7. Neuropathology Flashcards
The CNS contains four types of supportive neuroglial cell (glia), which are nonconducting cells located close to neurons • Astrocytes • Oligodendrocytes • Microglia • Ependymal cells
Starting with astrocytes:
• Star-like glial cells (glial cells are a general term for resident cells in the CNS)
• Cytoplasm contains: ____ (glial fibrillary acidic protein or GFAP) - used for
pathology when doing histo stains
Oligodendrocytes
• Myelinating cells of the ____ (Schwann is PNS)
Microglia
• small, elongated throughout CNS
• Inconspicuous, gray + white matter
• ____ surveillance
Ependymal Cells
• single ____ cells that line the ventricles + choroid plexus
• form specialized epithelium
intermediate filaments
CNS
immune
cuboidal
Astrocytes foot processes surround brain capillaries and control the exchange of chemicals
• Cytokines
• Homeostasis
• Gliosis (reactive astrocytes)
• Astrocytes participate in inflammatory + degenerative processes
• secrete ____ - common in CNS diseases w/ inflammatory components
i.e. MS
- take up ____ that’s released during neuronal activity
- maintains homeostasis in the CNS
◦ also take up + recycle ____ (I.e. glutamate) + can also produce
NT’s
• When neurons are lost or damaged, they proliferate + become reactive - try to
restore the ____ - ____
◦ so in the pic w/ the red arrow above, he’s saying when you see the cytoplasm this ____, it’s indicative of pathology
• Long standing reactive astrocytes can develop an eosinophilic, proteinaceous deposits called____
cytokines potassium neurotransmitters BBB gliosis visible rosenthal fibers
Oligodendrocytes produce myelin sheath that surrounds axons in the CNS • Myelin • Oligodendrocyte precursor cells • Demyelination • Dysmyelination
- Myelin - consists primarily of ____. insulating properties help primarily w/ conductivity
- a single oligodendrocyte makes up ____ segments of myelin that wrap around multiple axons (this does NOT happen in schwann cells - one cell makes ____ myelin component)
- ____ cells - never mature/always undifferentiated
- in MS, when you have damaged myelin, these cells helps repair
• in H&E stains, oligo’s have characteristic appearance of:
◦ conspicuous nuclei w/ white cytoplasm w/ ____ look
• Demyelination - loss of myelin w/ normal axons
◦ stained in purple + yellow dots show chronic plaque of demyelination - scarring; can’t re-myelinate
◦ other yellow dot area shows area trying to re-myelinate; hasn’t reached scar tissue stage yet
◦ Inflammatory cells mediate; MS is prototype of this pathogenesis
• Dysmyelination - myelin sheaths form normally but maintenance is problem - I.e. ____
lipid
multipleone
precursor
fried egg
leukodystrophies
Microglia have multiple roles that include phagocytosis and immune surveillance
• Hematopoietic origin
• Microglial nodules
• derive from ____ lineage - not true glial cells but have hematopoietic stem cell origin
◦ this separates them in classification due to their different origin
• normal state: inconspicuous
◦ activated: act as ____ for immune surveillance + release ____ (particularly against viruses)
• persistent activation -> may have a role in ____
• ____ properties
◦ can recognize damaged tissue + phago it
◦ when they aggregate around necrosis, it’s called a ____
monocyte/macrophage antigen presenting cell cytokines alzheimer's phagocytic
Ependymal cells are epithelial cells that line the ventricles and cover the choroid plexus
• Ependymal cells produce ____
• Cells are ____
• Atrophy
• Histo: single cell lining on the ____
◦ choroid plexus - extend into ventricular spaces as frond-like areas
• pathology/infection -> atrophy
◦ lose their cytoplasm + become flattened
◦ says here that they’re atrophic (upper lining), but then after this says “and here they’re in normal state” but I can’t see his laser go anywhere…. :/ feelsbadman
◦ causes: ____ - stretching due to increased ventricular spacing
•
CSF
cuboidal to columnar
choroid plexus
hydrocephalus
Hydrocephalus is an abnormal accumulation of CSF in the ventricles
• Clinical presentation varies with age
• Head ____ in infants increases
• CSF flows through series of openings in brain then moves out to the ____ space where it’s reabsorbed into the venous system
◦ if any obstruction of this flow, then accumulation under pressure of CSF -> hydrocephalus
◦ Brain can accommodate quite a bit of ventricular dilation without neuronal dmg, but if it’s persistent
enough eventually it will cause irreversible brain damage
◦ Infants: skull can expand quite alot b.c sutures are not ____ yet
‣ abnormal enlargement of head with ____ deviation of eyes
‣ vomiting, sleepiness, irritability
◦ Adults: not as much enlargement of the skull, but can get headache, vomiting, changes in vision,
downward eye deviation
‣ changes in ____ + memory loss
circumference subarachnoid ossified downward personality
Hydrocephalus can develop for a variety of reasons, sometimes as part of another condition
• Congenital
• ____
- Acquired
- ____
• this is a more common congenital anomalies affecting nervous system
◦ caused by aqueduct stenosis - passageway b/t ____ ventricle; when it becomes narrowed or
blocked, can develop congenital version of hydrocephalus
‣ ____ stenosis is most common congenital form
• Acquired hydrocephalus - caused by ____ of the meninges
◦ the exudate blocks the normal flow of the ventricular system
• left image: early stage of meningitis -> right is ____ of ventricular systems
aqueduct stenosis
meningitis
third and fourth
x-linked
inflammation
enlargement
Optimum treatment for hydrocephalus is controversial for infant hydrocephalus
• CSF ____
• Endoscopic third
ventriculostomy
• Complications
• traditional treatment = craniotomy - draining of the fluids in brain via a cut hole
• CSF ____ - is now the MOST COMMON
◦ diverts CSF from ventricles down into the ____ cavity - catheter runs subcutaneously with valve in between ventricular + distal catheters.
