Pathology: Neuro

Intro to Neuropathology ......................................................................................................................................................... 2

Trauma of the Nervous System .............................................................................................................................................. 7
Cerebrovascular Disease ....................................................................................................................................................... 13
CNS Tumors ........................................................................................................................................................................... 20
Peripheral Neuropathy ......................................................................................................................................................... 25
Pathology of Neurodegenerative Disease ............................................................................................................................ 30

1
 Intro to Neuropathology
Cellular Components
Neurons
 1011 in CNS; many different types; big variety of size/shapes
 Have selective vulnerability to hypoxia, neurodegenerative dz, other insults
 Generally lots of cytoplasm & large round nucleus with prominent nucleolus
o Look like “fried egg”
 Nissl substance: lots of RER (very metabolically active; need to sustain lots of cytoplasm)
 Dendrites (lots; tree) & axon (1) project from body (soma)
 Organized in groups (nuclei, ganglia) or layers

Neuronal reactions to injury:

 Acute neuronal injury  red neurons (after
hypoxia/ischemia/toxic/infectious insults)
 Atrophy/degeneration (chronic disease)
 Axonal reactions
 Neuronal inclusions

Glia
 Lots of different functions:
o mostly neuronal support system, react to injury, regulate metabolism
 Most numerous cells in CNS
 Astrocytes, oligodendroglia, ependymal cells, (microglia – not really glia)
 GFAP = IHC stain for glia
 Note: Neuropil = “nerve felt”; mix of neuron/glial cell processes (fluffly pink between cell bodies)

Astrocytes: found throughout neuroaxis

 Protoplasmic astrocytes in grey matter; fibrous in grey & white
 Structure:
o Round / oval nuclei; star-like processes
o Nuclei: round/oval, slightly larger than oligodendrocytes
 End-foot processes with TJs  BBB & CSF-brain barrier
o Abut neurons, vessels, pia, glia limitans
 Functions: metabolic buffers, detoxifiers, suppliers of nutrients, electrical
insulators, physical barriers
o Major cells in damage repair in CNS (fibroblasts of brain)

Oligodendroglia: found in white matter

 Processes wrap around, insulate axons
o Allow saltatory conduction
 1 oligodendroglia : several axons
 Round, regular, lymphocyte-like nuclei
with dense chromatin
o Can have halos around cells

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Ependyma
 Single layer of cuboidal to columnar cells lining ventricular system
 Cilia / microvilli on apical surface
 Brain / CSF barrier; involved in transport
 Choroid plexus is specialized ependymal structure (CSF-secreting)

Microglia
 NOT GLIA (mesoderm-derived, from bone marrow)
 Act like Mϕ / monocyte system in brain
o Proliferate / migrate in response to infection / injury
o Phagocytic
o Act as APC of CNS
 When activated, retract / thicken
processes & then can migrate to site
of injury/ infection
 Clean up dead neurons
(neuronophagia) – looks like sesame
chicken

Choroid / Meninges
Choroid plexus
 Specialized cells derived from ependyma; secrete CSF
 Papillary fronds of cuboidal epithelium covering vascular cores
 TJs maintain BBB
 20 mL CSF / hr made; normal CSF volume ≈ 140 mL
o (25mL in ventricles, rest in subarachnoid space)

Meninges
 Dura: fibrous; closely attached to periosteum
o Epidural space present in SC
 Leptomeninges = arachnoid, pia
o Made of meningothelial cells & connective tissue
 Arachnoid: thin, translucent, drapes over blain
 Pia: delicate; invests arteries as they penetrate brain, closely attached to cortical surface

CSF: circulates in subarachnoid space (between arachnoid / pia)

 Arachnoid granulations: small aggregates of arachnoid cells
o protrude into dural venous sinuses
o One way valves (CSF drains into dural venous sinuses)
o Blockage (e.g. meningitis)  hydrocephalus

