Alzheimer

Disease/Parkinson
disease
 Alzheimer Disease

Primary degenerative disease, most common

cause of dementia in elderly.
Insidious impairment of higher intellectual
function, with alterations in mood and
behavior.
Later, progressive disorientation, memory loss,
and aphasia severe cortical dysfunction.
 Over next 5 to 10 years, patient becomes
disabled, mute, and immobile.
Death from intercurrent pneumonia or other
infections.
Incidence 3%- 65 to 74 years old, 19%- 75
to 84 years, and 47%- 85 years or more.
 Pathogenesis
Most cases-sporadic, 5-10%- familial.
In general, rarely become symptomatic
before 50 yrs of age, early onset seen with
heritable forms.
Familial forms of disease accumulation of
peptide ( amyloid, or A) in brain initiates
chain of events that result in morphologic
changes of AD and dementia.
 Generation and accumulation of A occur
slowly with advancing age.
Mutations in APP(A is derived from a larger
membrane protein-amyloid precursor protein)
or in components of -secretase lead to early
onset familial AD by increasing rate at which
A accumulates.
 Accumulation of small aggregates of A-alter
neurotransmission, can be toxic to neurons
and synaptic endings.
Larger deposits-neuronal death, elicit local
inflammatory response further cell injury
altered region-to-region communication
through mechanical effects on axons and
dendrites.
 A also leads neurons to hyperphosphorylate
microtubule binding protein tau.
With ed level of phosphorylation, tau
redistributes within neuron from axon into
dendrites and cell body aggregates into
tangles also results in neuronal dysfunction
and cell death.
 Morphology
Gross:
Cortical atrophy with widening of cerebral
sulci- most pronounced in frontal, temporal,
and parietal lobes.
With significant atrophy, compensatory
ventricular enlargement (hydrocephalus ex
vacuo).

Fig: Alzheimer disease with cortical atrophy

most evident on the right
 Microscopy
Neuritic plaques (extracellular lesion); and
neurofibrillary tangles ( intracellular
lesion)-diagnostic.

1) Neuritic plaques:
Focal, spherical collections of dilated,
tortuous, silver-staining neuritic processes
(dystrophic neurites), around a central
amyloid core.
Size - 20 to 200 m in diameter.
 Found in hippocampus, amygdala, neocortex,
later in primary motor and sensory cortices.
Microglial cells and reactive astrocytes present
at their periphery.
Amyloid core contains A.
A deposits can be found that lack
surrounding neuritic reaction diffuse
plaques.
2) Neurofibrillary tangles:
Bundles of paired helical filaments visible as
basophilic fibrillary structures in cytoplasm of
neurons that displace or encircle nucleus.
Can remain after neurons die.
Found in cortical neurons, other sites-
pyramidal cells of hippocampus, amygdala,
basal forebrain, and raphe nuclei.
A major component is abnormally
hyperphosphorylated forms of protein tau.
AD. A, Neuritic plaque with a rim of dystrophic neurites surrounding an
amyloid core. B, Congo red stain of cerebral cortex showing amyloid
deposition in blood vessels and amyloid core of neuritic plaque (arrow).
C, Neurofibrillary tangles (arrowheads) are present within neurons (H &
E). D, Silver stain showing a neurofibrillary tangle within neuronal
cytoplasm.
 Parkinson Disease (PD)

PD is a neurodegenerative disease marked

by a prominent hypokinetic movement
disorder that is caused by loss of
dopaminergic neurons from substantia
nigra.
 Clinical syndrome of parkinsonism:
-diminished facial expression (masked facies)
-stooped posture,
-slowing of voluntary movement,
- festinating gait (progressively shortened,
accelerated steps),
- rigidity, and
-a pill-rolling tremor.

(https://www.youtube.com/watch?v=0-
t4RTQ0EsM)
 Similar symptoms of motor disturbance is
seen in a number of conditions that have in
common damage to nigrostriatal
dopaminergic system.
Also can be pharmacologically induced by
dopaminergic antagonists or by toxins that
damage dopaminergic system.
 Presumptive diagnosis of PD can be based
on presence of central triad of
parkinsonism (large part on presence of
motor symptoms, which reflect decreased
dopaminergic innervation of striatum)
tremor, rigidity, and bradykinesia in
absence of a toxic or other known
underlying etiology.
 There is also evidence of degeneration of
substantia nigra (which results in motor
symptoms) represents a mid-stage in a
progressive disease that begins lower in
brainstem progress to involve cerebral
cortex, leading to cognitive impairment.
 Dopaminergic neurons of substantia nigra
project to striatum, and their degeneration in
PD is associated with a reduction in striatal
dopamine content.
Severity of motor syndrome is proportional to
dopamine deficiency.
 Molecular Genetics and
Pathogenesis.

Associated with protein accumulation and

aggregation, mitochondrial abnormalities,
and neuronal loss in substantia nigra and
elsewhere in the brain.
Most PD is sporadic, some genetic causes
identified.
1.Mutations in gene that encodes -
synuclein, an abundant lipid binding
protein normally associated with synapses.
This protein is a major component of
Lewy body diagnostic hallmark of PD.
-synuclein forms aggregates; small
oligomers appear to be the most toxic to
neurons.
2.Mitochondrial dysfunction
Caused by mutations in genes that encode
proteins DJ-1, PINK1, and parkin.

DJ-1:
-ln oxidative stress it can relocate to
mitochondria have cytoprotective
effects.
 PINK1:
-a kinase that is degraded in mitochondria
under normal circumstances;
-with mitochondrial dysfunction, it recruits
parkin E3 ubiquitin ligase.
-Under normal circumstances, the
combination of PINK1 and parkin results in
clearance of dysfunctional mitochondria
through mitophagy.
 Intriguingly, levels of mitochondrial
complex I, a component of oxidative
phosphorylation cascade, are reduced in
the brains of patients with sporadic PD.
 Mutations in gene encoding LRRK2
(leucine-rich repeat kinase 2)- a
cytoplasmic kinase.
Pathogenic mutations increase kinase
activity of LRRK2, suggesting that gains in
LRRK2 function either
hyperphosphorylation of normal targets or
emergence of novel targets.
 Morphology

A characteristic finding:
Pallor of substantia nigra and locus
ceruleus, due to loss of pigmented,
catecholaminergic neurons in these regions.
Lewy bodies may be found in remaining
neurons.
These are single or multiple cytoplasmic,
eosinophilic, round to elongated inclusions
that have a dense core surrounded by a pale
halo.
 Ultrastructurally, Lewy bodies are composed
of fine filaments, densely packed in the core
but loose at the rim; these filaments are
composed of -synuclein.
Lewy bodies may also be found in
cholinergic cells of basal nucleus of Meynert,
in other brainstem nuclei including the locus
ceruleus and dorsal motor nucleus of vagus.
 Areas of neuronal loss also show gliosis.
Lewy neurites are dystrophic processes
that contain aggregated -synuclein.
 Dementia with Lewy Bodies

About 10-15% of individuals with PD

develop dementia, particularly with
advancing age.
Characteristic features of this disorder
include a fluctuating course,
hallucinations, and prominent frontal
signs.
Parkinson disease. A, Normal substantia nigra. B, Depigmented
substantia nigra in PD.