Pathology Flashcards
THE hallmark of all the neurodegenerative diseases
Loss of neurons
- Expanded ventricles (“hydrocephalus ex vacuo”)
- Narrow gyri and wide sulci
- Widespread neuronal loss, worst in the hippocampus**
- Generalized cortical atrophy
Alzheimer’s
TAU (gene MAPT) is a component of ____________.
microtubules
Taupathies involving neurons and their processes only: (2)
- Alzheimer’s dz / old age
- Chronic traumatic encephalopathy (boxer’s dementia)
Taupathies involving both neurons and oligodendroglia: (5)
- Classic Pick’s dz (i.e., with real tau-based Pick bodies)
- Progressive supranuclear palsy
- Corticobasal degeneration
- The Pick’s-plus-Parkinsonism (FTDP-17) from mutated tau
- Argyrophilic grain dz
Alpha-synuclein (gene SNCA) pentamers are located in (pre/post)synaptic terminals.
PREsynaptic
Synucleinopathies involving neurons: (3)
- Classic Parkinson’s dz
- Cortical Lewy body dementia
- Parkinson’s with mutated synuclein
Synucleinopathies involving both neurons and oligodendroglia: (1)
Multiple systems atrophy (*Papp-Lantos inclusions)
Amyloid precursor protein may be degraded abnormally to form _______ ____, which is central to 4 major diseases.
amyloid beta
Amyloid beta diseases of neurons and vessels: (2)
- Alzheimer’s dz
- Chronic traumatic encephalopathy
Amyloid beta diseases of vessels only: (1)
-Some versions of congophilic angiopathy
Amyloid beta diseases of skeletal muscle: (1)
-Inclusion body myositis
Diseases of neurons involving TDP-43 (TAR DNA binding protein, TARDBP): (2)
- TDP-related frontotemporal dementia
- Many cases of amyotrophic lateral sclerosis (ALS)
Many (but not all) pts with TDP-43 inclusion-related dz have mutations of: (3)
- TDP-43
- Progranulin (frontotemporal dementia only)
- C9orf72
FUS (“Fused in Sarcoma”) diseases involving neurons: (2)
- FUS-related frontotemporal dementia
- FUS-related cases of amyotrophic lateral sclerosis
Polyglutamine inclusions are seen in the nucleus in dz’s caused by genes with long polyglutamine-coding trinucleotide repeat regions: (3)
- Huntington’s chorea
- Several of the spinocerebellar ataxias
- Kennedy’s spinobulbar muscular atrophy
- MC dementia
- Incidence increases with age
Alzheimer’s dz
Certain mutations in ___ produce a more amyloidogenic product. The protein is on chr.21 and perhaps this is why Down’s adults usually get Alzheimer’s in their 40’s.
APP
Senile plaques are masses of A-beta amyloid in the neuropil, surrounded by neurites containing tau. Seen in:
Alzheimer’s
TQ: _______________ _______ stain with silver (binds to the phosphate). In tall neurons, they can look like flames. Seen in:
Neurofibrillary tangles
-Alzheimer’s
TQ: Neurofibrillary tangles and neuritic plaques. Silver stain. You think…
Alzheimer’s
Granulovacuolar degeneration. You think…
Alzheimer’s
Amyloid (congophilic) angiopathy. Almost all pts have amyloid in vessels and bleeding can occur. You think…
Alzheimer’s
Tomorrow’s tests for Alzheimer’s dz: (2)
- Diffusion tensor imaging (DTI)
- Serum clusterin
In addition to the selective atrophy of frontal and anterior temporal lobes (sparing of superior temporal gyrus), microscopy often shows balloon neurons.
Classic Pick’s dz
Frontotemporal dementia
- MC illness among a group in which cells are lost from the nigrostriatal system
- resting tremor (“pill rolling”), rigidity, mask-like face, cogwheel rigidity
- Alpha-synuclein-rich Lew bodies are found in the substantia nigra and locus ceruleus
Parkinson’s dz
Lewy bodies in substantia nigra with only a few neurons remaining. You think…
Parkinson’s dz
Clinically, parkinsonism and/or bizarre behavior. Pathologists look for NFT’s.
