyri in frontal lobes and temporal lobes.
 IHC for Tau protein

Pick bodies – silver stain

PARKINSON DISEASE 

• Clinical features 
• Age: onset > 50 and common > 70
• Slowly progressive disease
• Extrapyramidal dysfunction: 
• Rigidity (cogwheel rigidity of limbs, 
mask-like facies)  
• Resting tremors
• Slowness of movement
• Festinating gait
• Dementia occur in 20% of patient with 
Parkinson disease
striatum regulating the intensity of coordinated muscle activity such as movement,
balance and walking.

Insufficient levels of dopamine from the neurons of the substantia nigra synapsing
on neurons in the striatum is believed to be responsible for the primary symptoms
of Parkinson's.
 PARKINSON DISEASE 
• Gross
• Depigmentation of the substantia nigra and locus 
ceruleus

• HPE
• Neuron loss & Lewy body formation  
• Not confined to pigmented nuclei of the stem 
only but also in nucleus basalis and occasionally 
in the cerebral cortex
The loss of pigmentation in the substantia nigra of the midbrain at the left in a patient
with Parkinson's disease is contrasted with a normal midbrain at the right.
Right, normal numbers of neurons in the subtantia nigra are pigmented.
Left, there is loss of neurons and loss of pigmentation with Parkinson's disease.
At the left, an H and E stain demonstrates a rounded pink cytoplasmic Lewy body in a
neuron of the cerebral cortex .Lewy bodies can also be seen in substantia nigra with
Parkinson's disease. An UBIQUITIN immunohisto stain, helps demonstrate the
Lewy bodies.