Neuropathology II Flashcards
what is neurodegeneration ?
loss of neuron functionality
what are the symptoms based on Neuronal Population Loss?
- Cortical Neurons → Dementia
- Basal Ganglia Neurons → Movement Disorders
- Cerebellar Neurons → Ataxia
- Motor Neurons → Weakness
what are the neurodegenerative disorders that cause dementia?
- Alzheimer’s disease
- Dementia with Lewy bodies
- Parkinson’s disease
- Frontotemporal lobar degeneration (FTLD)
what are the vascular disorders that cause dementia?
- Large vessel disease, multiple infarcts
- Small vessel disease, Binswanger’s disease
- CADASIL
- Familial amyloid angiopathies
what are other causes of dementia?
- Inflammatory and immune-
mediated disorders - Viral infection (e.g. HIV, PML)
- Prion disorders (e.g. CJD)
- Toxic and metabolic disorders
- Alcoholism
- B12 deficiency
- Other conditions (e.g. tumors, traumatic injury)
what is Alzheimer’s Disease (AD)?
Alzheimer’s disease is a progressive, degenerative, and “incurable” neurological brain disease that causes deterioration of brain’s nerve cells and ultimately death
What are key epidemiological facts about Alzheimer’s Disease (AD) in the United States?
- Over 5 million Americans may have AD
- Most individuals show symptoms in their mid-60s
- AD is the 6th leading cause of overall death in the U.S
- It’s the 3rd leading cause of death for older adults, after heart disease and cancer
what causes Alzheimer’s Disease (AD)?
Complex interactions among multiple genetic, epigenetic, and environmental factors
What are the characteristics of Early-Onset Alzheimer’s Disease?
-Accounts for <1% of all AD cases and occurs in people <65 years old
- Often autosomal dominant inheritance caused by gene mutations in:
- APP (Amyloid Precursor Protein)
- PSEN1 (Presenilin-1)
- PSEN2 (Presenilin-2)
what increases early-onset risk in Alzheimer’s Disease?
Down syndrome (trisomy 21) due to extra APP gene and plaques can develop by age 40
What are the characteristics of Late-Onset Alzheimer’s Disease?
Most common form of AD, occurs after age 65, may be familial or sporadic and is strongly associated with APOE gene, especially:
- ApoE4 allele
**One copy = increased risk
**Two copies = much higher risk (found in ~2% of the population)
what is the most important known non-genetic risk factor for late onset of AD?
aging
what are the epigenetic mechanisms that lead to AD?
abnormal DNA methylation and histone modifications
what are the potential environmental risk factors for AD?
head injury, diabetes, hyperlipidemia, HTN, low education levels etc
how can a definitive diagnosis of Alzheimer’s be made?
brain autopsy after death that reveals hallmark changes like Amyloid plaques, Neurofibrillary tangles (tau protein) and Brain atrophy
Doctors rely on what clinical evaluations to diagnose Alzheimer’s while a person is alive?
Possible Alzheimer’s dementia
Probable Alzheimer’s dementia
what are the clinical features of AD?
- slow-onset memory loss (begins with short term memory loss, progress to long-term memory loss), eventually disorientation
- Changes in behavior and personality
- Loss of learned motor skills and language
- Mute and bedridden: infection is a common cause of death
What are the characteristic brain changes seen in Alzheimer’s Disease on imaging or autopsy?
- atrophy of the entorhinal cortex (an early and key area affected)
- dilation of the temporal horn of the lateral ventricles (due to surrounding tissue loss)
- small hippocampus
- atrophy of the amygdala (involved in emotion and memory)
what are the neuropathological hallmarks of AD?
amyloid plaques (senile plaques)
neurofibrillary tangles (NFTs)
what are amyloid plaques (senile plaques) in AD?
extracellular deposits of beta-amyloid (Aβ) peptides, which are cleaved fragments of the transmembrane Amyloid Precursor Protein (APP) that is found on chromosome 21 and they accumulate mainly in the cerebral cortex and hippocampus
What are neurofibrillary tangles (NFTs) and their forms in Alzheimer’s Disease?