Special Neuropath Stains

Stain For…
The Black Stain (Golgi’s silver) Lets you see single cells (dendrites, axon, etc) – only taken up by some cells
Gold chloride-mercury (Ramon y Cajal) Astrocyte stain, like Golgi’s Black stain
GFAP IHC for glia (glial fibrillary acidic protein)
Synaptophysin & NeuN IHC for neurons
Luxol Fast Blue Myelin
Hirano silver Alzheimer Dz
Methenamine silver (GMS) Fungi
(Note that other IHC stains are available for pretty much everything else too)
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 Pathology of Neurons
Neuronal Apoptosis
Pathology of Neurons
 Programmed cell death  Apoptotic neuronal cell death
 In normal development: eliminate extra neurons  Hypoxic / ischemic neuronal necrosis
o Can be seen in CNS disease too (e.g. brain tumor)  Neuronal loss (neurodegenerative dz)
 Axonal pathologies
 Clumped, fragmented chromatin o axonal degeneration after neuronal death
o Karyorrhexis o neuronal changes after axonal damage
(DNA fragmentation)  Neuronal inclusions
o Condensation (apoptotic bodies) (esp. infectious / neurodegenerative process)
o Individual cells, dispersed pattern

Necrosis
 Hypoxia, ischemia #1, also heat, toxins, hypoglycemia
 Particularly vulnerable: cortical layers 3/5, hippocampus (CA1), Purkinje cells

If acute: see: RED NEURONS (eosinophilic discoloration w/in 12 hrs)

 If severe: glia die too  Mϕ clean necrotic region afterwards

If chronic (E.g. neurodegenerative)  gradual neuronal loss (no red neurons)

Axonal pathologies

Axonal degeneration after neuronal injury (see pic: CST in ALS)

 Decoloration (myelin stain is negative; CD68+ for Mϕ )

Neuronal cell body reaction after axonal damage

(a.k.a. “axon reaction”)
 Dendrites retracted
 chromatolysis
(rounded shape, eccentric nuclei)
 Nissl substance lost

In PNS: Schwann cells (axons regenerate pretty well)

In CNS, oligos don’t help regenerate axons as well

Neuronal Inclusions (Neurodegenerative Disease)

Cytoplasmic
Alzheimer’s Neurofibrillary tangles
Parkinson’s Lewy bodies
Pick’s Pick body

Nuclear
Huntington’s Ubiquitin (+) inclusion
Generally proteinaceous debris in inclusions

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Metabolic Disease
 Many inherited metabolic diseases can result in neuronal abnormalities

Inclusions: viral infections

 Can see in both neuronal & glial cells often
 CMV, measles, adenovirus, herpes, VZV, rabies, etc.

Pathology of Glial Cells

Reactive Astrocytosis: non-specific reaction to infection, seizures,

autoimmune dz, infarction, etc.
 Normally: can’t see outline of astrocyte, just nucleus
 If you can see outline: astrocyte is starting to react & change!

Fibrillary gliosis: proliferation of reactive astrocytes

Pliod gliosis: can see around spinal cord cavities & other long standing reactive gliosis in cerebellum, hypothalamus

Genetic . metabolic diseases can involve glia too

 Most commonly leukodystrophies (disrupt myelination)

Progressive Multifocal Leukoencephalopathy ()

 Caused by JC virus glial inclusions
 Oligos infected (mostly in white matter; right)
 Mϕ come in to clean up damage (left)

Overview of basic CNS pathology

Infarction
Hours / days Neurons: eosinophilic, shrunken
PMNs: infiltrate lesion
Days / weeks Neurons gone
Mϕ infiltrate lesion
Reactive astrocytosis around edge
Months / years Cystic cavity

Viral infection

 Acute: tend to involve brain parenchyma (encephalitis)

 Lymphocytic infiltrates around vessels, in neural tissue
 Rod-shaped activated microglia, micoglial nodules
 Chronic: can have varied appearances

Bacterial infection
 Purulent meningitis or brain abscess
 Lots of PMNs

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Fungal infection
 Can involve either brain or meninges primarily
 Some can cause granulomatous inflammatory responses
 Immunosuppressed patients mostly

Aspergillis (trophic for blood vessels  hemorrhagic necrosis)

Also: blasto, mucor, candida, histo, crypto, coccidiomycosis

Demyelinating disease

 MS: sharply circumscribed plaques

o myelin gone or in foamy Mϕ
o Reactive astrocytes, preserved axons also present

Trauma
 Can cause: superficial contusions, hemorrhage at any site, frank necrosis
 Hemmorhage: epidural, subdural, subarachnoid, intraparenchymal

Diffuse axonal injury

 Microscopic damage to nerves
 Caused by severe acceleration or deceleration of head
 Worse with lateral motion
 Medial structures most affected
 Axonal swellings in white matter

