Pathology of Neurodegenerative

Diseases
Abeer Tabbarah, M.D.
 Objectives
• Learn the common features of neurodegenerative
diseases
• Become familiar with the neuroanatomic
distribution of neuronal loss in the most common
neurodegenerative diseases and the resulting
neurological symptoms
• Know the neuropathological features of
Alzheimer disease, Huntington disease, Parkinson
disease, amyotrophic lateral sclerosis, Friedreich
ataxia, and Creutzfeldt-Jakob Disease
 Neurodegenerative Diseases
• Alzheimer Disease
• Synucleinopathies
• FTLD-
Tau positive
– Pick disease
– Progressive supranuclear palsy
– Corticobasal degeneration
Tau negative
– FTLD-TDP43
• Triplet repeat disorders
PATHOGENESIS
Protein accumulation and degradation
• Intracellular
– Post-translational modification: NFT in AD
– Mutations: Tau gene in tauopathies
• Extracellular
– AD
– Prion disease
ALZHEIMER DISEASE (AD)
 AD
• Most common neurodegenerative disease
• Single most common cause of dementia
• Slowly progressive course (years)
• Early memory loss (especially short-term) Auguste D
• Loss of other cortical functions
– Language, judgment, abstract reasoning,
impaired visuospatial skills
• Average survival 5-10 years after onset
• About 10% of all cases have strong family history
 Prevalence
• 5.3 million Americans of all ages in 2015
• 5.1 million ≥ 65 years
• Two-thirds are women
 Genetics of AD
• Pathology of autosomal dominant and
sporadic AD similar
• 50-70% late-onset sporadic AD have a genetic
component
• APOE4 increased deposition of Aβ
• Risk of AD:
• 1 allele- increased 3x
• 2 alleles- increased 15X
 Gross findings
Normal brain AD brain
Granulovacuolar degeneration
Hirano bodies
 Neuritic plaques
Extracellular
Amyloid-β
Abnormal neurites
(organelles plus
tau)
Reactive microglia

Hirano silver stain (modified Bielschowsky)

 Neuritic plaques

• Most important
feature for
diagnosis of AD
• Multiple neurons
contribute
neurites to each
plaque
• Decreased
number of
synapses within
plaques
Hirano silver
 Amyloid-β peptide (Aβ)
• Key component of plaques, also found in
vessels
• Derived from Amyloid Precursor Protein (APP),
a normal transmembrane protein, via
abnormal cleavage by β-,γ-secretases
• Peptides of varying lengths; Aβ42 more toxic
than Aβ40
• Smaller oligomers more toxic than larger
aggregates
Amyloid Precursor Protein

Annu. Rev. Neurosci. 2011. 34:185–204

 Neurofibrillary tangles (NFT) and threads
 Classic feature of
AD
 Intracytoplasmic
neuronal inclusions
 “Ghost tangles”
remain after the
cell dies
Tau: a microtubule-associated protein

 Hyperphosphorylation → tau dissociation

from microtubules → self-aggregation of
tau into paired helical filaments (PHF)
 Mutations in tau cause non-AD
neurodegenerative diseases

EM – PHF
Greenfield’s Neuropathology, 7th ed, 2002
 Functions of microtubules
• Mitotic spindles
• Organization of cytoplasm
• Growth of cell processes
• Transport along axons and dendrites
• Amino-terminal region of tau may affect microtubule
interactions with cell membrane and other
organelles
 Diagnosis of Alzheimer disease:
the ABC method
National Institute of Aging – Alzheimer’s
Association (NIA-AA) system assesses:
 Aβ: the A score
 NFTs (Braak score): the B score
 Neuritic plaques (CERAD rating): the C
score

Reported as “Alzheimer-related
neuropathology (A_, B_, C_)”
Alzheimer’s Dement., 2012:8(1):13
Assessment of Aβ distribution: Thal score
Any evidence of diffuse or neuritic plaques
by Aβ immunohistochemistry (or Hirano
silver stain):
• A0: no amyloid
• A1: neocortex, hippocampus,
entorhinal cortex
• A2: thalamus and striatum
• A3: brainstem and cerebellum
Arch Pathol Lab Med, 1993;117:132
Alzheimer’s Dement., 2012:8(1):13
 Assessment of NFTs: Braak score
• Concept: tangles begin in mesial
temporal lobe and spread throughout
hemisphere

