Neurodegenerative Diseases

Jeffrey W. Oliver, M.D.

 Learning Objectives
• Explain the pathophysiology behind the
relationship between Alzheimer disease and
Down syndrome.
• List the various factors involved in the
pathogenesis of Alzheimer disease and
discuss how they interplay, as discussed in
class.
 Learning Objectives
• Compare and contrast the morphologic
features of Alzheimer disease, Pick disease,
and normal aging brain changes.
• List diseases and conditions which can
cause Parkinsonism.
• Recognize the clinical and morphologic
features of Parkinson disease and
progressive supranuclear palsy.
 Learning Objectives
• Compare and contrast the clinical features of the
multisystem atrophy syndromes: striatonigral
degeneration, Shy-Drager syndrome, and
olivopontocerebellar atrophy.
• Explain the concept of trinucleotide repeat
syndromes, and name two neurodegenerative
diseases with this pathophysiology.
 Learning Objectives
• Describe the clinical and morphologic
features of Huntington disease, as well as its
transmission.
• Compare and contrast the clinical and
morphologic features of Freidreich ataxia
and ataxia-telangiectasia syndrome.
• Recognize the clinical and morphologic
features of amyotrophic lateral sclerosis.
 Neurodegenerative Diseases
• Characterized by progressive loss of
neurons
• Generally no identifiable inciting event
• Only selected groups of neurons involved
• Primarily cerebral cortex: dementia (never
a normal finding)
• Primarily subcortical: movement disorders
 Alzheimer Disease
• The most common cause of dementia
• Insidious onset of higher level intellectual
impairment, mood and behavior changes
followed by progressive memory loss,
disorientation, aphasia, eventually mute and
immobile
• Onset generally after age 50, with
increasing incidence with increasing age
 Alzheimer Disease
• 5-10% of cases familial
• Pathologic changes identical to AD occur in
almost all trisomy 21 patients who live
beyond age 45
• Definitive diagnosis requires post-mortem
brain examination, but clinical and
radiographic assessment 80-90% accurate
 Alzheimer Disease
• Atrophy is primarily frontal, temporal, and
parietal; may have hydrocephalus ex-vacuo
• Primary microscopic features include
neurofibrillary tangles, senile (neuritic) plaques,
and amyloid angiopathy
• All of these features can be seen (to a lesser
degree) in elderly non-demented brains
• Diagnosis requires combination of clinical
information + assessment of number of plaques
&/or tangles
 Alzheimer Disease
• Neurofibrillary tangles: bundles of
intracytoplasmic filaments that displace or
encircle the nucleus “flame cells”
• Remain visible after death of the neuron
• Primary components: microtubule-
associated tau protein, ubiquitin, amyloid β-
peptide (Aβ peptide)
 Alzheimer Disease
• Neuritic plaques: extracellular spherical
collections of dilated, tortuous, neuritic processes,
20-200 microns
• Microglial cells and astrocytes often seen at
perimeter
• Primary component = Aβ peptide
• The most commonly used diagnostic criteria
require counting number of plaques and relating to
patient age
 Alzheimer Disease
• Amyloid angiopathy: almost always present in
AD; deposition of Aβ peptide in cerebral vessel
walls
• Granulovacuolar degeneration: Neuronal
intracytoplasmic vacuoles containing granules
• Hirano bodies: ovoid pink extracellular bodies
containing paracrystalline arrays of beaded
filaments
 Alzheimer Disease
• Pathogenesis incompletely understood
• Amyloid: Amyloid precursor protein (APP) is a
transmembrane protein coded for on chromosome
21; if endocytosed and degraded by β− and γ-
secretase, forms Aβ peptide which is found in
plaques, tangles, and amyloid angiopathy;
mutations of APP gene implicated in some cases
of familial AD, gene dosage phenomenon in
Down syndrome
 Alzheimer Disease
• Presenilins: Presenilin-1 (chromosome 14) and
presenilin-2 (chromosome 1); mutations increase
production of Aβ peptide; responsible for most
cases of early-onset familial AD
• Apolipoprotein E (Apo E): chromosome 19;
mutations increase risk of development of AD and
decrease age of onset; mechanisms unknown
 Pick Disease
• Rare disease with progressive dementia,
behavioral and personality changes, and language
disturbances
• Severe “knife edge” atrophy of frontal and
temporal lobes
• Neuron loss is most severe in cortex of these
lobes, surviving neurons often have swelling (Pick
cells) or cytoplasmic inclusions (Pick bodies)
 Parkinsonism
• Clinical syndrome with decreased facial
expression, stooped posture, festinating gait,
rigidity, “pill-rolling” tremor
• Due to damage to the nigro-striatal dopaminergic
system from a variety of causes: drugs/toxins
(MPTP, dopamine antagonists), idiopathic
Parkinson disease, progressive supranuclear palsy,
multiple system atrophy, postencephalitic
 Idiopathic Parkinson Disease
• Parkinsonism in the absence of any other