Neoplasia

 Gliomas: most common CNS tumors

o Infiltrate through brain
o can’t fully excise surgically

 All CNS cell types can give rise to tumors

Neurodegenerative diseases
 Affect various populations of cells, have disparate mechanisms
 Characterize by distinctive inclusions and associated neuronal / glial cell loss

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 Trauma of the Nervous System
Introduction
 Most traumatic brain / SC injuries can be prevented
 Trauma of brain often accompanied by trauma of spinal cord
 Complications of TBI: secondary brain edema, herniations, infarctions, hemorrhages

Brain & SC protected: skull, spine, CSF (shock absorber) Complex pathogenesis:
 But bony structures can become source of injury!  Stress
 Mass effects
 2° vascular perturbations
& edema
Epidemiology
 1.5M / yr with TBI; 50K die, 80k  long-term disabilities
 5.3M in USA living with disability as result of TBI
 Cause: Transportation > falls > firearms, assault, others

Lesions by anatomical location

Scalp injury
abrasions, contusions, lacerations, hematomas (collection of
blood outside vessels)

 Examine scalp  may be able to locate site of impact

 Can have brain injury without scalp lesions (“shaken
babies”, auto accidents)

Skull Fractures
 Falls: non-depressed fractures in calvarium (skullcap) with linear or complex pattern
 Severe trauma: fractures of calvarium extend to base of skull
 Blunt trauma: depressed fractures are more common

Brain contusions / lacerations frequently result from depressed fractures (but linear fractures can cause too!)
 At time of impact: edges of fracture can become depressed for an instant  cause damage  instantly realign

Basal skull fracture: often from severe trauma

 difficult diagnostically (complex radiographic appearance of base
of skull); some signs:
o blood in ear canal
o hemmorhagic discoloration over mastoid (Battle’s sign)
o CSF leak through nose

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Dura mater & Leptomeninges
Hemorrhages
Type Etiology Characteristics

 Arterial origin  rapid development, life-

Epidural Fx of squamous portion of temporal bone threatening volume in hours (FAST!).
(=extradural) laceration of middle meningial artery  Treat with surgical burr, can have good recovery
 Bulges out away from skull (convex: high pressure)

Venous or capillary origin  slow growth (days)

Esp. in pts with severe brain atrophy: vessels
Common in all types of trauma
bridging dura / brain become stretched, susceptible to
Subdural From cortical contusions or tears of
tears with minor trauma – e.g. old pts in falls
bridging vessels (shearing)
 Can be chronic and calcify
 Can re-bleed with next injury or spontaneously

Variable distribution; prominent over convexity of

Most common path consequence of head
hemispheres (vs aneuyrism  at base of brain)
Subarachnoid trauma, also often from rupture of
aneyurisms (berry aneurysm @ base of brain)  May block normal CSF circulation 
hydrocephalus

Can see contusion on edge of brain if traumatic;

Inside brain parenchyma, e.g. if someone falls
Parenchymal multiple parenchymal hemorrhages  probably
(old person, etc.)
traumatic

MRI appearance of four types of acute, post-traumatic intercranial hemorrhage

 Right: epidural (lens-shaped, convex, doesn’t cross sutures)
 Left: subdural (follows surface of brain, concave, crosses sutures)
 Top: subarachnoid (penetrates down into gyri)
 Top, just below subarachnoid: parenchymal (ball-shaped)

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Cortical Contusions
Bruising of brain (most frequently cerebral
cortex) from impact against skull
 Most (not all) hemorrhagic
 Can lead to focal neuro
manifestations and/or seizures

Can become cavitated
 Mϕ remove debris, astrocytes
(fibroblasts of brain) respond, see
hemosiderin (brown pigment)
Contusion vs. Concussion
Contusion Concussion
A traumatic lesion characterized by tissue necrosis, damage to Transient impairment of consciousness due to head
small vessels, interstitial bleeding, and edema, without trauma, without a determinable structural lesion of the
disruption of the continuity of the tissues. brain.
 Concussion has a functional connotation

Post-concussive syndrome: for < 6 mo:

 Headache  dizziness / vertigo
 sleep cycle abnormalities  attention / concentration impairment
Lacerations of the brain
Wounds or cuts in parenchyma; result from high mechanical stress / skull fracture

Hemorrhages / hematomas
 Traumatic hemorrhages can be single or multiple
 Cerebral white matter is common site
 Amyloid deposition in cerebral blood vessels (older pts)  ↑ risk of traumatic
hemorrhage

