Neurodegenerative Diseases Flashcards
1
Q
What is the definition of dementia?
A
- A progressive loss of cognitive function
- Multiple cognitive domains affects (language, motor skills, calculations, spatial reasoning, judgment, memory (short and long term)
- May be gradually progressive or stepwise
- NOT a function of normal aging
2
Q
What are some treatable causes of dementia?
A
- Vitamin B12 (cobalamin) or B1 (thiamine) deficiency
- Toxins (lead, mercury, alcohol)
- Depression (pseudodementia)
- Infections (syphilis, HIV, etc)
- Endocrine problems (adrenal disease, thyroid disease)
- Inflammation (vasculitis)
- Structural problems (brain tumors, NPH)
3
Q
Which gender is at greatest risk of Alzheimer’s?
A
Women (2:1 ratio, but might be due to larger women population)
4
Q
What is Mild Cognitive Impairment?
A
-
Memory complaints with objective evidence of impaired recent memory, but intact daily function and intact non-memory cognitive function
- Not all MCI develop into AD
5
Q
What are some risk factors for developing Alzheimer’s?
A
- Old age
- Lower baseline intelligence and/or education level
- Smaller head size
- Family history of AD
- History of significant head injury (in males)
6
Q
What is the clinical presentation of Alzheimer’s?
A
- Primary symptom is progressive memory loss (initially short term, long term later on)
- Language disturbances
- Apraxia (loss of ability to perform learned tasks)
- Acalculia (trouble with calculations)
- Visuospatial difficulty
- Sequencing problems
- Behavioral problems
- Neurological problems (EPS, loss of frontal lobe inhibition, urinary incontinence, seizures, abulia, death)
7
Q
What is diagnostic of Alzheimer‘s disease (AD)?
A
- Neurofibrillary tangles upon autopsy
- β-amyloid plaques
- Sulci widening due to atrophy of the brain
8
Q
What area of the brain and what neurotransmitter is affects in Alzheimers?
A
- Basal Nucleus of Meynert (BNM)
- ACh is decreased in AD
9
Q
What is the result of β-amyloid accumulation?
A
- May stimulate free radical production resulting in neuronal apoptosis (programmed cell death)
- Free radicals result in MLP (membrane lipid peroxidatoin)
10
Q
Describe the way β-APP is cleaved correctly?
A
- α-secretase cleaves β-APP (an integral membrane protein) and releases sAPP (secretory form)
- sAPP activates receptor R which increases cGMP
- cGMP activates PKG
- PKG activates NF-κB (survival factor)
- PKG also promotes K+ efflux (hyperpolarization) a protective measure
11
Q
Describe the way β-APP is cleaved incorrectly? (secretase pathway)
A
- β-secretase and γ-secretase cleave β-APP which releases β-amyloid (Aβ)
- Aβ aggregates into insoluble plaques that induce membrane lipid peroxidation (MLP)
- MLP impairs Na+, Ca<strong>2</strong>+ and glucose transport resulting in apoptosis
12
Q
Describe the defect when there is a Presenilin-1 (PS-1) mutation.
A
- Presenilin-1 (PS-1) is an ER membrane protein
- Mutations in PS-1 increases Ca2+ release via ryanodine receptors (RYRs) and IP3 receptors
- Enhanced Ca2+ release triggers further Ca2+ influx
- Altered Ca2+ homeostasis leads to apoptosis and excitotoxicity
- Increased Ca2+ also alters APP processing to increase Aβ production
Increases risk of AD!
13
Q
Mutations in what genes/chromosomes are associated with increased risk of familial early-onset AD?
A
- 21 (β-APP) - Down’s syndrome patients almost always develop AD
- 14 (PS-1)
- 1 (PS-2)
PS mutations responsible for most familial early onset cases
14
Q
Mutations in what genes/chromosomes are associated with increased risk of sporadic onset AD?
A
- ApoE4 (ε4) - Chromosome 19 ApoE is a protein modulator of phospholipid transport and may have a role in synaptic remodeling
- IL-A & IL-B - Chromosome 2
15
Q
What gene/chromosome is slightly protective of AD?
A
ApoE2 (ε2) - Chromosome 19
16
Q
Describe neurofibrillary tangles.
A
- Intracellular (cytoplasmic) inclusions
- Composed of tau protein (hyperphosphorylated) and microtubule associated protein (MAP)
- Paired helical filaments (PHF) are composted of tau
- Found in hippocampus and medial temporal lobe, parieto-temporal regtions, and the frontal association cortices leading to cell death
17
Q
What is shown in this image?
A
- Neurofibrillay tangles
- Seen in Alzheimer‘s disease (AD) Also seen in
- Progressive Supranuclear Palsy (PSP) in the brainstem
18
Q
What is the result of hyperphosphorylated tau protein in AD?
A
- Tau is a microtubule associated protein that causes microtubules to fall apart and create aggregates
- Aggregates form neurofibrillary tangles
19
Q
What stimulates the hyperphosphorylation of tau protein?
A
Aβ fibrils or aggregates
20
Q
Describe what accompanies neurofibrillary tangles and plaques.
A
- Neuronal death and synapse loss occurs near regions of neurofibrillary tangles and plaques
- Results in granulovacuolar degeneration - Cytoplasmic clearing with granular deposits
- Also effects cholinergic neurons in BNM leading to decrease ACh
- Also results in loss of serotonergic neurons in median raphe and adrenergic neurons in locus ceruleus leading to deficits in 5-HT and NE
21
Q
(T/F): Inflammation may play a role in developing Alzheimer’s.
