Neurodegenerative Diseases Flashcards
What is the definition of dementia?
- 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
What are some treatable causes of dementia?
- 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)
Which gender is at greatest risk of Alzheimer’s?
Women (2:1 ratio, but might be due to larger women population)
What is Mild Cognitive Impairment?
-
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
What are some risk factors for developing Alzheimer’s?
- Old age
- Lower baseline intelligence and/or education level
- Smaller head size
- Family history of AD
- History of significant head injury (in males)
What is the clinical presentation of Alzheimer’s?
- 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)
What is diagnostic of Alzheimer‘s disease (AD)?
- Neurofibrillary tangles upon autopsy
- β-amyloid plaques
- Sulci widening due to atrophy of the brain
What area of the brain and what neurotransmitter is affects in Alzheimers?
- Basal Nucleus of Meynert (BNM)
- ACh is decreased in AD
What is the result of β-amyloid accumulation?
- May stimulate free radical production resulting in neuronal apoptosis (programmed cell death)
- Free radicals result in MLP (membrane lipid peroxidatoin)
Describe the way β-APP is cleaved correctly?
- 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
Describe the way β-APP is cleaved incorrectly? (secretase pathway)
- 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
Describe the defect when there is a Presenilin-1 (PS-1) mutation.
- 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!
Mutations in what genes/chromosomes are associated with increased risk of familial early-onset AD?
- 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
Mutations in what genes/chromosomes are associated with increased risk of sporadic onset AD?
- 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
What gene/chromosome is slightly protective of AD?
ApoE2 (ε2) - Chromosome 19
Describe neurofibrillary tangles.
- 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
What is shown in this image?
- Neurofibrillay tangles
- Seen in Alzheimer‘s disease (AD) Also seen in
- Progressive Supranuclear Palsy (PSP) in the brainstem
What is the result of hyperphosphorylated tau protein in AD?
- Tau is a microtubule associated protein that causes microtubules to fall apart and create aggregates
- Aggregates form neurofibrillary tangles
What stimulates the hyperphosphorylation of tau protein?
Aβ fibrils or aggregates
Describe what accompanies neurofibrillary tangles and plaques.
- 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
(T/F): Inflammation may play a role in developing Alzheimer’s.
True. Inflammation may play a causative role
People who take NSAIDs are less likely to develop AD than people that don’t
What drugs are used to treat Alzheimer’s?
-
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
What is vascular dementia?
- 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)
What conditions increase the patients risk for Vascular dementia?
- Hypertension
- History of stroke
- Focal neurologic signs and symptoms
What are the symptoms of Parkinson’s disease?
- Tremor (at rest)
- Rigidity (cogwheel)
- Akinesia (or bradykinesia)
- Postural instability (late)
- Shuffling gait
Dementia develops in about 40% of Parkinson’s patients
What neuron changes are associated with Parkinson’s?
- Loss of dopaminergic neurons in substantia nigra (pars compacta)
- Results in decrease Dopamine
What is seen histologically in Parkinson’s patients?
Lewy bodies - Cytoplasmic inclusions composed of α-synuclein
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
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
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
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
What is seen histologically with Pick‘s Disease?
- Swollen (ballooned) neurons (Pick cells)
- Argentophilic neuronal inclusions (Pick bodies) composed of tau proteins
What is the most common frontotemporal dementia (FTD)?
Pick’s Disease
What is shown in this image?
Pick bodies (tau protein inclusions)
What is shown in this image?
Pick cells (pale, swollen neurons)
Familial form of Picks disease is linked to what chromosome?
17q21-22 (associated with tau protein)
What is the primary presentation of Pick’s Disease?
Loss of language is main symptom (known as Primary Progressive Aphasia)
What is the cause of Huntington’s Disease (HD)?
Increased CAG repeats in huntingtin gene of chromosome 4
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
What is the juvenile form of Huntington’s Disease (HD)?
Westphal Varient
What are the symptoms of Huntington’s Disease (HD)?
- Choreiform movements
- Aggression
- Depression
- Dementia
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
What is seen histologically in CJD?
- Transmissible spongiform encephalopathy
- “Spongy” due to holes left by dead/dying neurons
What is shown in this image and what disease is it characteristic of?
Spongiform Enecephalopathy Seen in CJD
What is Kuru?
- A degenerative dementia in New Guinea due to ritual cannibalism of deceased elders
- Prion disease
What disease in animals are prion diseases similar to?
Similar to Scrapie disesae in cows and sheep
How is CJD transported in humans?
- HGH (human growth hormone)
- Pituitary extracts
- Transplanted tissues
What is Gerstmann-Straussler-Scheinker (GSS) disease?
A similar disease to CJD but with hereditary transmission
What is the changes in the protein that causes Prion disease?
PrPc (alpha helix) is misfolded to PrPsc (beta sheet) in post-translational modification