◦ Ventricular Peritoneal Shunt (VPS)
◦ common failure is due to ____ - occurs in up to 40% of children within first 2 days of placement
• Endoscopic third ventriculostomy - pinpoint hole in ____ ventricle to let excess CSF drain out
into other area of the brain
◦ high rate of ____ failure esp in infants
• Complications - see sub-bullets above
shunting shunting peritoneal mechanical obstruction third early
Meningitis is inflammation of the lining around the brain caused by infectious agents
- Children under age of ____ are highest risk for infection
- Pneumococcal caused by ____
- Meningococcal caused by ____
- ____
can be caused by bacteria, fungi, virus, or parasitic
◦ Bac meningitis is much worse/fatal than viral meningitis
H. influenza type B - more often in ____ globally
◦ more common in adults in the US (younger children usually vaccinated for this strain)
These 3 pathogens all cause meningitis
2
streptococcus pneumonia
neisseria meningitidis
haemophilus influenza type b
infants
Bacterial meningitis is often preceded by \_\_\_\_ illness or a sore throat • Fever, headache, nausea, vomiting • Mental status change • \_\_\_\_ • Nuchal rigidity • \_\_\_\_; bulging fontanelles in children
• Pathogensis
◦ starts as ____ tract infection -> travels through bloodstream + up into brain
• Tx
◦ antibiotics/steroids to counter bad + lower inflammation
◦ children coming into contact w/ sick patients are given ____ as preventative prophylaxis
respiratory
photophobia
hydrocephalus
upper respiratory
antibiotics
Bacterial meningitis is characterized by acute inflammatory infiltrate and ____ purulent exudate
• Exudate can encase ____ nerves
• ____ in the subarachnoid space and in leptomeningeal veins
cloudy, glazing of the b9rain post-mortem (first pic) infiltration of cranial nerves can lead to deficits
◦ nerves most commonly affected are CN ____
‣ Pic: exudate encasing CN’s
◦ Hypoglossal nerve dmg -> paralysis of the tongue; deviates ____ side of damage
◦ (Shows a video); tongue clearly deviating towards right so right sided dmg
◦ exudate can also infiltrate the ____ system -> hemorrhagic infarction
Last pic on right: pathology
◦ ____ of inflammatory cell infiltrate
thick
cranial
neutrophils
3, 4, 6, 7
towards
venous
band
Bacterial invasion of through the blood brain barrier
- Pneumococcal surface protein C binds to ____ receptor on brain endothelial cells
- Pneumococci can also enter in between ____ of endothelial cells
- Antigen Presenting Cells recognize bacterial components and release ____ proteins
• no one really knows how the bac crosses the BBB
◦ Pneumococcus: binding to Laminin protein on endothelial surfaces
‣ ____ on bacteria latches onto endothelial surface where it then releases MMPs to degrade endothelium + enter CSF
◦ Tight junctions can be degraded by bacterial enzymes + can enter this way
‣ (I apologize if this seems somewhat jumpy or unorganized he kinda just starts saying stuff then completely shifts his thoughts halfway through after reading his presentation notes on the comp)
◦ APCs in CSF recognize the bacteria through their ____ + release cytokines -> recruits neutrophils + create inflammatory response
• Question (can’t hear)
◦ this model for pneumococcus is kinda hypothetical because other mechanisms aren’t known but
assumed to be similar
laminin
tight junctions
proinflammatory
PSPC (pneumococcal surface protein C)
receptors
Deficiency in downstream signaling cascade have been associated with invasive pneumococcal disease, including meningitis
• ____ deficiency in children
• Appears specifically important at
____ age
• some children have a predilection for reoccurrence
• Receptors on APCs
◦ Toll receptors - recognize ____ or sugars from bacterial cell wall
‣ upon recognition causes cascade in APC -> production of cytokines that recruit other
inflammatory cells
◦ deficiency in any point in this pathway will prevent proper recruitment of cells
• back to children bullet
◦ IRAK-4 deficiency - predisposed to recurrent ____ infections + meningitis
◦ in children that have recurrent meningitis but intact IRAK-4, they have a ____ defect
‣ something along the cascade has association with recurrence
◦ children > ____ y/o do NOT have fatalities associated w/ bac meningitis + NO report invasive infections
in children > ____
‣ age-related deficiencies - important @ young age
◦
IRAK-4 young pneumolysin pneumococcal Myd88 8 q4
Bacterial meningitis can have lasting effects even after infection
• ____ damage, brain damage
• ____ loss
• ____ complications