Parkinson’s Variant: Dementia Pugilistica / Chronic Traumatic Encephalopathy
A taupathy involving primarily the substantia nigra and other subcortical structures. Look for globose neurofibrillary tangles.
Progressive Supranuclear Palsy (PSP)
A taupathy with tau-containing inclusions in both brainstem and cortex
Corticobasal Degeneration
- Alpha-synuclein inclusions in the glia (esp oligodendroglia) and more damage to the white matter
- “Hot cross bun” sign on T2 results from selective loss of the pontine raphe nuclei
Multiple System Atrophy (MSA)
- Cerebral cortex tends to be spared
- Pts have trouble moving their eyes, especially looking down
- Trucal rigidity and falls are more of a problem than tremor
Progressive Supranuclear Palsy (PSP)
“Globose” neurofibrillary tangles in the substantia nigra
PSP
Tau “smoke puffs” around an astrocyte - the pathognomonic “astroglial plaque”
Corticobasal Degeneration
Tau coils next to neuron nuclei
Corticobasal Degeneration
- Same pathology as striatonigral degeneration with the addition of damage to some autonomic neurons in the cord
- Cause of orthostatic hypotension
Shy-Drager (MSA type A)
Tiny basis pontis
MSA-C
- Relatively common dz that mimics Alzheimer’s but with a faster course, visual hallucinations and paranoia
- Lewy bodies are seldom numerous, and it’s through that the damage is done by small aggregates of alpha-synuclein
Lewy body dementia
- Autosomal dominant, full-penetrant dz with genetic anticipation
- Caused by a CAG trinucleotide-repeat mutation at HTT (huntingtin)
- The polyglutamine protein accumulates in the nucleus and causes loss of neurons, esp in the caudate**
- Pts present with emotional changes, a curious dance-like movement disorder, and eventually dementia
Huntington’s dz
- The neurons of portions of the hippocampus die off and are replaced by glia
- Not treatable
- Younger patients tend to have a history of seizures
Hippocampal Sclerosis
- Striatonigral degeneration
- Putamen takes the worst damage
MSA type P
- Flattening / loss of head of caudate
- Polyglutamine in the nucleus
Huntington’s dz
- Develops around age 10
- Mutation in Torsin A (DYT-1)
Dystonia Musculorum Deformans / Torsion Dystonia
- Caused by mutated frataxin, which allows iron overload within mitochondria
- Posterior columns and corticospinal tracts are gone
Friedreich’s Ataxia
- Autosomal recessive dz caused by defective ATM (11q22-q23), involved in the repair of DNA breaks and more
- Purkinje and granular cells are lost from the cerebellum during childhood, esp the vermis
- Hypoplastic thymus with defective T-cell immunity
- Prominent arteries (“telangiectasias”) esp on eye surfaces
Ataxia-Telangiectasia
“Louis-Bar dz”
- Involves disappearance of both UMNs and LMNs
- Fasciculations in the tongue
- Best-known gene SOD1 - superoxide dismutase
- Pyramidal motor cells gone
- Hypoglossal nucleus gone
- Anterior horns and corticospinal tracts lost
- Bunina bodies present
- Many but not all of these pts have mutated germline FUS and an early onset
Amyotrophic Lateral Sclerosis
“Motor Neuron dz”
- X-linked recessive dz with genetic anticipation and polyglutamine causing a toxic product
- Lesion is in the androgen receptor
- Both UMN and LMN lost
- Milder than ALS
Kennedy’s spinobulbar muscular atrophy
TQ:
- Autoimmune inflammation and demyelination of CNS
