Neurodegenerative diseases Flashcards
1
Q
Broadly describe neurodegenerative diseases
A
- Definition: Degeneration of neurons and their synapses affecting brain function.
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Common Themes:
- Progressive neuronal loss (selective).
- the progression follows a pattern
- it is selective i.e. occurs in specific location and will present based on site
- Neurons often functionally related, leading to stereotypic signs.
- Accumulation of intraneuronal protein aggregates due to mutations, altered processing, or balance issues (clearance < synthesis).
- Progressive neuronal loss (selective).
2
Q
Describe protein aggregates and the types
A
Intraneuronal Protein Aggregates
- Recognized histologically (diagnostic “inclusions.”)
- Resistant to degradation and damaging to neurons (toxic gain of function i.e. ROS production + Loss Of Function, stress response).
- Act similar to prions in causing conformational changes in normal proteins (propagation) but not transmissible.
Types of Protein Aggregates
- Inherited mutated protein (e.g., Huntington’s disease polyglutamine).
- Peptide product of a precursor protein (e.g., APP → Aβ amyloid in Alzheimer’s disease).
- Unexplained alteration of a normal protein (e.g., alpha-synuclein in Parkinson’s Disease).
- Categorized into “Tau-opathies,” “Alpha-Synucleinopathies,” “Polyglutamine tract diseases,” etc.
3
Q
Describe general features and classification of neurodegenerative disease, as well as principles of pathophysiology
A
- Affecting Memory (Dementia): E.g., Alzheimer’s.
- Affecting Movement: E.g., Parkinsonism.
- Distinct stereotypic signs and symptoms, with some diseases having genetic alterations leading to inherited familial forms.
- Selective neuronal loss in distinct anatomical areas.
Classification Basis:
- Symptomatology/Signs.
- Neuroradiology (Anatomic locations of disease).
- Histopathologic findings.
principles pathophysiology
- Progressive loss of neurons leading to grey matter changes.
- The pattern of neuronal loss is selective.
- Typically affects previously healthy patients.
- Development of intraneuronal protein aggregates.
- These protein aggregates are resistant to cellular mechanisms of degradation and are cytotoxic to neurons.
4
Q
Why study it?
A
- Impact: Severely affects patients’ ability to care for themselves and live independently.
- Community Support: Requires the care and services of the community.
- Treatment Approaches: Can involve surgery, medication, and long-term care.
- Research Significance: Etiology, pathogenesis, and response to various novel treatments are crucial for better care.
5
Q
Provide an overview of AD, inc. nature and symptoms
A
- Nature: Cortical degenerative disease leading to dementia and progressive loss of cognitive function.
- Symptoms: Insidious onset, thought content disorders, perception disorders, affect disorders, behavioral disturbances, personality changes, amnesia, aphasia, immobility.
- Etiology: Unknown; 5-10% familial, increased in Down’s Syndrome.
- Incidence: Increases with age (1% of 60-64, >40% above 85). Both environmental and genetic factors may contribute.
- Genetics: Genes on chromosomes 21, 14, 1.
- Diagnosis: Combination of clinical assessment and radiology allows for an 80-90% correct diagnosis rate. Definitive diagnosis through autopsy.
6
Q
Describe the pathophysiology of AD
A
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Genetics: Relate to metabolism of APP, with familial mutations in APP or enzymatic processors, or increased copy number in trisomy 21/Down’s.
- APP soluble fragment cleaved, monomers aggregate, creating plaques and tangles
- Apolipoprotein E (ApoE) alleles, with Ɛ4 dose equating to high risk.
- Key Features: Increased intraneuronal accumulation of Tau and Amyloid beta (Aβ) due to excess production or inadequate removal, leading to plaques in neuropil for Ab and tangles for tau, which can move from IC to EC environment.
- Role of Inflammation? Under investigation.
7
Q
Describe AD pathology
A
Normal brain vs. Alzheimer’s disease, showcasing cortical atrophy, widened sulci due to neuronal loss, narrowed gyri, ventricular dilatation, and thinned cortical ribbon.
Alzheimer Disease Histopathology
- Key Findings: Neuritic plaques, neurofibrillary tangles, and amyloid angiopathy.
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Tau Immunohistochemistry: Highlights neurofibrillary tangles.
- ![[Pasted image 20240315133751.png]]
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Neuritic Plaques:
- Focal spherical structures
- Occur along neurofibrils
- In hippocampus, amygdala, neocortex
- Central amyloid core with surrounding dilated, tortuous, dystrophic neurites, reactive astrocytes, and microglia at the periphery.
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Neurofibrillary Tangles:
- Elongated flame-shaped or basket weave pattern
- in hippocampus and amygdala
- intracellular bundles of filament in cytoplasm encircle or displace nucleus
- may persist as ghosts after neurons death
- composed of paired helical filaments and hyperphosphorylated tau.