• Braak score reflects distribution (not

numbers) of tangles
– 1 – entorhinal cortex
– 2 – hippocampus
– 3 – inferior temporal
– 4 – association cortex (MFG,
SMTG, IP)
– 5 – occipital area 18
– 6 – occipital area 17
Assessment of neuritic plaques (CERAD )

C1 C2 C3
• 3 standard sections
• Neuritic plaques: sparse,
moderate, or frequent in worst
area of worst slide
Arch Pathol Lab Med, 1993;117:132
Alzheimer’s Dement., 2012:8(1):13
 CERAD
• Age-adjusted plaque score
• NIA-AA scores: C0, C1, C2, or
C3
Level of AD neuropathologic change
PARKINSON DISEASE (PD)
 PD
• Second most common neurodegenerative disease
• 1% of population over 65
• Usual onset 55-65 years
• Slight male predominance
• “TRAP”: resting tremor, rigidity, bradykinesia, postural
instability
Well pigmented nigra Pale substantia nigra
 PD: microscopic findings

 Loss of pigmented dopaminergic

neurons in substantia nigra
 Lewy bodies
α-synuclein
 Lewy neurites
α-synuclein
 Other affected brainstem areas :
Locus ceruleus (pons)
Dorsal nucleus of vagus (medulla)

H&E/Luxol fast blue

 Microscopic findings
Substantia nigra
Normal PD
Microscopic findings
Substantia nigra

H&E Alpha-synuclein
 Causes of PD

• Genetic factors
– Inherited PD is rare: <5% have disease-causing mutations
– Having a first-degree relative with PD increases risk 2-3 fold
 Parkinson disease and dementia
• Co-existing disorders, particularly Alzheimer disease
• Severe, end-stage PD itself (Parkinson disease dementia)
• Dementia with Lewy bodies (dementia develops first or within
one year of a diagnosis of PD)
HUNTINGTON DISEASE (HD)
 Huntington Disease
• Described by Huntington in 1872
• Symptoms
– Chorea
– Memory deficit
– Personality changes
– Depression
George Huntington
– Bulbar dysfunction
• Onset mid-life (mean=35-45, 2-80) with death 10-15
years post onset
• Prevalence 7-10/100,000
 HD
• HTT- subtelomeric gene on 4p
• Huntingtin protein widely expressed in fetal
and adult tissues but unknown function
• CAG repeat sequence at N-terminus
• Normal gene 9-37 CAG repeats
• HD 37-100 repeats or more
 HD

• Atrophy of
striatum,
especially caudate
nucleus
• Corresponding
dilation of
ventricles
• Cortical atrophy
appears later
 HD
• Neuronal loss and reactive astrocytosis
– Loss of 50% of striatal (spiny) neurons: onset of
symptoms
• Intranuclear inclusions: huntingtin
– Similar inclusions in other polyglutamine diseases

H&E - control H&E - HD Huntingtin

Ubiquitin

Vonsattel et al. Handb Clin Neurol. 2011;100:83-100.

 GFAP

HD Normal

http://neuropathology-web.org/chapter9/chapter9eHD.html#hd
• Neostriatal degeneration with time moves
simultaneously in the following directions:
– Caudorostral
– Dorsoventral
– Mediolateral
• Grade of striatal disease correlates with other
brain regions
Huntington disease: Vonsattel grading
FRIEDRICH ATAXIA
 Ataxia
• Cerebellar- disease of cerebellum and/or
afferent/efferent tracts leading to failure of
cerebellar cortical function
• Sensory- disease of peripheral nerves, dorsal
root ganglia, or ascending tracts in the spinal
cord
 Etiology
• Acquired- toxic, nutritional, metabolic,
inflammatory, infective, ischemic,
paraneoplastic
• Hereditary
• Non-hereditary
 Friedreich Ataxia (FRDA)

• First described by Friedreich in 1863 as

a spinal cord abnormality

• Most common inherited ataxia: 1 in 50,000

• Symptoms start ~10 to before 25 years of age From Bramwell: Atlas of Clinical Medicine