- Pts can present with optic neuritis
- Essential lesion = “yellow/jaune plaque”
- Relapsing and remitting course
- Most often affects women in their 20s and 30s, more common in whites
- Periventricular plaques **
- Link to HLA-B15 and DQ6 **
- Myelin destroyed, axons spared
Multiple Sclerosis (MS)
- Immunity against myelin that tends to follow viral illness
- Myelin loss is widespread and diffuse
- “T-cell rampage”
Acute disseminated encephalomyelitis
- Immune attack on brain’s myelin and blood vessels
- Neutrophils ARE involved
- Outcome is usually death or severe disability
Acute necrotizing hemorrhagic leukoencephalitis
-Caused by antibodies against glutamic acid decarboxylase
Stiff person syndrome
- “Duck foot Purkinje cells”
- Zebra bodies
- Deposits in the intima
Hurler’s
TQ:
- Lysosomal storage dz, MC due to arylsulfatase A deficiency
- Accumulation of sulfatides leads to impaired production of myelin sheath
- Acid cresyl violet stain - stains sulfatides (in histiocytes) brown
Metachromatic leukodystrophy
- Myelin gone from white matter
- Lysosomal storage dz due to deficiency in galactosylceramide
- Causes accumulation of abnormal lipids within myelin
- Peripheral neuropathy, developmental delay, optic atrophy, “globoid histiocytes”
Krabbe’s leukodystrophy
-Can’t break down GFAP
Alexander’s
-Loss of EIF2B complex, which prevents cell death from minor stress
Vanishing white matter dz
- Aspartoacylase deficiency…
- Causes accumulation of aspartic acid in white matter of the brain, esp right under the cortex…
- Pulls water in by osmosis, unraveling the myelin and making a bubbly appearance
Canavan’s dz
- X-linked genetic disorder typically affecting males
- Disrupts metabolism of very-long-chain fatty acids…
- Leads to buildup in nervous system, adrenal gland, and testes
- Lack gene ABCD1
Adrenoleukodystrophy
- Portions of brain are affected by accum of lactic acid, and there is a mild mitochondrial myopathy
- Little strokes may result
MELAS
Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes
-Mitochondrially inherited, often with a tRNA synthetase
MERRF
Myoclonic Epilepsy and Ragged Red Fibers
- Result of mutations that prevent proper oxidative phosphorylation
- Symmetric, widespread destruction of the brain results
Leigh’s subacute necrotizing encephalopathy
Bleeds in mammillary bodies
Wernicke’s (acute)
TQ: Shrunken, discolored mammillary bodies.
Wernicke’s (old)
Hemorrhagic necrosis of the putamen
Methanol toxicity
Necrosis of the globus
Carbon monoxide toxicity
- Miners and foundry workers
- A movement disorder which combines Parkinson-like symptoms and dystonia
- Unlike true Parkinson’s dz, the major damage is probably to the globus pallidus
Manganese toxicity
- Garlic breath
- Symmetric CNS necrosis
- Necrosis of GI epithelium
- Stocking and glove neuropathy
Arsenic poisoning (acute)
- Garlic breath
- Pigment (neck, armpits, nipples)
- Muscle weakness
- Increased keratin on palms
- Mee’s lines (after 6 weeks)
- Numbness, worst in legs
Arsenic poisoning (chronic)
Copper in basal ganglia
Wilson’s
Caused by pantothenate kinase deficiency
Brain iron accumulation type I
Indirect bilirubin can cross the newborn’s brain and high levels can cause damage
Kernicterus
Methotrexate increases the risk of:
Radiation necrosis
Carboplatin and anti-Hu may cause a ______________ - dorsal root ganglion cells are killed.