• Recruited neutrophils cause damage to bacteria but also parenchyma + brain tissues
• ____ - direct cellular dmg to brain parenchyma
◦ long term: neuronal + Brain dmg
‣ hearing loss - not really clear how this is occurring but up to 30% of patients that have had bac meningitis experience uni or bi-lateral hearing loss which is often ____
‣ cochlear involvement may be direct result of CSF to the cochlear peri-lymphatic system
• Strokes
◦ pathogenesis is unclear but thought to be disregulation of ____ + coagulation pathways
neuronal
hearing
cerebrovascular
H2O2
permanent
fibrinolytic
Vaccination is a successful intervention for preventing meningitis globally, but there’s still work to do
- ____ virtually eliminated in high- income countries
- Pneumococcal ____ vaccination has resulted in significant declines in disease beyond age groups targeted for vaccination
- However, epidemics remain a threat in the meningitis belt countries in ____
• Pneumococcal conjugate vaccine
◦ made by linking small conjugate from bacterial sugar coat to protein that child’s immune
system can bind to
‣ ____ on bacterial coat canNOT be detected by child’s immune system so it needs to be conjugated to ____ that CAN be recognized- definition of conjugate
◦ “meningitis-belt” - likely still prevalent due to poor conditions of these countries
‣ difficult to diagnose b.c requires CSF which is expensive to do
‣ also, poor resources + ____ conditions create environment ideal for bac meningitis
H. influenzae
conjugate
sub-saharan africa
sugars
proteins
dusty
Encephalopathy is a term for any diffuse disease of the brain that alters function or structure • Infectious • Metabolic dysfunction • Tumor • Toxicity • Poor nutrition • Lack of oxygen
• Encephalopathy is a generalized term for a diffuse dx that alters function/structure
◦ Caused by many etiologies
◦ Hallmark = altered ____ state
‣ Some dx we discuss later -> clinical presentation = encephalopathy
• Other clinical presentations of enceph: cognitive changes, personality changes and inability to concentrate
◦ Muscle ____ is also seen with enceph
◦ Rapid voluntary ____ movement and tremor/muscle atrophy and weakness
• ____ studies can be used to differentiate bt infectious vs tumor causes of enceph
mental
twitching
eye
blood tests/imaging
Multiple sclerosis is a disease that destroys myelin that disrupts nerve • Early adulthood usually 20 to 40 \_\_\_\_ • Generally increases with increasing \_\_\_\_ from the equator • HLA-\_\_\_\_ • Vitamin D • Smoking risk • Obesity • Infectious • Epstein Barr virus
• We don’t know a lot about MS
• Tends to present early in adulthood, and thinks that it’s caused by geographic/environmental and
genetic factors
• Mainly found in europeans; rare in asians/AA/native Americans
◦ Higher in females than males (3:1)
• Correlation w higher latitudes; the further away from the equator > inc presence and incidence of MS is
found
◦ May be seen in association w lack of ____, but will be a combo of diff environmental factors, but vitamin D is consistent
• Genetic factors -> HLA-DRB1 is related to the prevalence of MS
• ____ has an increased risk for MS
• ____ is associated w a 2-3 fold inc in MS
• Infectious dx -> ____ is controversial, but it has been suspected as a trigger for MS
◦ May be related to ____, normally the bodies immune system attacks infectious
agents, so if a molecular part of your own body resembles a component on a microbe, then both molecules can be targeted by your immune system
‣ A particular protein on that EBV resembles the myelin protein -> so then this AI attack on myelin is triggered by an infection
females distance DRB1 vitamin D smoking obesity EBV molecular mimicry
The clinical courses of MS are purely descriptive
- Clinically isolated syndrome
- Relapsing remitting MS
- Reversible or irreversible
- Secondary progressive MS
- Irreversible
- Primary progressive MS
• MS is divided into different clinical courses, but there isn’t a diff prognosis for these courses
◦ Don’t get caught up in the granular details; be able to distinguish what’s going on bt MS and
Alzheimer’s (i.e., which dx is associated w demyelination in that sense)
• Onset of MS is characterized by an ____
◦ ____ episode of neurological dysfunction due to the demyelinating lesions in the optic nerve (also seen in spinal cord, brainstem and cerebellum)
• A lot of other CNS diseases can present w this so its not ____ to diagnose MS
• You have that pre-symptomatic CIS stage that has that initial presentation (???)