intracytoplasmic accumulations of hyperphosphorylated tau protein, appearing as flame-shaped fiber-like bundles in neurons, with early forms called “pre-tangles” (perinuclear, non-fibrillary tau-positive structures) and “ghost tangles” remaining after neuron loss
what is Cerebral amyloid angiopathy (CAA)?
condition in which beta-amyloid protein deposits accumulate in the walls of small- to medium-sized blood vessels in the brain, particularly in the parieto-occipital region
what is an ABC score in AD?
assess the severity and staging of Alzheimer’s pathology
- AB plaque score: AB parenchymal deposition
- Braak Stage (Neurofibrillary Tangles)
- CERAD: plaque density
If the brain shows an intermediate or high ABC score
considered a sufficient explanation for the person’s memory loss or dementia
what is Parkinsonism?
group of neurological disorders that cause movement problems such as tremors slow movement and stiffness
what is the key step towards diagnosis of Parkinsonism?
accurate recognition of the entire clinical phenotype
what are the categories of Parkinsonism?
- Parkinson’s disease
- Atypical Parkinson’s disorders (Parkinson’s plus )
- Secondary or symptomatic parkinsonism
- Common mimics of parkinsonism
what is Parkinson’s Disease (PD)?
progressive neurodegenerative disorder with:
- Loss of dopaminergic neurons in the substantia nigra (SN) of the midbrain
- Lewy bodies (abnormal protein aggregates made of alpha-synuclein) found in the brainstem that cause significant neuronal loss of locus coeruleus
- classical clinical syndrome
what are the risk factors for Parkinson’s Disease?
- age
- hereditary/genetic factors
- sex
- exposure to toxins (herbicides, pesticides)
what risk factor causes Juvenile Parkinsonism (onset <21)?
hereditary and genetic factors
what risk factor causes Young Onset Parkinsonism (onset 21-40)?
hereditary and genetic factors
why do males have a higher chance of developing Parkinson’s Disease?
females have a neuroprotective effect from estrogen
What are the key molecular features and pathogenesis of Parkinson’s Disease?
accumulation and aggregation of alpha-synuclein, mitochondrial abnormalities, and progressive neuronal loss in the substantia nigra and other areas of the brain.
what is the clinical presentation of Parkinson’s Disease?
TRAP
* Tremor: Pill rolling tremor at rest; disappears with movement
* Rigidity: Cogwheel rigidity in the extremities
* Akinesia/Bradykinesia: Slowing of voluntary movement; expressionless face
* Postural instability and shuffling gait
what are the non-motor symptoms for Parkinson’s Disease?
o Cognitive changes (e.g. dementia)
o Depression (up to 45-50%)
o Diminished sense of smell
o Sleep disturbances
what are the greatest challenges to quality of life and appropriate management in PD?
non-motor symptoms due to them effecting 90% of patients and non-responsiveness to dopamine therapy
what is Neuromelanin and how is it affected in PD?
a dark pigment found in certain brain cells, especially in the substantia nigra that decreases due to the degeneration of pigment-containing dopaminergic neurons
What are the major atypical parkinsonism disorders?
- Dementia with Lewy bodies (DLB)
- Multiple system atrophy (MSA)
- Progressive supranuclear palsy (PSP)
- Corticobasal degeneration (CBD)
How do atypical parkinsonism disorders differ from classic Parkinson’s Disease?
- More rapid disease progression
- A poor response to dopamine replacement therapy
- More wide spread brain pathology
What are the key features of Dementia with Lewy Bodies (DLB) and how is it differentiated from Parkinson’s Disease Dementia (PDD)?
DLB involves numerous Lewy bodies in the cerebral cortex, with symptoms including visual hallucinations, fluctuating consciousness, and parkinsonism
- If dementia begins within 12 months of motor symptoms → it’s likely DLB
- If parkinsonism precedes dementia by more than 12 months → it’s likely Parkinson’s Disease Dementia (PDD)
