NEURODEGENERATIVE DISEASES Flashcards
Disease
Alzheimer’s disease
Parkinson’s disease
Huntington’s disease
Amyotrophic lateral sclerosis
What is the most common cause for dementia?
Alzheimer
Alzheimer’s disease: epidemiology
6th leading cause of death
- 6.5M people with AD (1 in 9 over 65)
- Increase with age (primary risk factor)
- More common with women (2x)
- Number of people with AD is increasing
Alzheimer’s disease: age of onset
Early Onset AD (familial)
Late Onset AD (sporadic)
Early Onset AD
Age of onset <65 yrs of age
- <5% of AD cases
- Familial
- Mendelian genetics: Autosomal dominant inheritance (only need one gene)
- 3 known genes (PSEN1, PSEN2, APP)
Late Onset AD
Age of onset >65 yrs of age
- >95% of AD cases
- Can be familial (mainly sporadic)
- Complex gentic with mutiple genetic risk factors (disease associated SNPs)
Alzheimer’s disease: risk factors
Age
Family History
Genetics (shared genes or environment)
- APOE
– E4 Increase Risk
– E2 Decrease Risk
Alzheimer’s disease: health disparities
African American and Hispanic are more likely to get it
Alzheimer’s disease: Clinical Symptoms
Progressive declines that are different than typical age-related changes
- Memory loss, Confusion about time or pace, Visual and spatial problems, Decreased or poor judgement, Social withdrawal, Changes in mood, personality and behavior
Most common cause of death is infections and damage in lungs
Alzheimer’s disease: gross anatomy
- Decrease in overall brain weight
- Cortical atrophy
- Loss of pigmented neurons in the locus coeruleus
- Areas preserved (Pigmented neurons in the substantia nigra, Occipital lobe, Cerebellum)
What happens in Cortical Atrophy
Cortex Shrinks
- Widening of sulcal spaces and narrowing of gyri
- Enlarged ventricles
- Degeneration in temporal, parietal, and frontal lobes
Where do the loss of pigmented neurons happen?
In locus coeruleus
What areas gets perserved?
- Pigmented neurons in the substantia nigra
- Occipital lobe
- Cerebellum
Alzheimer’s disease: pathological hallmarks
Hallmarks required for diagnosis
- Amyloid plaques: aggregates of amyloid fibrils outside neurons, amyloid beta (Aβ)
- Neurofibrillary tangles: accumulation of hyperphosphorylated tau protein inside neurons, tau
Neuronal Loss:
- Glutamatergic pyramidal neurons in entorhinal cortex and hippocampus
- Cholinergic neurons in basal forebrain
- Noradrenergic neuron in locus coeruleus
Amyloid plaques involves? and where?
It involves the aggregation of amyloid fibrils
- It happens outside neurons (amyloid beta)
Neurofibrillary tangles involves the accumulation of? and where
Involves the accumulation of hyperphosphorylated tau protein
- Happen INSIDE neurons, tau
Which neuron in basal forebrain?
affected by neuronal loss
Cholinergic
Which neurons in locus coeruleus?
affected by neuronal loss
Noradrenergic
Which neurons in in entorhinal cortex and hippocampus?
affected by neuronal loss
Glutamatergic pyramidal neurons
What do acetylcholinesterase inhibitor do?
it inhibit ACH receptors
When you get Late onset AD you develop?
Plaques, Tangles (Hallmarks) and your APOE gene mutate
Movement Disorders
Hypokinetics Disorders
- Parkinson’s Disease
Hyperkinetic Disorders
- Huntington’s Disease
Parkinson’s disease: epidemiology
- Age of onset
– Typically 60s-70s (~95%)
– Early onset: before 50 (~5%) - 60000 new cases each year (1-2% of population above 65)
- 1 M people in the US living with PD
- More COMMON in men in the US
- FASTEST growing neurological disease
Parkinson’s disease: environmental risk factors
Increased risk of PD
- Exposure to specific types of pesticides and industrial toxicants
- Exposure to heavy metals
- Head injury
Decreased risk of PD
- Cigarette smoking
- Caffeine consumption
- Physical activity
Do smoking increase or decrease your risk of Parkinson’s disease?
Decrease
Parkinson’s disease: genetic risk factors
Familial PD
- SNCA (α-synuclein) ** **
– protein found in Lewy bodies, one of the pathological hallmarks of disease
- LRRK2 (Most common)
- GBA (Most common)
Sporadic PD
- SNCA (α-synuclein) ** **
- LRRK2 (Most common mutat)
- GBA (Most common)
- HLA genes
Parkinson’s disease: medical risk factors
Constipation
REM sleep behavior disorder
Depression
Hyposmia
Excessive daytime sleepiness
Diabetes
High plasma urate (decreased risk)
Parkinson’s disease: clinical symptoms
Cardinal motor symptoms: have two
- Bradykinesia (slow movement)
- Rigidity (stiffness)
- Tremor (at rest)
- Postural instability
Non-motor symptoms:
- Constipation
- RBD
- EDS
- Loss of sense of smell
- Mood disorders
- Sexual dysfunction
Difficult to diagnose;
Parkinson’s disease: Pathological
hallmarks
Hallmarks required for diagnosis:
- Nigrostriatal degeneration: degeneration of pigmented dopaminergic neurons in
the nigrostriatal pathway
- Lewy bodies: aggregates of α-synuclein protein and other cellular components
inside neurons of the substantia
Extra-nigral and peripheral pathology:
- Lewy pathology in other regions of the central and peripheral nervous systems
What is the degeneration of pigmented dopaminergic called?Where does it happen?