◦ During the disease course of relapsing remitting MS there are further clinical episodes that occur known as ____, and these relapses last for more than 24 hour and occur in ____ of fever and infection
‣ This is where MS can ____ to be suspected
• Symptoms of a clinical attack in relapsing remitting MS tend to show an ____/subacute onset that can worsen over days/weeks
◦ Characterized by occurrences of relapses that occur at irregular intervals that occur w either incomplete or complete neurologic recovery
‣ ____ onset of clinical symptoms -> describes relapsing/remitting MS
• If this continues -> secondary progressive MS -> onset of symptoms are ____
◦ Permanent neurologic defects -> progressive clinical disablity
• Minority of patients have primary progressive MS -> from the start bypass all of the ____ MS and start w perm neurologic deficits for more than a year without relapses
◦ Separate clinical presentation
initial clinical attack (CIS)
unpredictable
easy
relapses absence start acute unpredictable irreversible CIS and relapsing/remitting MS
Neurologic dysfunction of multiple sclerosis is variable and depends on the ____ of demyelinating lesions
• Optic neuritis
• Central scotoma
- Sensory symptoms
- Spinal cord
- Lhermitte’s sign
- Brainstem/cerebellar
- Hearing loss
Optic neuritis ◦ Is the first episode in a large number of patients ◦ Total visual loss in \_\_\_\_ eye ‣ With a \_\_\_\_ spot ◦ Deficiency in color vision ◦ Or pain w eye movement
Sensory symptoms
◦ ____ inflammation
‣ Parasthesia = ____ sign
• Electric shock down the spine when flex the ____
• Seen in sensory symptoms of MS
◦ Reduced pain and light touch sensation -> can worsen w inc body ____
◦ Damage to the brain stem/cerebellar region
‣ Symptoms: facial ____, sensory loss, hearing loss or nausea
◦ Depending on where the damage of the myelin occurs -> corresponds to where the symptoms are
that these patients experience in MS
location
one
blind
spinal cord lhermitte's neck temp numbness
Motor manifestations affect almost all patients during the course of the disease
• Motor manifestations
• Spinal cord
• Brainstem and cerebellar symptoms
Motor manifestations are often characterized by pyramidal signs -> involving cortical spinal tract Classic motor manifestation of MS is the ____ sign and ____ (muscle spasms that have stop- and-go flexing of the muscle)
Shows a video of Babinski sign
◦ 1:04:30 for the video
‣ When touch rod on bottom of foot -> babinski sign the toes curl ____ and the toes
____ (as opposed to the normal toe curling forward reflex) -> indication of a CNS defect
‣ Clonus is another sign of MS -> when dorsiflex the foot -> see a continual ____ (1:07:30)
-> indicates CNS damage
• After an ischemic stroke, so this is a ____ sign but can be indicative of CNS
dysfunction
• Above were the motor symptoms you can see in the spinal cord, in the brain stem has different manifestations:
◦ Involuntary ____ movement - nystagmus (1:09:00 for a video) ◦ Visual phenomena -> objects in visual field oscillate
◦ Double vision
‣ CN ____ palsy
‣ CN VI innervates lateral rectus -> when not contracting properly the eye turns inwards ____ the nose (1:09:30 for a video)
• “Right CN VI palsy; looks straight ahead the right eye is deviated ____, when looks
right the right eye hardly moves, when looks to the left both eyes move ____”
◦ Lose muscle control in arms/legs -> gait disturbance, imbalance and poor coordination
‣ ____ - pt has a hard time turning (video at 1:12:30), and has a tough time touching his nose and then the practitioner’s finger
◦ Develop ____ speech
◦ Loss of complex movements
babinski clonus backwards spread spasm non-specific eye VI towards
inwards
normally
ataxia
slurred
Other symptoms of multiple sclerosis
• ____ impairment
• Fatigue
- ____
- Trigeminal neuralgia
Can have cognitive impairment
Fatigue is also a symptom that occurs in a majority of MS patients
◦ Unclear whether it’s due to the insomnia that MS patients also experience Pain is also another feature of MS
◦ Trigeminal neuralgia
‣ Compression of a neurovascular bundle > pressing on CN V leading to the symptoms of
trigeminal neuralgia
• Paroxysmal spasm and intense pain with the ____ of triggers (feather, blow of wind
can trigger)
• Usually ____
• More common to ____ branches
‣ A lot of clinicians tend to use trigeminal neuralgia as a waste basket diagnosis for ____ pain
cognitive
pain
lightest
unilateral
V2 and V3
TMJ
Pathophysiology of multiple sclerosis involves multiple cells secreting inflammatory mediator • T cells • CD4+ • CD8+ • Microglia • Bcells • Macrophages • Astrocytes
- Active lesion
- Inactive lesion
• Thought that you have abnormal T cells from the periphery that come to the CNS and BBB, release ____ and enter the CSF
◦ Microglia then release factors (____) -> stim T cells to release additional cytokines -> persistent inflame process that destroys the myelin
• Also thought to be involved are B cells -> inc ____ production in the CNS and they ____ T cells to the CNS themselves