- ![[Pasted image 20240315133949.png]]
Note many histopathological techniques to pick up findings
8
Q
Describe other aspects of Alzheimer’s disease
A
- Cerebral Amyloid Angiopathy: Intramural deposits of amyloid in small arterial vessels, sporadic or associated with Alzheimer’s disease
- results in hardening of vessel walls
- potentially leading to intracerebral bleeding, dementia, or epilepsy.
- cannot constrict to stop bleeding due to deposits in wall
- ![[Pasted image 20240315134019.png]]
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Hirano Bodies and Granulovacuolar Degeneration:
- HB: elongated glassy eosinophilic, crystalline beaded bodies
- GVD of neurons
![[Pasted image 20240315134107.png]]
9
Q
Describe physiological changes in the aging brain
A
- Atrophy: Marked by decreased brain weight, shrinkage of gyri, expansion of sulci, and enlargement of ventricles.
- Including vascular changes, pigment accumulations (lipofuscin), loss of pigment (substantia nigra), and the presence of senile plaques, both neuritic and non-neuritic
10
Q
Provide an overview of PD
A
- Nature: Progressive movement disorder affecting the extrapyramidal system, crucial for coordinating communication between the brain’s neurons and the body’s muscles.
- Key Areas Affected: Substantia Nigra and Locus Ceruleus, characterized by the loss of dopaminergic neurons.
- Treatment Response: Positive response to dopamine replacement therapy (e.g., L-DOPA).
Clinical Features
- Lack of blink reflex, arm swing.
- Symptoms include tremor, rigidity, akinesia, and postural instability.
- In 10-15% of patients, cortical neurons are affected, leading to Lewy body dementia.
- Depression is a common symptom.
- Associated with diseases like Progressive Supranuclear Palsy, Corticobasal Degeneration, and Multiple System Atrophy.
- Note dementia is a secondary presentation
Epidemiology
- Prevalence ranges from 0.5 to 1% among individuals 65 to 69 years old, increasing to 1 to 3% among those 80 years and older.
- A minor proportion is familial, with autosomal dominant and autosomal recessive patterns.
- Environmental toxins and repeated head injuries can cause Parkinsonism by damaging neuronal pathways.
11
Q
Describe PD pathology
A
- Midbrain Cross Sections: Left shows a pale substantia nigra compared to the right with normal melanin pigmentation.’
- ![[Pasted image 20240315134534.png]]
- Pons Cross Sections: Loss of pigmentation in the Locus ceruleus.
- ![[Pasted image 20240315134548.png]]
- ![[Pasted image 20240315134608.png]]
- Histopathology: Loss of pigmented catecholaminergic neurons and presence of Lewy bodies in remaining neurons (appear round to elongated cytoplasmic eosinophilic inclusions), composed of α-synuclein, parkin, ubiquitin, tightly paced.
- Lewy bodies are pathognomic for PD
- mitochondrial dysfunction may also play roles.
![[Pasted image 20240315134703.png]]
12
Q
Provide an overview of HD
A
- Genetics: Autosomal dominant condition linked to chromosome 4, involving the protein huntingtin and triplet nucleotide repeat expansion; exhibits anticipation.
- Characteristics: Progressive movement disorders and dementia due to degeneration of striatal neurons.
Clinical Features
- Insidious onset typically between 35 to 45 years of age.
- Symptoms include chorea, dementia, emotional/psychiatric symptoms, sometimes parkinsonian syndrome, and depression.
13
Q
Describe HD pathology
A
- Marked by atrophy of the caudate and putamen, alongside widespread (secondary) cerebral atrophy affecting the striatum and cerebral cortex.
14
Q
Describe HD diagnosis
A
- Differentiation from other causes of chorea, dementia, and psychosis.
- Utilizes genetic testing for HD, MRI, and PET scans to confirm diagnosis.
15
Q
Provide an overview of ALS
A
- Nature: A neurodegenerative disorder involving the destruction and loss of upper and lower motor neurons, leading to denervation and atrophy of corresponding muscle fibers.
- Etiology: Over 90% of cases are sporadic with an unknown cause, with a speculated viral trigger. Incidence rate is 2 per 100,000. A minority of cases are hereditary, linked to mutations in genes such as SOD1, ALS2, NEFH, and VAPB. The SOD1 gene, which codes for superoxide dismutase, suggests that excess free radicals may contribute to neuronal cell death in ALS.
- Prognosis: ALS is universally fatal, typically due to respiratory compromise or infection, within 2-5 years of diagnosis.
Clinical Features
- Progressive loss of voluntary muscle contraction, and wasting/atrophy of affected muscles.
- Spontaneous muscle twitching of motor units (fasciculations).
- Difficulties in chewing, swallowing, and facial movements.
- Progressive physical disability, while mental functions and physical sensation remain intact.