Axonal shearing
White matter injury often from acceleration / deceleration injuries (e.g. automobile accidents)
 Causes cognitive / motor deficits in aftermath of head trauma

Brain edema / swelling

↑ brain volume due to ↑ water content
 Vasogenic (from trauma / tumors) – tight junctions open in BBB
 Cytotoxic (hypoxia / ischemia)

Can be localized (around contusion / laceration) or generalized (diffuse axonal

injury in acceleration / deceleration)

Signs:
 Flattened cortical gyri
 Collapsed ventricular system / aqueduct of sylvius
 Cerebral herniations (if severe)

ICP rises exponentially with volume (>75-100mL excess - ↑↑ ICP rapidly)

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Herniations
Parenchyma of brain extrudes through openings in skull
Herniation Description
unilateral supratentorial lesion pushes uncus (mesial portion)
of temporal lobe through tentorial notch
Transtentorial / Uncal  Often compress CN III
 can lead to Duret’s hemorrhage
unilateral supratentorial lesion pushes
Cingulate / subfalcial
cingulate gyrus under dural falx

bilateral supratentorial lesion pushes

Central
diencephalon & hypothalamus downwards
posterior fossa lesion pushes
Tonsillar cerebellar tonsils through foramen magnum
 compresses medulla, CV/resp centers  bad

Vascular complications: blood vessels stretched / compressed during herniation

 Duret’s hemorrhage: midline hemorrhage of the pons (blood vessels stretched after transtentorial herniation)
 Occipital lobe ischemic / hemorrhagic infarcts from compression of PCA in uncal herniation

Mechanisms of head injury & patterns of lesion

Note that there’s usually a combination of mechanisms, not just one
Blows to the Head
 Scalp laceration / contusion, skull fracture, underlying contusion / laceration of brain parenchyma
 Can see subarachnoid, epi-, subdural hemorrhage too

Falls (Coup-Contrecoup)
Primary forces are translational (not much rotation)
 Point of impact: scalp contusion or laceration ± skull fracture

 Coup injury directly under point of impact: small

lesions

 Contrecoup injuries on opposite side of skull:

extensive cortical contusions
o Base of brain is rough! Back of brain is
smoother – posterior fossa, etc)

Most survive; can have frontal lobe problems

 Can have behavioral problems
o (plan, drive, impulsivity  prefrontal cortex)
 Occasionally see seizures

Example: fall backwards, hit back of head.

 Point of impact: scalp contusion, subgaleal hematoma, no skull fracture, no
cerebellar / occipital lesions
 Large cortical contusions of frontal / temporal poles, orbitofrontal regions

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Acceleration / Deceleration (Diffuse Axonal Injury)
Automobile & sports accidents: neuro impairments with “closed head trauma”
 Angular / rotational forces  axonal & microvascular shearing

 Scalp, skull intact; Imaging, external exam of brain unremarkable

(± some edema, subarachnoid hemorrhage)

Path:
Macroscopic: linear hemorrhages
(frontal/temporal white matter, corpus callosum,
periaqueductal region)

Microscopic: extensive axonal shearing

 “Axonal balloons” – axonal swelling
o means that axon has been cut
(can be ischemic too)
 Pallor in myelin-stained sections
“Shaken Baby Syndrome”
 750-3750 / yr in US; 1/3 die, 1/3 permanent injury, 1/3 spared
 Kids with TBI from child abuse usually have other traumatic injuries too (ribs, limbs, etc.)
 See acceleration / deceleration injuries on path
 Retinal hemorrhage can be seen too (but not just in trauma: 25% neonates for 1st 4-6 wks, but goes away)

Sports & TBI

 Concussion is most common brain injury in sports (300k/yr), 90% boxers, 1 in 3.5 football games
 Superficial cortex, neurons & astrocyte problems result; hippocampus / parietal cortex  memory probs
 Chronic traumatic encephalopathy in adults: boxers, football players
o Brain atrophy, hydrocephalus in young people (with tau accumulation!)