◦ The B cells have abnormal property in producing proinflam cytokines, and lack ____ cytokines that hamper the cytokine release, so they’re constantly creating an inflam environment
• Healthy individuals have low levels of ab in the CS, but MS patients have abnormally increased production of levels of ____ in the CNS
• Macrophages are involved in that they engulf myelin, exposing the axonal surface -> releasing ____ -> cell damage
• Astrocytes release additional ____ to this cytokine-heavy environment -> adding to the inflame response, and can limit the ____ process that is trying to occur to hear the damage
• The inflame process can prevent the oligodendrocyte ____ cells from helping to repair MS
• In the ____ stages -> characterized by active lesions -> all cells release cytokines, so under the
microscope you see a lot of inflame and cell activity
• In the ____ stage -> plaques reach the burn out stage -> inactive lesions that are scar tissue
MMPs cytokines ab attract regulatory ab
free radicals
cytokines
precursor
early
late
Pathologic hallmark is the development of focal plaques which are areas
of demyelination
• ____ can assess disease activity and
treatment efficacy
MRI
Alzheimer’s is a progressive disease characterized by temporal and parietal lobes dysfunction
• Loss of ability to carry ____
• Seriously affect person’s ability to carry out daily activities
• Symptoms can first appear after age of 60
• Risk increases with ____
• Clinical presentation is older people getting lost or an inability to deal with the new situations (???)
• Basic mundane activities become a challenge for these types of patients
• Final stages may result in deterioration of cognition or loss of mobility, and in severe cases mutism
• Affects older patients, but this is a dx of ____ lobes
◦ Temporal lobe dysfunction w impairment of ____ is the first stage
◦ Later, parietal lobe dysfunction characterized by poor ____ and inability to speak or talk
• Alzheimer’s is the main ____ syndrome
conversation age temporal and parietal memory coordination tempero-parietal
The causes of Alzheimer’s are unknown, but suspected to be multifactorial
• ____ is definitely a risk factor
- Family history, i.e. genetics
- ____
- Education, diet, and environment
- Risk factors for ____ disease and stroke
- Poor oral health? Oral bacteria?
- Physical, mental, and social activities may ____ the risk
• Like MS, the real cause is not known but it is thought to be multifactorial
◦ Uncommon in young people, and seen in older people; however, there are genetics behind
Alzheimer’s and we’ll see how it affects younger people
• Genetic component thought to be involved -> ____, and ____gene is thought to be
involved
• Oral hygiene may be linked with Alzheimer’s disease
◦ May be a result of infection by P gingivitis; it produces ____ which is an enzyme that degrades cytokines -> gives rise to ____ proteins that are found in Alzheimer’s
◦ Take w a grain of salt -> experiments done in mice, be cautious of the conclusions
• Gingipains can cause damage to brain cells, but there’s no evidence linking it to Alzheimer’s
◦ Still need to be cautious of this link
age
presenilin-1
heart
reduce
presenilin-1
apolipoprotein E
gingipains
misfolded
Diffuse gyral ____ and ventricular ____ is a common gross finding in Alzheimer’s
• Brain weight can be ____
• ____ cortex, ____, ____, and ____ cortex are most affected
From a post-mortem finding in an Alz brain -> thinning of gyro and sulci ◦ L = normal; R = degenerative changes
Cross-section of normal brain, the sulci and gyri have characteristic changes for Alz
atrophy
dilatation
decreased temporal amygdala hippocampus entorhinal
Alzheimer’s Disease is characterized by histologic abnormalities, but these are not pathognomonic • \_\_\_\_ deposition • \_\_\_\_ • \_\_\_\_ threads • Loss of \_\_\_\_
• What makes the diagnosis of Alz? ◦ Reads list
◦ NFTs are the hallmarks of Alz disease
amyloid B
neurofibrillary tangles (NFTs)
neuropil
synapses
Amyloid β clump together to form plaques in brains of people with Alzheimer’s disease
- Defective clearance of ____
- Amyloid deposition in arteries and arterioles
- Diffuse deposits of amyloid β (____ stain)
- Amyloid β is ____ to neurons
• Amyloid beta deposition in Alz dx, and it’s really the defective clearance of this protein compound (amyloid B)
◦ Amyloid B is a part of a larger precursor -> ____
◦ Enzyme is failing to properly digest APP -> misfiled proteins that deposit within the brain -> helpful
in making the diagnosis for Alz
• Deposition of amyloid material in the ____ walls, and in the brain parenchyma
• Can see in H+E and also in silver stain (black circles)
• When amyloid B is present -> damage to synaptic clefts and can kill the neurons
amyloid B
silver
toxic
amyloid precursor protein
vascular
Neurofibrillary tangles are deposits of tau protein in the neuronal body
- Intracellular accumulation of ____ protein
- When tau proteins accumulate in ____, they are neuropil threads
- Cognitive decline correlates better with NFTs than with diffuse plaques
NFTs are the other pathological findings in Alz, and the accumulation of tau protein (??)