– Progressive gait ataxia

– Upper motor dyscoordination
– Tremors
– Pes cavus, distal muscle wasting, cardiomyopathy…etc
 FRDA
• Autosomal recessive
• FRDA gene in centromeric region of 9q
• Frataxin- mitochondrial membrane protein
• Commonest mutation is expansion of a GAA
triplet repeat in intron: 200-1700
• Normal number of repeats: 6-34
• Repeat expansion results in reduced
transcription and loss of expression of frataxin
 FRDA
• Brain grossly unremarkable
• Spinal cord and dorsal roots atrophic
• Degeneration and astrocytosis of the posterior
columns (gracile > cuneate), spinocerebellar
and corticospinal tracts
• Cerebellum: white matter with astrocytic
gliosis, cortex normal, severe cell loss in
dentate and marked atrophy of superior
cerebellar peduncle
 FRDA
• Cerebral cortex: no specific pathologic
changes, functional imaging showed cortical
atrophy and reduced metabolism
• Peripheral nerves loss of dorsal root ganglion
cells with severe depletion of large myelinated
axons from posterior roots and sensory nerves
Nodules of Nageotte
AMYOTROPHIC LATERAL SCLEROSIS
(ALS)
 ALS

• “Motor neuron disease”

• Both upper motor neurons and lower motor
neurons (spinal cord, medulla)
• 40-60 years of age; male > female
• Progressive weakness and atrophy,
eventually involving respiratory muscles
• Usual duration 3-5 years; 10% > 10 years
• 5-10% familial

www.faqs.org/health/images/uchr_06_img0576.jpg
http://www.telegraph.co.uk/telegraph/multim
edia/archive/00441/news-graphics-2007-
 ALS: gross findings
Anterior
spinal artery
 Atrophy of ventral
roots
 Rarely, atrophy of Anterior
root
motor cortex

Posterior
root

Ellison et al., Neuropathology, 2nd ed, 2004

 ALS: microscopic findings
 Loss of myelinated axons in corticospinal tract
• Loss of myelinated axons in ventral roots , motor nerves
• Loss of motor neurons
motor root sensory root

LFB (myelin) H&E/LFB

Ellison et al., Neuropathology, 2nd ed, 2004

 ALS: neuronal inclusions containing
ubiquitin and TDP-43

L
Normal:
Eosinophilic
Nissl bodies,
Inclusion
Lipofuscin
(H&E)
(H&E) N

Skein Round
Inclusion Granular
(TDP-43) Inclusion
(ubiquitin)
PRION DISEASE
 Prion disease
• Sporadic Creutzfeldt-Jakob disease: 85-90%
• Inherited: Familial CJD
Gerstmann–Sträussler–Scheinker syndrome
Fatal familial insomnia
• Acquired: Iatrogenic CJD
variant CJD
Kuru
 Prion disease
• Cellular PrP is a normal membrane-associated
protein
• Disease occurs when PrPc undergoes
conformational change to a β-pleated sheet
configuration that is resistant to degradation
by proteinase K
 PrP gene
• Polymorphism at codon 129 acts as a
susceptibility factor
• Codes for either methionine or valine
 Sporadic CJD
• Etiology unknown
• Incidence 1-2/ million/ year
• Most cases homozygous for M or V at codon
129
• Clinical: rapid progressive dementia,
myoclonus, ataxia, typical EEG, + 14-3-3 CSF
 Gross findings
• Brain may be normal or show atrophy
• Atrophy includes caudate, thalamus, and
cerebellar folia
 Microscopic findings
• Spongiform change
• Loss of synapses
• Astrocytic gliosis
• Activation of microglia
• Hyperphosphorylation of Tau
• Accumulation of abnormal PrP
Sporadic CJD
 Variant CJD
• Cerbral cortex and cerebellum contain
amyloid plaques surrounded by vacuoles
“florid plaques”
• All are MM at codon 129
• Accumulation of PrPSc in lymphoreticular
tissue
 Transmission of human spongiform
encephalopathies

• Iatrogenic: Pituitary extracts, dural grafts,

corneal transplants, depth electrodes
• Oral: Kuru, vCJD
• Aerosolization: Scrapie

Not proven: maternal-fetal, blood products,

occupational
 CJD: Infectivity of organs

• High: Brain, spinal cord, pituitary, dura, eye

• Medium: Lymphoid tissue (including bowel),
placenta, CSF
• Low: Peripheral nerve, bone marrow,
pancreas, lung, liver, thymus

Not detected: Muscle, kidney, fat, bone, blood,

saliva, urine, feces, semen, milk
 CJD: Route of inoculation

• Infectivity depends on route of inoculation

• Intracerebral > intravenous > intraperitoneal >
subcutaneous
• 10,000-fold difference between intracerebral and
subcutaneous routes

J Comp Pathol (1979) 89:551

THANK YOU