5. Depending on the area of involvement in the brain
• Cortex – dementias- alzheimers
• Basal ganglia and brain stem- bradykinesia - parkinsonian
• Cerebellum – ataxia- spinocerebellar ataxias
• motor neurons - muscle atrophy- amyotrophic lateral
sclerosis.
INTRODUCTION
8. PATHOGENESIS
Histologic hallmarks of specific disorders
• Accumulation of protein aggregates
• Aggregates may arise because of mutations that alter the
protein’s conformation or disrupt pathways involved in
processing or clearance of the proteins.
• Imbalance between protein synthesis and clearance (due to
genetic, environmental, or stochastic factors) - gradual
accumulation of proteins.
9. PROTEIN ACCUMULATION
-
Accumulation of protein aggregates
Genetic mutation alter protein
conformation
1.Disrupt the pathway of protein clearance
2. Accumulation of protein
3. Resist degradation
Imbalance in protein synthesis
and clearance
Localization neuron
INCLUSIONS
10. PROTEIN INCLUSIONS
Disease Clinical Pattern Protein Inclusions
Alzheimer disease (AD) Dementia
Aβ (plaques) ,
Tau (tangles)
Frontotemporal lobar
degeneration (FTLD)
Behavioral changes, language
disturbance
Tau
TDP43 Others (rare)
Parkinson disease (PD)
Hypokinetic movement
disorder
α-synuclein
Tau
Huntington disease (HD)
Hyperkinetic movement
disorder
Huntingtin (polyglutamine
repeat expansions)
Spinocerebellar ataxias Cerebellar ataxia
Various proteins
(polyglutamine repeat
expansions)
11. ALZHEIMER DISEASE
• Commonest cause of dementias (majority)
• Older adult
• Sporadic, 5-10% familial
• insidious onset of impaired higher intellectual function, memory impair-
ment, and altered mood and behavior
• CORTICAL (grey matter) ATROPHY
• NEURITIC PLAQUES* (extraneuronal)
• NEUROFIBRILLARY TANGLES (intraneuronal)
• AMYLOID!!! (i.e., “BETA” amyloid)
12. GROSS
• variable degree of cortical atrophy
• widening of the cerebral sulci, most pronounced in the frontal,
temporal, and parietal lobes
• compensatory ventricular enlargement
• medial temporal lobe, hippocampus, entorhinal cortex and amygdala,
are involved early in the course and are usually severely atrophied in
the later stages
ALZHEIMER DISEASE
13.
14.
15. MICROSCOPY
• Neuritic plaques : focal, spherical collections of dilated, tortuous,
neuritic processes often around central amyloid core.
• Neurofibrillary tangles are tau-containing bundles of filaments in the
cytoplasm of the neurons that displace or encircle
the nucleus.
ALZHEIMER DISEASE
23. PARKINSON'S DISEASE
• second most common neurodegenerative disorder
• .
BRADYKINESIA- slowness of movement,
RIGIDITY
RESTING TREMOR AND
POSTURE INSTABILITY.
24.
25. • 60 years of age or older
• It results from the death of dopamine-generating cells in the
substantia nigra, a region of the midbrain.
• loss of the nigrostriatal dopaminergic pathway
• Pathologic hallmark of parkinson disease: neuronal inclusions
Lewy bodies
PARKINSON'S DISEASE
26.
27. PATHOGENESIS
Associated with
• protein accumulation and aggregation,
• mitochondrial abnormalities, and
• neuronal loss in the substantia nigra and elsewhere in the brain.
Based on the genetics of PD
• abnormal protein and organelle clearance due to defects in autophagy and
• lysosomal degradation.
28. MECHANISM :
accumulation of protein alpha- synuclein bound to ubiquitin in the
damaged cells.
The alpha- synuclein- ubiquitin complex cannot be directed to the
proteosome.
forms proteinaceous cytoplasmic inclusions called Lewy bodies.
diagnostic feature of the disease is the Lewy body, a characteristic
inclusion containing α-synuclein, a protein involved in synaptic
transmission
29. Fig: Parkinson disease. A, Normal substantia nigra. B, Depigmented
substantia nigra in
idiopathic Parkinson disease.
31. SUMMARY
Definition
Age of onset
Clinical features
Pathogenesis
Part of brain involvement
Stages
Mechanism of protein accumulation
Morphology- gross and microscopy
Complication