◦ Tau proteins are ____ associated proteins
◦ In the early stages, the tau protein has a more diffuse deposition pattern
◦ In the established stage -> tau becomes abnormally ____ -> form paired helical
filaments -> tangled morphology in the neuron body
◦ When you see the same process happening in dendrites -> called neuropiles
Through time, this process kills the neurons -> cellular debris is removed, but the tangles and filaments ____; this is what you’re seeing on pathology (???)
◦ Collection of tangled bits
NFTs compared to amyloid B -> better correlation w cognitive decline when it comes to the brain
◦ Even in patients without Alz you still see these ____, but there is a characteristic finding in post-molten Alz-diseased brains
tau
dendrites
microtubule
phosphorylated
remain
changes
No ____ lab tests for Alzheimer’s Disease
- ____ history
- Neuroimaging
- ____ scan
• Specific ____ of NFTs and amyloid plaques along with history of dementia
• Autopsy will help w the diagnosis
• Can try taking CSF and look for tau/amyloid B
• Pts w a strong family history may have genetic testing
• fMRI is one scan that is done, but the PET scan looks at the ____ metabolism of brain
◦ Normal setting the brain metaboliczes a lot of glucose, but in Alz they use ____ glucose and the PET scans can shows areas of decreased glucose metabolism
◦ Early diagnosis is difficult bc the changes in glucose are much more subtle
• L is a normal brain and red shows glucose metabolism, and in Alz the pattern of glucose metabolism is
much less and different
• Despite the lack of lab testing -> rely on the location of NFTs and amyloid plaques along w a history of
dementia in order to give a loose framework of the diagnosis of Alz disease
definitive
family
PET
location
glucose
less
Genetics of Alzheimer Disease
• Early-onset Alzheimer’sDisease
• ____
- Late onset Alzheimer’s disease
- ____ and genetic factors
- ____ gene(APOEε4)
• Alz disease is primarily a disease of the elderly, but there is an early-onset version ◦ The genetics involve presenilin 1 and 2
‣ Involved in the breakdown of ____ -> overproduction of amyloid B peptide
‣ Having this mutation has an association with early-onset Alz
• Classic late Alz has a combination of environmental and genetic factors
◦ APOE -> responsible for producing the lipoprotein
‣ Patients w ____ has an inc risk in Alz disease
• APOE are involved in ____ disease processes
presenilin 1 and 2
environmental
apolipoprotein E
APP
hypercholesterolemia
both
Will we ever cure Alzheimer’s? (Pam Belluck The New York Times)
• Drugs targeting misfolded proteins have largely failed in clinical trials
• No drugs have stopped or reversed ____
• Damage to brain in people with Alzheimer’s can begin decades before dementia
• SO much money has been invested in addressing amyloid proteins as a way to cure Alz -> they work fantastically, but don’t do anything regarding ____
◦ By the time the dementia occurs -> late stage changes -> becomes irreversible
dementia
dementia
“A possible Alzheimer’s treatment with clicks and flashes? It worked on mice” (Pam Belluck The New York Times)
• Li-Huei Tsai and her colleagues showed light and sound delivered at ____ Hertz or 40 flashes per second appears to synchronize the brain’s ____ waves
• Increased activation of ____ cells, removing plaques
• Certain light and sound frequencies activate the microglial cells -> have a phagocytic characteristic ◦ Produce sound at 40 Hz or 40 flashes per second -> stimulates microglial cells to clean up
proteins in the brain
40
gamma
microglial
Which of the two children shows clinical signs for acute lead poisoning?