Nigrostriatal degeneration: Happen in the nigrostriatal pathway
What is aggregates of α-synuclein protein called? Where does it happen?
Lewy bodies: Happens inside neurons in the substantia
Parkinson’s disease: affected regions
- Enteric nervous system
- Olfactory bulb, brain stem
- SN
- Neocortex
Parkinson’s disease: basal ganglia
Basal ganglia controls voluntary movement
- Output to motor cortex
- Motor cortex sends info to muscles via corticospinal tract
What is Basal ganglia do?
Basal ganglia controls voluntary movement
Parkinson’s disease: Current FDA- approved treatments
Deep brain stimulation (DBS): Surgery
Symptomatic (motor symptoms)
- Levidopa/carbidopa (most common
treatment)
DA replacement
Levidopa/carbidopa: Precurser to dopamine
Tremor is not specific to PD; what can indicate that it is PD?
Tremor at rest and L-DOPA responsive
For PD; what treatment is most likely to help treat the motor symptoms?
L-Dopa
Huntington’s disease: epidemiology
- About 40,000 patients with HD in the US
- Increasing worldwide 9-20% each decade
- Not evenly distributed geographically (European is more affected)
Rare disease
Huntington’s disease: genetics
- Autosomal dominant inheritance
- Independent of sex
Huntington’s disease: genetics
CAG repeat expansion in Htt gene:
- Htt encodes huntingtin protein, a synaptic protein
- CAG encodes the amino acid glutamine
- Polyglutamine expansion in Huntingtin
Genetic Anticipation:
- Number of repeats increase with each generation (more copies = earlier onset)
Huntingtin protein is encoded by?
Htt
Huntington’s disease: clinical progression
- Age of motor symptom onset: 30-50 (<20:5-10%)
- Life expectancy after diagnosis: 15 years
- Long prodromal phase: 10-15 years
Pneumonia is a common cause of death
Huntington’s disease: clinical symptoms
- Chorea: brief involuntary dance-like movements (Clinical Hallmark)
- Difficulty with voluntary motor behavior
- Motor impersistence
- Impairments in fine motor activity
- Variability of the pace of walking
Is Chorea voluntary or involuntary?
involuntary dance-like movements
Huntington’s disease: gross anatomy
- Striatal (caudate) atrophy
- Atrophy of basal ganglia and brain stem
- Cortical thinning
- Degeneration and reduced volume of cerebellum
- Resulting enlargement of ventricles
Huntington’s disease: pathological
hallmarks
HTT inclusions:
- Inclusions of mutant HTT protein found inside of neurons, intranuclear and cytoplasmic
Loss of GABAergic medium spiny neurons:
- Specific degeneration of MSNs in the striatum, the target of nigrostriatal DA neurons
Where do the degeneration of MSN happen?
Striatum; Target of Nigrostriatal DA neurons
What do GABA do?
Inhibit cortex; no control of motor neurons
Huntington’s disease: treatments
Symptomatic (motor symptoms):
- Decrease DA signaling
- Medication that reduce movement as side effect
What is the pattern of inheritance for the mutation in the Htt gene?
Autosomal dominant
Typical age of onset for HD is younger/older than AD or PD
Younger: 30-50 yrs old
What is the major pathological observation on gross examination in HD?
Striatal (caudate) atrophy
Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic: Muscle atrophy
Lateral Sclerosis: Hardening of the spinal cord lateral columns
ALS: epidemiology
- Age of onset: average 55
- 32,000 people in the US living with ALS
(450,000 worldwide) - Slightly more common in men
- Most live 2 years after diagnosis
- Earlier age of diagnosis => better prognosis
ALS: Risk factors
- Age
- Sex
- Family History (inherited dominantly)
- Genetics: TARDBP(TDP-43)
ALS: environmental risk factors
Risk factors
- Smoking
Protective Factors:
- Diet
ALS: Clinical symptoms
Skeletal and muscle:
- Lower motor neuron signs
- Upper motor neuron signs
Lower motor neuron signs
Spinal cord ==> Muscle
- Muscle weakness
- Muscle atrophy
- Fasciculations
Upper motor neuron signs
Motor Cortex ==> Spinal Cord
- Overactive reflexes (Babinski, Hoffman)
- Spasticity
- Difficulty chewing/swallowing
- Psudobulbar effects
- Slurred and nasal speech
ALS: pathology
- Degeneration of UMNs
- Sclerosis of the pyramidal tracts
- Degeneration of LMNs in spinal cord
- Muscle atrophy
ALS: pathological hallmarks
Inclusions by appearance
- Ubiquitinated inclusions
Inclusions by protein
- TDP-43 (95% of sporadic ALS have it)
ALS: FDA-approved treatments
Disease-modifying
Symptomatic
- Most just extent lifespan by 3-6 month
- Can’t take pills
What disease has the fastest progression after diagnosis (from the 4)
ALS
What 2 pathways degenerate in ALS?
Corticospinal and Corticalbulbar
ALS is characerized by
Degeneration of upper and lower motor neurons.
