Neurodegenerative Disorders - Fremont-Smith Flashcards
alzheimers
cortical
parkinsons
midbrain
huntingtons
caudate
CAG repeats
spinocerebellar degeneration
ALS
UMN and LMNs
dementia
loss of mental power
with pathology of brain damage
stroke, hippocampal sclerosis, trauma, hydrocephalus, CNS infections, metabolic disorders, demyelinative, neuropsych, organ failure, med effects
and neurodegenerative diseases
neuronal storage diseases
mutations in synthesis/storage of sphingolipids, mucolipids, mucopolysaccharides
accumulation of substrates
leukodystrophies
defect in myelin synthesis or turnover
mito encephalomyelopathies
disorders of ox phos
-mutations of mito genome
neuronal ceroid lipofuscinoses
lysosomal storage disorders - lipofuscin accumulation
blindness, mental and motor deterioration, seizures
krabbe disease
auto rec leukodystrophy
deficiency of galactocerebroside beta-galactosidase
-no breakdown of galactocerebroside
toxic to oligodendrocytes
weakness/stiffness 3-6 months of age - survival < 2 years
globoid cells
glycolipid engorged macros around blood vessels
in krabbe disease
metachromatic leukodystrophy
auto rec
-deficiency of arylsulfatase
sulfatide accumulate and block oligodendrocyte differentation
myelin loss and gliosis
macros with metachromatic maaterial
adrenoleukodystrophy
progress loss of myelin and adrenal insufficiency
inability to catabolize long chain FAs
pelizaeus-merzbacher disease
X-linked leukodystrophy
mutation in myelin proteins
mitochondrial encephalopathy, lactic acidosis, and strokelike episodes
MELAS
most common neuro syndrome with mito abnormalitles
recurrent neuro dysfunction and cognitive changes
-reversible deficits
mutation - mito tRNA
leigh syndrome
subacute necrotizing encephalopathy
1-2 yo with developmental arrest
feeding problem, seizure, extraocular palsy, hypotonia, lactic academia
brain - B/L damage with spongiform changes
-midbrain periventricular gray matter, pontine tegmentum, thalamus, and hypothalamus
beta-amyloid
alzheimers
cerebral amyloid angiopathy
tau
AD, FTLD, picks, progressive supranuclear palsy, corticobasal degeneration
TDP43
FTLD, and some ALS
synuclein
PD, dementia with lewy bodies disease, multiple system atrophy
huntingtin
huntingtons
prion
CJD, vCJD, GSS, FFI
vCJD
variant
-consumption of food with prions
sCJD
sporadic
-majority of cases
neurodegen disorders
may have basis around protein misfolding - like prion disease
may be link
tau and beta-amyloid
alzheimers
alzheimers
older age >65yo
slow progressive memory dysfunction
dysphasia, dyspraxia
most sporatic
down syndrome
more likely to develop alzheimers
memory loss, poor planning, confusion with time and place, problem word findings, misplace objects, decreased judgment, social withdrawal, mood/personality changes
alzheimers clinical
alzheimers deposition
amyloid - outside neuron
tau - inside neuron
BACE
beta-amyloid converting enzyme
- causes aggregates in alzheimers
- releases insoluble amyloid beta aggregates and forms fibrils
familial AD
beta amyloid precursor protein
21q21
early onset AD
presenilin 1 (14q24.3) presenilin 2 (1q31-q42)
apolipoprotein E gene
19q13. 2 - E4 isoform
- increased beta amyloid formation
- increased risk for AD 25%
tau protein mutation
17q21.1 - with AD
most cases of AD
sporadic
beta-amyloid plaques
AD
tau
stabilizes microtubules
-aggregates if abnormal - in neuron and axon
early asymptomatic alzheimers
pre-tangle tau aggregates and tau protein tangles
silver stain
tau positive
poor recovery after head trauma
tau protein in CSF
hyper-P of tau
makes it abnormal
plaque and neurofibrillary tangle
AD
- beta-amyloid plaque
- tau tangles
diffuse A-B plaques and neuritic plaques
AβPs are spherical exracellular Aβ deposits
NPs are AβPs containing degenerating neuronal processes with tau paired helical filaments
cerebral amyloid angiopathy
not AD, but if AD present - this is almost always present
deposition of beta-amyloid in small vessels
result in ischemia or hemorrhagic lesions
vessel wall weak and can break
CSF biomarkers for AD
decreased beta-amyloid
increased tau
not diagnostic
frontotemporal lobar degeneration
FTLD
-includes picks, progressive supranuclear palsy, corticobulbar degeneration
personality, behavior and language changes BEFORE memory (as opposed to AD)
smooth contoured inclusions of tau
pick disease
type of FTLD
FTLD tau
only tau aggregation - no beta-amyloid
tangle tau
FTLD tau
TDP43
also cellular inclusion in FTLD
picks disease
45-65yo
- progressive symptoms
- advanced- similar to AD
atrophy frontal and temporal lobes
pick bodies - tau spherical neuro inclusions
progressive supranuclear palsy
tauopathy progressive truncal rigidity, disequilibrium, falls, eye movement difficulty
50-70yo
Males 2x females
disease fatal - 5-7 years after onset
loss of dopaminergic neurons from substantia nigra
parkinson disease