Firearm use & TBI

 Firearm use is leading cause of death related to TBI
o (10% of all TBIs, 44% of TBI-related deaths)
 9/10 people with GSW of brain die
Long-term consequences of head trauma
Chronic subdural hematomas, limited to hemosiderin-stained subdural membrane; cortical contusions
 Cause posttraumatic seizures

Hydrocephalus: after subarachnoid hemorrhage impairs flow / reabsorption of CSF

 Variable clinical expression
 can lead to dementia, gait apraxia, incontinence (normal pressure hydrocephalus)

Cranial nerves can be injured: vision (II), ocular motility (III/IV/VI) often

After diffuse axonal injury: Can cause severe motor / sensory / behavioral / cognitive deficits
 brain atrophy  2° loss of myelin in frontal, temporal lobes
 hydrocephalus

Clinical consequences:
 Neuro impairments affecting consciousness, cognitive, sensory, motor domains
 Executive function impairment (cognitive / behavioral) often overlooked
o From frontal lobe lesions, esp. after diffuse axonal injury
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 Spinal Cord Trauma
Most frequent causes: motor vehicle accidents, falls, gunshot wounds, sports accidents (diving / football)
 Males 15-25 have highest risk
 Often combined with head injuries Traumatic Spinal Cord Injury
 11k/yr in US; 190k living with
Most SC injuries: from compression 2° to paralysis due to SC injury
fractures, dislocations, subluxations of  24 h survival is important: 85% of
vertebrae those who survive 24h after
 Possible to have SC damage without injury still alive 10 yrs later
obvious injury of vertebral column too
 Cervical, lumbar spines most vulnerable (↑ mobility)
 Thoracic less susceptible (rib cage, costal-vertebral ligaments  ↑ stability)

Cervical spine / cord injuries between C4 & C8 are most common nonfatal spinal injury associated with head trauma
 Always damage ligaments  dislocation / subluxation (partial dislocation) of vertebrae
 Hyperextension, hyperflexion, hyperrotation, compression
o Compression: e.g. diving accident, football head-on tackle: one cervical vertebrae compressed, “ burst” fracture,
compresses cord
Lumbar, lower thoracic spine / cord  mostly rotation / flexion (vehicular accidents / falls)

Pathology of spinal cord injury

Acute
segmental softening
variable degrees of necrosis & hemorrhage
 Necrosis most severe centrally (gray & white
matter), tapers off in caudal / cephalic areas
Later: (1+ months post-injury)
necrosis replaced by central cavity
 Degeneration of ascending / descending spinal
pathways on microscopy
 Leads to irreversible axonal injury

Pathogenesis of SC injury (animal models)

 1° injuries (immediate): mechanical disruption of membranes, abnormal electrolytes, ATPase ↓
 2° injuries (1st 24 hrs): ischemia, reperfusion, free-radical generation, Ca-mediated toxicity
o 2° injuries = target for treatment now (steroids, adrenergic blocking agents, endorphin inhibitors, etc)

Clinical Features
Segmental signs at level of injury
 Muscle atrophy / weakness at one or two root levels (LMN involvement)
 Ascending long-tract signs (loss of all sensory modalities below level of lesion)
 Descending long-tract signs (UMN involvement)
o Paralysis, Spasticity, Hyperreflexia, Extensor plantar responses below level of lesion

Above C4  highest risk of fatality (PHRENIC NERVE  diaphragm paralysis, also tetraplegia)

Level, extension of lesion determines:

 Tetraplegia (paralysis of all extremities) vs Paraplegia (paralysis of lower extremities)
 Total or partial paralysis

Cervical, high thoracic injuries: extra problems

 Resp / autonomic control
 Bladder, bowel, sexual functions compromised

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 Cerebrovascular Disease
Introduction
Brain needs blood! 2% of body wt, but gets 15% of cardiac output & uses 20% body’s oxygen
 Has no glucose stores of its own
 Cerebral blood flow is highly regulated (under normal arterial pressures, no significant change in flow)
o Gray matter > white matter for blood flow
o ↑ PCO2 in interstitial space with ↑ neuronal activity  local vasodilation  ↑ local cerebral blood flow

Stroke: happens when vascular supply is interrupted (infarction or hemorrhage)

 3rd leading cause of death in US
 All ages; ↑ incidence with age

Anatomy review
Internal carotids & vertebral – basilar arteries form dual blood supply to brain
Circle of Willis formed from these – variable sizes of anastamoses