known cause
• Usually sporadic, but can be autosomal
dominant (mutations in the gene for α-
synuclein)
 Idiopathic Parkinson Disease
• Pallor of substantia nigra and locus ceruleus
due to loss of pigmented neurons in these
nuclei
• Lewy bodies: large round eosinophilic
inclusion with a halo in the cytoplasm of
neurons; contain neurofilaments, α-
synuclein, and ubiquitin
 Idiopathic Parkinson Disease
• Treatment with L-dopa helpful, but some
patients become refractory over time;
stereotactic transplantation of fetal
mesencephalic tissue into the striatum can
also be effective
• 10-15% of IPD patients develop dementia,
and may have Lewy bodies throughout
cortex (diffuse Lewy body disease)
 Progressive Supranuclear Palsy
• Truncal rigidity, dysequilibrium, abnormal
speech, vertical gaze palsy which
progresses to difficulty with all eye
movements, mild progressive dementia
• Onset usually 5th-7th decades, M:F = 2:1;
lethal within 5-7 years
• Widespread midbrain neuron loss and
globose neurofibrillary tangles
 Multiple System Atrophy
• Neurodegenerative disorders affecting
multiple neural pathways, characterized by
oligodendroglial cytoplasmic inclusions
• Includes striatonigral degeneration, Shy-
Drager syndrome, and olivopontocerebellar
atrophy, which are distinguished by clinical
features and distribution of neuron loss, but
some overlap
 Striatonigral Degeneration
• Loss of neurons in both substantia nigra and
target neurons in caudate and putamen, with
gliosis, no Lewy bodies
• Clinically similar to IPD, but no response to
L-dopa
 Shy-Drager Syndrome
• Combines features of IPD or striatonigral
degeneration with autonomic disturbances
due to degeneration of neurons in
intermediolateral column of spinal cord
• Autonomic features: impotence, orthostatic
hypotension, sweat & salivary disturbances,
pupillary abnormalities
 Olivopontocerebellar Atrophy
• Loss of neurons of pontine nuclei, inferior
olives, and Purkinje cells of cerebellum
results in ataxia, eye & somatic movement
disorders, rigidity, dysarthria
• Quite variable presentation, even within a
pedigree
• Most cases autosomal dominant, some AR,
some sporadic
 Huntington Disease
• Relentlessly progressive AD disease with
jerky, hyperkinetic movements (chorea) and
dementia; may develop parkinsonism;
average course = 15 years
• Loss of GABA-containing neurons in basal
ganglia increases inhibition of subthalamic
nucleus, which prevents it from regulating
motor output
 Huntington Disease
• HD gene on chromosome 4 codes for huntingin
protein (function unknown), and contains multiple
repeats of CAG trinucleotide
• Trinucleotide repeats are expanded during
spermatogenesis, and paternal transmission causes
early onset in the next generation “anticipation”
• More repeats = earlier onset
 Huntington Disease
• Atrophy: caudate > putamen > globus
pallidus > frontal cortex > parietal cortex
• Often with dilatation of lateral and third
ventricles
 Freidreich Ataxia
• Autosomal recessive progressive disease
beginning in childhood with ataxia, then
hand clumsiness & dysarthria; most DTRs
absent, loss of proprioception, vibratory,
pain, and temp sensation.
• Most patients have pes cavus and
kyphoscoliosis, arrythmias, and CHF, DM
in 10%
 Freidreich Ataxia
• GAA trinucleotide repeat in gene for
frataxin on chromosome 9
• Atrophy of neurons & axonal loss from
spinal cord, brain stem, cerebellum, and +/-
motor cortex; atrophy of dorsal root
ganglia; heart enlarged, pericarditis and
myocarditis may be present
 Ataxia-Telangiectasia
• AR disease of childhood, usually lethal by
second decade
• Recurrent resp tract infections are followed
by ataxia, dysarthria, and eye movement
disorders; telangiectasias of skin &
conjunctivae
• Most patients develop lymphoid
malignancies, gliomas, or carcinoma
 Ataxia-Telangiectasia
• Abnormalities of ATM gene on
chromosome 11impairs DNA repair
• Heterozygous carriers may be at increased
risk of cancer (esp. breast cancer)
 Ataxia-Telangiectasia
• Loss of Purkinje and granular cells of
cerebellum, degeneration of dorsal columns,
spinocerebellar tracts, and anterior horn
cells; peripheral neuropathy
• Cells in many organs have huge bizarre
nuclei “amphicytes”
• Lymph nodes, thymus, gonads hypoplastic
 Amyotrophic Lateral Sclerosis
(Lou Gehrig Disease)
• Motor neuron disease where loss of upper
and lower motor neurons lead to muscle
atrophy, fasciculations, and hyperreflexia;
can involve cranial nerve nuclei
• Onset usually in older adults
• 10% are AD, sometimes due to mutations in
SOD1 gene on chromosome 21; familial
cases usually have earlier onset
 Amyotrophic Lateral Sclerosis
• Atrophy of precentral gyrus, anterior spinal
roots, and muscles (denervation atrophy)
• Loss of anterior horn neurons along the
entire length of the spinal cord, with gliosis;
also loss of neurons in cranial nerve nuclei
• Demyelination from corticospinal tracts to
anterior roots