• No ____ symptoms
• There is no ____ level for lead
• ____ children are susceptible
• Now we’re going to discuss the metabolic and toxic effects on CNS
• There are not acute symptoms for acute lead poisoning
◦ Exposure to lead is known as a ____ pediatric epidemic ◦ There is no safe level for lead
‣ Usually from inhalation of lead particles or ingestion from lead-contaminated dust or pipes; also in lead paint in homes built before 1978
• Children are more susceptible bc they absorb lead ____x more than adults
◦ Profound permanent adverse effects from lead exposure
◦ Not so much the acute presentation but the long term effects -> behavioral changes and IQ
decline
• Children at greater risk are those living in old housing or in poverty
◦ Outside of the US -> lead poisoning in countries that do battery recycling -> lead seeps into the dust, and then in dry climates it gets sent into atmosphere
◦ Countries in Africa, children have experienced lead poisoning
acute safe young silent 4-5
The central nervous system of children are especially susceptible to lead intoxication • Central nervous system changes • \_\_\_\_ • Ataxia
- Behavorial
- Non-CNS changes
• Once lead enters the body -> distributed to diff organs -> brain, liver, kidneys and bones
• In pregnant situation, women exposed to lead, the lead stored in bone can be remobilized into the
blood during ____
• ____ children are more susceptible -> body absorbs more of that lead if other nutrients are not
available
• ____ when there is lead exposure and when consequences are seen -> manifest in school issues or
behavioral problems
◦ Lead associated w delinquent behavior and deficits in IQ, although we don’t understand why that
is happening
• High levels of lead can be associated w ____ in children
◦ Can present as hyper-irritability, ataxia, convulsions as well as stupor, coma and death
◦ When blood levels exceed ____ ug/dL -> when children need to be admitted to the hospital
‣ Treatment is ____; to take the lead out of the body
• Although the lead is taken out, the chelation doesn’t change the ____
outcome, the damage has already been done
◦ Small window of exposure can lead to permanent irreversible damage
Chronic lead exposure can involve non-CNS changes
◦ Pt here presents w oral manifestations of lead exposure
◦ Arrow shows the bluish line -> ____ line
‣ Blood levels of ____ ug/dL of lead
‣ The lead is reacting w the metabolites of the oral bacteria -> discoloration of the gum ◦ Where do you think the lead came from?
‣ Chewing ____
• Whoever he was buying from, tried to make the product heavier by adding lead to it
(“cutting it”)
hyperirritable
pregnancy malnourished time lag encephalopathy 40 chelation neuordevelopmental
bruton’s
100
opium
Lead likely targets learning and memory processes of the brain by inhibiting the ____
• Lead is a ____
• Calcium signaling
• NMDA is an AA derivative that acts like ____ which normally binds to these receptors (???)
• NMDA is a receptor that is activated by the NT glutamate
◦ When activated at the synoptic cleft -> entry of ____, ____ and ____
◦ Critical for the development of the process of learning, memory and neuroplasticity
◦ Known to be responsible for converting patterns of neuronal activity into ____ memory
‣ When you have lead come in -> a non-competitive antagonist, it stays attached to the NMDAR and they can no longer function (hypo function)
‣ Leads to impairment in learning, memory loss all due to the characteristic of lead being a non- competitive antagonist
‣ Getting the lead out of the blood system will not reverse the neurologic damage happening to children
N-methy-D-aspartate receptor (NMDAR)
non-competitive antagonist
glutamate calcium sodium potassium long-term
Myasthenia gravis is a chronic autoimmune neuromuscular disease that causes weakness in the ____ muscles
• Most common in ____ adult
women (younger than 40)and ____ men (over 60)
• Nearly always includes the ____ muscles, with ptosis and diplopia
• Difficulty breathing
• ____
• Mysathenia gratis is characteristic of muscle weakness that worsens after exercise/physical activity, once you rest the symptoms improve
• Reads the slide
• In addition to the eye symptoms -> ____ speech, difficulty swallowing, chewing fatigue and neck/
limb weakness
• When difficulty in breathing occurs -> crisis of MG -> intercostal muscles in diaphragm weaken and
patients have a difficult time breathing
• Tymoma
◦ ____ tumor of thymus gland
◦ MG patients have to be concerned about
skeletal young older eye thymoma
slurred
benign
In myasthenia gravis, antibodies are directed against the components of the postsynaptic muscular membrane • \_\_\_\_ receptors • \_\_\_\_ • \_\_\_\_ • \_\_\_\_
- Blood tests can detect antibodies and help diagnose subgroups
- Thymoma
• What’s happening on a cellular level?
• As an AI disease -> ab’s directed towards acetylcholine receptors at the NMJ (responsible for
movement of skeletal tissue) -> explains the clinical symptoms associated with it
• In addition to the acetylcholine, there are MuSK that are involved in ab destruction -> important for the ____ of acetylcholine receptors as well as NMJ formation -> when MuSK is destroyed you can see
the symptoms of MG
• LRP4 is the other component of the MuSK protein, this can also be affected in MG by AI destruction
• Rapsyn is a post-synaptic membrane protein that helps w the ____ of acetylcholine receptors;
these can also be destroyed
• There’s a way to classify MG, and it’s based on which receptor is being destroyed
◦ ____ can help figure out the different subgroups
acetylcholinesterase
muscle-specific kinase (MuSK)
lipoprotein receptor-related peptide 4
rapsyn
clustering
clustering
blood tests
Treatment depends on the sub-group of myasthenia gravis
- AChR+
- MuSK+
- LRP4+
- Ocular
- Thymoma MG versus non-thymoma
- Early onset versus late onset
• These subgroups help dictate treatment
• If the AChR are the ones being destroyed -> can have clinical signs that are different from a receptor
where you have MuSK that is being primarily destroyed
◦ In acetylcholine receptors, characterized by ____ weakness and ____ weakness w the
fluctuations in muscle strength -> classic MG
• Can also classify MG patients where the AChR are fine, but the immune system is destroying the MuSK
receptors (MuSK+)
◦ Predominately affect ____
◦ Increased risk in generalized dx -> some patients only get symptoms of the eye (droopiness); but
when it becomes generalized it goes from ____ to overall muscle weakness (more severe
weakness than of the classic type [???])