ICAs  “anterior circulation”

 anterior cerebral a. (ACA), middle cerebral a. (MCA), anterior choroidal a., posterior com. a. (P-com)
Vetebral aa.  “posterior circulation”
 posterior cerebral a. (PCA), superior cerebellar a. (SCA), anterior inferior cerebellar a. (AICA), posterior inferior
cerebellar a. (PICA)
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Artery
Anterior cerebral artery (ACA)
Middle cerebral artery (MCA)
Posterior cerebral artery (PCA)
Path Features:
 blurring of gray/white junction
 petechial hemorrhages in affected areas
Cortical Blood Supply
Territory Deficit of stroke Pictures
 Contralateral legs
Medial walls of:
 Frontal lobe
 Motor + sensory (primary motor,
 Parietal lobe
primary somatosensory cortex)
Lateral walls of:  Face, arms > legs (primary motor,
primary somatosensory cortex)
 Frontal lobe
 Parietal lobe
 Speech centers
 Temporal lobe
(if dominant hemisphere – usu. L)
 Medial and inferior  Visual cortex
surfaces of temporal lobe (or optic radiations)
 Occipital lobe  Contralateral visual field cut
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 Blood Supply to Deep Nuclei
Basal ganglia, thalamus, hypothalamus: supplied by perforating branches of ACA, MCA, PCA
 ACA: anterior hypothalamus, anterior caudate /
putamen, anterior limb of internal capsule
 MCA: posterior caudate / putamen, most of globus
pallidus, genu / post. Interal capsule, middle
hypothalamus
 PCA / P-com: post. Hypothalamus, subthalalmic
nucleus, dorsal thalamus, choroid plexus

Picture: stroke going right through internal capsule

(pure motor stroke!)

Blood Supply to Brainstem

Midbrain Posterior cerebral a. (PCA); basilar artery
Pons, cerebellum Basilar artery, PCA
Medulla Vertebral arteries
Note that multiple unnamed branches supply medial, lateral portions of brainstem too
Pic: old lateral medulla infarct
 Lateral medullary syndrome: PICA or vertebral artery occluded; takes out lateral medulla
o Lose pain/temp contralateral in body, ipsilateral in face (crossed)
 STT damaged (contralateral body); trigeminal nucleus (ipsilateral face)
 Motor to body spared (CST in pyramids; not affected)
o Also dysphagia, ataxia, slurred speech, facial pain, vertigo, Horner’s syndrome, diplopia

Blood Supply to Spinal cord

Spinal arteries originate from vertebral arteries

Anterior spinal artery (1) Anterior 2/3 of cord

Posterior spinal arteries (2) Dorsal columns

Reinforced by medullary arteries

 enter cord with nerve roots
 artery of Adamkiewicz @ lumbar level is most important

Infarcts usually happen in anterior spinal artery distribution

 Disrupt a. of Adamkiewicz can cause infarction of middle, lower levels of cord (Ao dxn or repair of AO dxn, aneyurism)

Pathogenesis of Infarction
Large Vessel vs. Small Vessel Disease

Large vessel disease Small vessel disease

Named vessels & branches (see above) Basal ganglia, cerebral white matter, pons affected
 Lacunar infarcts
Usually from atherosclerosis, thrombosis, embolism Usually from HTN or DM
Note that HTN is important in both (↑ BP  ↑ risk atherosclerosis, also damages small vessels directly)
Lacunar infarcts
 Small “holes” from occlusion of small vessels
 Affect deep gray nuclei, deep white matter, cerebellum,
base of pons

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Embolic vs Thrombotic infarcts

Thrombotic infarcts: thrombosis of large vessels

 caused by atherosclerosis in intercranial or neck vessels (e.g. bifurcation of carotid)
 single infarcts (one vessel occluded)
 nonhemorrhagic: generally remains occluded for long period of time; little / no reflow

Embolic infarcts: showers of embolic material travel to many vessels

 usually from carotid, can be from left heart
o particles from atherosclerotic plaques, mural thrombi, vegetations on cardiac valves
 multiple infarcts
 hemorrhagic: fragments break down  reflow

Selective Vulnerability
 Function of cell type (neurons > glia > blood vessels)
o Hippocampus (CA1), large neurons in cortical layers 3 & 5, Purkinje cells especially vulnerable
 Gray matter more vulnerable than white matter (more metabolically active)

Clinical implications: laminar necrosis with transient / lower levels of ischemia

 Cardiac arrest or global hypoxia-ischemia: selective for big neurons / areas listed above

Regional Vulnerability / Watershed Infarcts

 Function of vascular anatomy
 Most cerebral arteries are end-arteries ACA
o so ↓ BP  poor perfusion of distant arterial territories