neuronopathy
- Loss of proprioception and vibration
- “Fall in the dark”
Large fiber neuropathies
-Loss of pain and temperature, perhaps paresthesias / pain
Small fiber neuropathies
Mononeuritis multiplex. Think…
Vasculitis or vasculopathy
-Lupus, Sjogrens*, and hep C can all produce either a vasculitis or a polyneuropathy
- Autoimmune condition that destroys Schwann cells
- Causes inflammation and demyelination of peripheral nerves and motor fibers
- Illness is often preceded by an infection, famously CMV, campylobacter, H. flu
Guillain-Barre Acute Inflammatory Demyelinating Polyneuropathy
- Bacteria grow inside the Schwann cells
- Loss of pain/temp
- Tendency not to notice injuries is famous
- Tuberculoid form more likely to see anesthetic, hypopigmented patches*
Leprosy (Hansen’s dz)
-Produces an axonal neuropathy by molecular mimicry between the microbe and an axonal protein
Lyme dz
- MC and most complex of the peripheral neuropathies
- Attributed to products of non-enzymatic glycosylation but not fully understood
- Axons, myelin, and vessels are all involved
- Symmetric sensorimotor neuropathy
- Starts distally
Diabetic neuropathy
- Family of variously-inherited dz’s in which the longest nerve fibers die off first, either from failure of the myelin or the axons
- Mutations in the essential proteins of myelin
Charcot Marie Tooth
TQ:
- In children, most often found in posterior fossa (e.g., cerebellum)
- Risk factor = neurofibromatosis type I (NF1)
- Usually feature mutated BRAF
- Contain Rosenthal fibers
- GFAP(+)
- Benign, good prognosis
Pilocytic astrocytoma
grade I astrocytoma
TQ:
- Common, highly malignant primary brain tumor
- Found in cerebral hemispheres
- Pts usually present with headaches, personality changes and/or seizures
- 1-year median survival
- “Pseudopalisading” pleomorphic tumor cells around area of necrosis
Glioblastoma multiforme
grade IV astrocytoma
____ is amplified or point-mutated in about 50% of primary glioblastomas.
EGFR
epidermal growth factor receptor
The big new discovery is that most gliomas (90% of glioblastomas) bear a point mutation in __________ ____________.
isocitrate dehydrogenase
-Leads to production of 2-hydroxyglutarate, which alters epigenetic controls
The MC change in both primary and secondary glioblastomas is loss of heterozygosity on:
10q (PTEN)
TQ:
- Most often affects younger adults
- Grade II tumor
- Pts with NF1, NF2 or Li Fraumeni are at extra risk
- Tame-looking cells, lots of fibers
- These tumors often bear TP53 mutations and/or loss of 17p
Diffuse astrocytoma
What gene, if knocked out, makes the glioblastoma more vulnerable to the alkylating agent temozolomide?
MGMT
methylguanine methyl transferase
TQ:
- Grade III tumors of astrocytes
- Distinguished by increased cellularity, nuclear atypia, and mitotic activity
- Risk factors same as diffuse astrocytomas, many have 9p loss
- Majority of these tumors transform into glioblastoma within two years
Anaplastic astrocytoma
TQ:
- Relatively rare, slow growing
- Grade II tumors
- Most often in frontal lobes, but usually in cerebral hemisphere (headache, seizure, personality change)
- “Fried egg” cells**
- Often calcified
- Only known risk factor = old radiation
- Loss of 1p and 19q
Oligodendroglioma
TQ:
- Grade II tumors
- MC primary tumor of spinal cord, but most commonly found in 4th ventricle*
- Most pts are children and young adults
- Characteristic perivascular rosettes
- Rod-shaped blepharoplasts (basal ciliary bodies) found near nucleus
Ependymoma
- Grade I tumors
- On the cortex
- Seizures
- BRAF V600E
- Surgery is curative
Ganglioglioma
- Grade I tumors
- Children with seizures
- Surgery is curative
Dysembryoplastic neuroepithelial tumors
- Grade II tumors
- Walls of ventricles
Central neurocytoma
TQ:
- Highly malignant cerebellar (vermis) tumor
- Grade IV tumor
- MC aggressive childhood brain tumor (peak age 7 yo)
- A form of primitive neuroectodermal tumor
- Can compress 4th ventricle, causing hydrocephalus
- Can send “drop metastases” to spinal cord, encases spinal cord*
- Homer-Wright rosettes
- Solid, small blue cells on histo
- Molecular target is sonic hedgehog pathway
Medulloblastoma
TQ:
- Grade I tumor
- Common, typically benign primary brain tumor
- Most often occurs in convexities of hemispheres (near surfaces of brain) and parasagittal region
- Arises from arachnoid cells
- Headache, personality change, seizures
- Spindle cells concentrically arranged in a whorling pattern
- Psammoma bodies
Meningioma
Increased mitotic figures** in a meningioma increases the grade from Grade I to Grade __, and is called ________ __________.