◦ More common in the ____ areas of Europe
limb ocular women droopiness meditterean
Treatment depends on the sub-group of MG
• Skips LRP4 because of time
• Can also group MG into ocular
◦ Involves ____ and the ____ groups
‣ No MuSK+ group
• Thymoma group
◦ Indicates patients will need removal of the thymus bc of the likelihood of developing a thymus tumor
◦ ____ and ____ antibodies are usually not associated with the thymoma group
- Early onset more likely to be ____
- Late onset is more likely to have a ____ population and have ____ and ____ type of MG
• Last group is seronegative (grey)
◦ Have all symptoms of MG -> but their blood doesn’t show any ____ to any receptors we talked about
• “Won’t test knowing which group falls into which”
◦ “NO - so sadistic, why would I want you to know that?”
◦ I want you to appreciate that MG has moved from Ach destruction to a more granular disease that
has subgroups that have implications in treatment
AChR+
LRP4+
MuSK
LRP4
female
generalized
ocular
non-thymoma
antibodies
Different treatment modalities exist for myasthenia gravis
- Anticholinesterase medication
- Immunosuppresive drugs
- Steroids
- ____
- Thymectomy
- Myasthenic crisis is an emergency
- Avoid certain pharmacology
- Muscle relaxants
- Antibiotics
rituximab
• Some patients go a long time without having an actual ____
• “I’ll let you read over this”
• Patient was sent from specialist to specialist
◦ MG is a subtle dx w a progressive presentation of symptoms, so diagnosis can take a very long time
◦ If you have seronegative case -> will further delay appropriate diagnosis
diagnosis
In the peripheral system, all axons are enveloped by ____ cells
• ____-diameter fibers are wrapped by concentric layers, i.e. myelin sheath
• Concentric layers of Schwann cell plasma membrane rotate around axon
schwann
large
Each Schwann cell covers only a segment of an axon
• Axon is insulated with ____ membrane layers
• Myelin prevents ____ fluxes across the axon membrane
lipid
ion
Peripheral nerves are composed of ____ of nerve fibers
• Within each fascicle, there isa ____ fiber and ____ cell
• Adjacent vessels provide ____ supply
fascicles
nerve
schwann
blood
Individual myelin sheaths are seen as small round structures
• Most of the nuclei seen are ____ cell
• Fibroblasts are also present from connective tissue surrounding the bundles
• In tumors, these cells can become neoplastic
• IN black is the fascicle, and the smaller round bits are the axons and each blue dot is a Schwann cell
◦ The ____ cell can become neoplastic
schwann
schwann
Wavy shape of the Schwann cell nuclei help identify nerve tissue
• Nerve fibers follow a wavy ____ pattern in ____ section
• Difficult to distinguish between ____
Nuclei of a Schwann cell is spindle shaped and wavy
Can distinguish from a fibroblast by looking at the context
◦ The black demarcation signifies a different type of tissue then the surrounding fibroblast ◦ The red dot is the nuclei which corresponds (???)
zigzag
longitudinal
fibroblasts
- Although they may look the same close up, stepping back and appreciating the larger context can help you appreciate the different cell types
- Presentation of a patient in your chair, one differential diagnosis can be a ____ disease process
neural
Traumatic neuroma is not a true neoplasm but a ____ proliferation of neural tissue
• Smooth-surfaced, dome-shaped papule, usually less than one cm.
• Tongue, buccal ____ are often affected
• May be tender on ____
• Traumatic neuroma is not a neoplasm but a reactive response
◦ Following surgery, nerves are cut and that regeneration process will often be okay, but occasionally
will hit ____ tissue or will not properly regenerate or form a tumor-like mass
reactive
vestibule
palpation
scar
Schwannoma is a benign neural neoplasm from a Schwann cell
• ____ tumor
• Oral schwannomas
• Rare ____ transformation
• Convey that this is a schwannoma
◦ Neoplastic process of Schwann cell
◦ Can occur in mouth and within ____
◦ Rare for ____ transformation
encapsulated
malignant
bone
malignant