A
True. Inflammation may play a causative role
People who take NSAIDs are less likely to develop AD than people that don’t
22
Q
What drugs are used to treat Alzheimer’s?
A
-
Anticholinesterases (increase ACh at synapse)
- Donepezil
- Rivastigmine
- Galantamine
- Tacrine
-
NMDA receptor antagonist (Glu antagonist)
- Memantine
- New ideas: Antibody or vaccination against Aβ or γ-secretase inhibitors
23
Q
What is vascular dementia?
A
- Progressive loss of cognitive function after strokes or other vascular diseases
- Abrupt onset
- Stepwise decline
- Physical complaints
- Emotional incontinence (sudden bursts of tears or laughter)
24
Q
What conditions increase the patients risk for Vascular dementia?
A
- Hypertension
- History of stroke
- Focal neurologic signs and symptoms
25
What are the symptoms of Parkinson's disease?
* **T**remor (at rest)
* **R**igidity (cogwheel)
* **A**kinesia (or bradykinesia)
* **P**ostural instability (late)
* **S**huffling gait
Dementia develops in about 40% of Parkinson's patients
26
What neuron changes are associated with Parkinson's?
* Loss of **dopaminergic** neurons in **substantia nigra** (pars compacta)
* Results in **decrease Dopamine**
27
What is seen histologically in Parkinson's patients?
**Lewy bodies** - Cytoplasmic inclusions composed of **α-synuclein**
28
What is Dementia with Lewy Bodies (DLB)?
* Essentially **Parkinson's patients** that have **cortical LB** as well as LB in the substantia nigra
* **Fluctuating** levels of **alertness** or **cognitive** function
* Frequent visual **hallucinations** (commonly of **little people**)
* Other signs of dementia and/or PD
29
What is the **Braak Hypothesis**?
* Explains early **constipation** associated with **REM behavior** disorders **prior** to **Parkinson**'s and progression to dementia
* **α**-**synuclein** deposits first occur in **enteric nervous system** and **olfactory bulb** in asymptotic patients
* Then **spread** rostrally into **medulla** and up the **brainstem** (stereotypic temporal pattern) progressing through **substania nigra** in midbrain and eventually to **amygdala** and **cerebral cortex**
* Disease starts in periphery and gains access to **CNS** through **retrograde transport** along projection neurons from **GI tract**
30
What is frontotemporal dementia (FTD)?
* **Atrophy** involving the **frontal** and **temporal** lobes
* **Disordered personality** and **social** **conduct**
* Perception, spatial skills, skilled motor tasks and memory are relatively well preserved
31
What are the signs and symptoms of frontotemporal dementia (FTD)?
* **Decline** in **social** interpersonal **conduct**, inappropriate behaviors, disinhibition, abnormal joking, inappropriate sexual comments or behaviors
* **Emotional blunting** and loss of insight
* Decline inperonsal hygeine and grooming
* Mental rigidity and inflexibility
* Distractibility and impresistence
* Hyperorality
* Perservative and stereotyped behavior
32
What is seen histologically with **Pick**'**s** **Disease**?
* **Swollen** (ballooned) **neurons** (**Pick cells**)
* Argentophilic neuronal inclusions (**Pick bodies**) composed of **tau** proteins
33
What is the most common frontotemporal dementia (FTD)?
Pick's Disease
34
What is shown in this image?
Pick bodies (tau protein inclusions)
35
What is shown in this image?
Pick cells (pale, swollen neurons)
36
Familial form of Picks disease is linked to what chromosome?
**17q21-22** (associated with **tau** protein)
37
What is the primary presentation of Pick's Disease?
**Loss of language** is main symptom (known as **Primary Progressive Aphasia**)
38
What is the cause of Huntington's Disease (HD)?
Increased **CAG repeats** in **huntingtin** gene of chromosome **4**
39
What is the result of Huntington's Disease (HD)?
* **Atrophy** of the **caudate** nucleus and **putamen** (due to **loss** of **cholinergic** and **GABAergic** neurons)
* **Inclusions** of **huntingtin** protein aggregates seen in cytoplasm or nucleus
40
What is the juvenile form of Huntington's Disease (HD)?
Westphal Varient
41
What are the symptoms of Huntington's Disease (HD)?
* **Choreiform** movements
* **Aggression**
* **Depression**
* **Dementia**
42
What are the symptoms of Creutzfelt-Jacob Disease (CJD)?
* **Rapidly progressive dementia**, universally **fatal**
* Memory loss, personality changes, hallucinations, speech impairment (**mutism**)
* Myoclonus (sudden jerks), balance coordination and walking problems (ataxia), rigid posture, seizures
* **Infectious partical** is a **protein** called a **prion**
43
What is seen histologically in CJD?
* **Transmissible spongiform encephalopathy**
* "Spongy" due to **holes left by dead/dying neurons**
44
What is shown in this image and what disease is it characteristic of?
Spongiform Enecephalopathy Seen in CJD
45
What is Kuru?
* A **degenerative** dementia in New Guinea due to ritual **cannibalism** of deceased elders
* **Prion** disease
46
What disease in animals are prion diseases similar to?
Similar to **Scrapie** disesae in **cows** and **sheep**
47
How is CJD transported in humans?
* **HGH** (human growth hormone)
* **Pituitary** extracts
* **Transplanted tissues**
48
What is Gerstmann-Straussler-Scheinker (GSS) disease?
A similar disease to **CJD** but with **hereditary transmission**
49
What is the changes in the protein that causes Prion disease?
**PrPc** (**alpha** helix) is misfolded to **PrPsc** (**beta** sheet) in **post**-**translational** modification