dementia with lewy bodies
severity of motor syndrome - proportional to dopamine deficiency
etiology of PD
idiopathic form
MPTP - drug form
GUAM - toxic AA in cycad plant seed
aluminum - in drinking H2O
and other conditions damaging the substantia nigra
to find substantia ingra
cut mid-brain across the superior colliculus
tremor, rigidity, bradykinesia
parkinsons
stooped posture rigidity tremor slow movement masked facies - diminished expressions
diagnosis of PD
symptomatic response to L-Dopa
deep brain stimulation
may get rid of motor symptoms of PD - poorly understood mechanism
synucleinopathy
PD
fibrils of insoluble alpha synuclein - in neuron cell body
cytoplasm inclusions - lewy bodies
lewy bodies
alpha synuclein fibrils deposited in neuronal cell body
cause neural degeneration and death
lewy neurits
alpha synuclein - in neuronal processes and in astrocytes and oligodendroglial cells
diffuse lewy body disease
DLBD
second most common cause of dementia after alzheimers
DLBD
dementia and parkinsonism
fluctuating attention and cognition
hallucinations**
motor parkinsonism manifestations vary in severity and appear late
depression, sleep disorder, autonomic dysfunction
alzheimers brain
atrophic
DLBD brain
lewy bodies in neocortex, limbic system, brainstem
multiple system atrophy
MSA
3 circuits involved
1 - striatonigral circuit - parkinsonism
2 - olivopontocerebellar circuit - ataxia
3 - autonomic - orthostatic hypotension
alpha-synuclein inclusions in oligodendrocytes
atrophy of putamen
alpha-synuclein in oligodendrocytes
key features of MSA
huntington disease
auto dom
40-50yo
behavioral change, chorea, dementia
caudate and putamen absent
in huntingtons disease
IHC for huntingtin protein
for huntingtons disease
intranuclear inculsions in neurons
-also with ubiquitin
CAG repeats on chrommosome 4p16.3
huntingtons disease
-huntingtin protein
repeat expansion
during spermatogenesis - paternal transmission - associated with early onset in next generation - known as anticipation**
occurs with huntingtons disease
polyglutamine polyQ disease
huntingtons disease
repeat of CAGs - lots of glutamine
abnormally folded protein
mechanisms for trinucleotide repeats to cause disease
LOF affected gene - silences gene - repeats in non-coding part ofgene
**toxic GOF - alteration of protein structure - aka huntingtons
toxic GOF mediated by mRNA - fragile X tremor-ataxia syndrome
huntingtons
degeneration of cholinergic and GABA-ergic cells in basal ganglia
get excess dopamine
amyotropic lateral sclerosis
ALS
-degeneration of UMN and LMN
LMN - muscle weak, atrophy, fasciculations
UMN - spasticity, clonus, hyperactive DTR, babinski
dementia often with ALS
prognosis of ALS
majority of patients die - respiratory paralysis
-2-3 years after symptom onset
motor neurons in ALS
die by wallerian degeneration with secondary gliosis
diagnosis of ALS
clinical progression and needle electromyography or nerve conduction studies
fridereichs ataxia
auto rec
GAA repeats - frataxin gene
1st decade hand clumsiness, gait ataxia, and pes cavus
also with diabetes
spinocerebellar ataxias
auto dom
CAG repeats on multiple chromosomes
degeneration of posterior columns of spinal cord
atrophy of dorsal roots
friedreichs ataxia
-degenerative disorder
destruction of ganglion cells and their axons
loss of sensory ganglion cells - cannot coordinate movement
also with cardiovascular disease - pes cavus
auto dominant spinocerebellar ataxia
ADSCA
- CAG triplet expansion
- polyglutamine (polyQ) on affected protein
anticipation - worse with more generations
cerebellar degeneration
multiple sclerosis
destruction of myelin
neuromyelitis optica
NMO
-demyelinating
intense pain with vomiting
- B/L optic neuritis
- more in women
- auto-Ab against aquaporin 4 water channel of astrocyte
tx - plasmapharesis and anti-CD20 Ab therapy
progressive multifocal leukoencephalopathy
PML
demyelinative disease
-polyoma virus JC
-acquire virus at young age - latent in kidneys - immunosuppression reactivation
patient with AIDs, cancer, inflammatory disorder, organ transplant recipient
guillan barre syndrome
acute inflammatory demyelinating polyneuropathy
demyelination of spinal nerve roots and peripheral nerves
family hx of MS
7x increased risk
measles virus
with MS
multiple sclerosis
autoimmune demyelinating - relapse and remitting episodes
Th1 and Th17 lymphocytes react to myelin antigens
-type 4 hypersensitivity
loss of saltatory conduction
associated with northern latitudes
diagnosis of MS
T2 active plaques
T1 atrophy and black holes of neuron loss
CSF - IgG oligoclonal bands
MS CSF
normal glucose
normal protein - but monoclonal bands
central pontine myelinolysis
CPM
- osmotic demyelination syndrome
- hyponatremic patients corrected rapidly
- severe hyperosmolar not preceded by hyponatremia
often asymptomatic
-seen on MRI
demyelination of axons