- Grade II
- Atypical meningioma
-Meningioma featuring obvious anaplasia and/or 20+ mitoses per 10 high power fields
Anaplastic meningioma
Grade III
TQ:
- Grade I tumors composed of curious blood vessels that arise sporadically in the cerebellum*
- Associated with von Hippel Landau syndrome*
- Can produce erythropoietin leading to secondary polycythemia*
- Odd vessels, surrounded by big pale benign clear (lipid-filled) cells
Hemangioblastoma
- Most hated of all “benign” tumors
- Arise from notochord remnants on clivus or sacrum
- “Bubble cells”
Chordoma
TQ:
- Benign childhood tumor, may be confused with pituitary adenoma (both can cause bitemporal hemianopia
- MC childhood supratentorial tumor
- Derived from remnant of Rathke pouch*
- Calcification is common* (tooth enamel-like)
Craniopharyngioma
TQ:
- Grade I benign subtype of craniopharyngioma, seen in adults*
- Tumor arises in or just above the sella turcica*
- Derived from remnant of Rathke pouch*
- Pts present with visual and/or endocrine and/or emotional disturbances
- Regions of tumor filled with “machine oil” rich in cholesterol
- Benign squamous cells, no columnar cells or calcification
- Mutated BRAF
Papillary craniopharyngioma
TQ:
- Most familiar subtype of craniopharyngioma
- Age peaks among children age 5-15 and adults ages 45-60
- Rare in US, common in Nigeria and Japan
- Calcification is common
- Feature columnar cells bordering more squamous regions, as in a developing tooth
- Mutated beta-catenin (CTNNB1)
Adamantinomatous craniopharyngioma
- Benign (Grade I) brain tumors
- Produce huge amounts of CSF, causing hydrocephalus
Choroid plexus papillomas
- Affect 3rd ventricle and are benign but contain mucus
- Obstruct the foramen of Munro
- Positional headaches
Colloid cysts
- Tumor often seen in young people
- Present as precocious puberty*
- Tumors that mimic testicular germ cell cancers are common here for some reason (esp seminoma)
- Grade 1 and Grade IV varieties
Pineocytoma (Grade I)
Pineoblastoma (Grade IV)
MC cancer in the CNS
Metastatic cancer
MC source of metastatic cancer
Lung, especially oat/small cell and adenocarcinoma
Where do mets begin in the brain?
Gray-white junction
where spreading cancer cell gets stuck in a blood vessel
TQ:
- Usually found at cerebellopontine angle
- Areas with nuclei arranged as zebra stripes (“Verocay bodies”)
- Often localized to CN VIII
Schwannoma
“acoustic schwannoma”
TQ:
Genes for tuberous sclerosis: (2)
-Angiomyolipoma of kidney
-Adenoma sebaceum on face
- Hamartin (TSC1)
- Tuberin (TSC2)
TQ: Gene for von Hippel-Lindau: -Strange vessels on back of eye -Hemangioblastoma in cerebellum -Renal cell carcinoma
VHL (Chr. 3)
TQ: Gene for neurofibromatosis type I: -Cafe-au-lait spots -Lisch nodules on iris -Bilateral optic nerve gliomas
NF1, neurofibromin (Chr. 17)
TQ:
Gene for neurofibromatosis type II:
-Bilateral acoustic schwannomas ("neuromas")
-Juvenile cataracts
-Meningiomas and ependymomasNF2, merlin (Chr. 2)
- anti-Yo, anti-PCA-1
- Destroys Purkinje cells
- Ataxia and then no movement at all
- Mostly breast, ovary, uterus cancer
Cerebellar degeneration
- anti-Hu, anti-NMDA, others
- Can destroy amygdala
- Appalling behavioral changes
Limbic encephalitis
The 5 MC cerebral paraneoplastic syndromes caused by immunity directed against tumors:
- Cerebellar degeneration
- Limbic encephalitis
- Opsoclonus
- subacute sensory neuropathy
- Eaton-Lambert myasthenia