“Watershed” / “border zone” infarcts develop (at junction between territories) MCA MCA
 Border between ACA / MCA or MCA / PCA
 Can be single, multiple, or continuous
 Often hemorrhagic when flow restored (to necrotic vessels) PCA

Time Course of Pathological Changes

Early changes (hours-days)
Time Path changes
0-4 hours Nothing
4-6 hours Hyperchromasia of neurons (“red neurons”)
 “Red neurons” more prominent
12-24 hours
 Discoloration & softening grossly
Edema (here with big midline shift, looks like ↑
24 hours
white matter size)
 Neuronal hyperchromasia Edema (acute MCA infarcts).
 Glial necrosis Note midline shift in right specimen
1-4 days Neuronal hyperchromasia
 Scattered PMNs (“red neurons”)
 Worse edema
People die from stroke if interference with cardio / resp function occurs

Possible complications:
 Transtentorial Herniation (compress 3rd nerve, with hemorrhage)
 Duret hemorrhage (secondary - push on brainstem, pull on small arteries in
midbrain / pons  stretch  hemorrhage)

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Later changes (weeks / months)
Time Path changes
5-7 days Mϕ start appearing, cleaning up
 Rest of cells pale
8-14 days  Reactive astrocytes appear Reactive astrocytes (above)
 Pink cyto, full of IFs
 Edema resolves
 Liquefied necrotic tissue removed Organizing infarct (left)
wks / months
 Cyst formation  Well-defined border
 Liquefactive necrosis
Long-term changes (months / years)  Gradual cystic change
 Takes months / years for large infarcts to resolve
completely (slow rate of removal of liquefied necrotic Falling apart; border becomes
more distinct. Remember: no
tissue)
fibroblasts in brain (astrocytes)!
 No fibrosis (no fibroblasts)  CYST results
 Volume of cyst is smaller than original tissue volume
o so ipsilateral dilation of lateral ventricle / midline shift towards lesion can result

Primary intracranial hemorrhages

(Vs. secondary hemorrhages (trauma, Duret hemorrhages))
Other causes (aside from list to right): Major causes
 coagulopathies (esp. in hospitalized pts) – platelet, clotting factor deficiencies of 1° intercranial hemorrhages
 Disorders of blood vessels (amyloid, vasculitis, Aspergillus / Mucor infection)  Hypertension
 Amyloid angiopathy
Hypertensive Hemorrhages  Berry aneuyrisms
 Most common cause of primary intracerebral hemorrhage  Vascular malformations
o (also #1 for occlusive stroke: HTN is common!)
 Blood pushes brain
Base of brain! aside
 Deep gray matter, esp. putamen Putamen  Can often do well if
 (pons, cerebellum too) you survive (not
destructive)

Can:  Rapidly fatal (herniate

 rupture into lateral ventricle (fatal) Pons  compress resp.
 resolve as hemosiderin stained slits centers)

Pathogenesis of hypertensive hemorrhages:

thought to arise from Charcot – Bouchard aneurysms
 microscopic dilatations
 develop at branch points of penetrating blood vessels
 theory: one ruptures  pushes on adjacent ones  they rupture

Arterial tortuosity may play a role too

Diagnosis of hypertensive hemorrhage for intraparenchymal hemorrhage:

 History of hypertension (or HTN path changes on autopsy)
 Location of bleeding (base of brain?)

17
Amyloid angiopathy

Associated with Alzheimer’s disease & aging

 deposition of β-amyloid (abnormal breakdown of APP)
 deposited in media of small vessels (arterioles); Congo red birefringence
 Rare families have inherited forms

Location: usually supratentorial and relatively superficial with lobar distribution

 Think: LOBAR HEMORRHAGE in OLD PATIENT

Berry (saccular) aneurysms

 From arterial branch points in / near the circle of Willis
o Usually anterior circulation
 Small (3-10 mm) saccular dilations
o arise from congenital defects
o may be multiple, sometimes familial (25% have >1)
o may be asymptomatic if small, or rupture

Subarachnoid hemorrhage: if berry aneurysm ruptures

 ↑ risk of rupture with ↑ aneurysm size
o 1/3 ruptures associated with acute ↑ ICP
(straining at stool, lifting heavy objects)

 Early – mid-adulthood (rupture)

o 1st episode may be “sentinel bleed” (warning sign)

 “worst headache of my life” is classic description

o Can produce cranial nerve sx (compression)
o Can extend to brain parenchyma / ventricular system (hydrocephalus)

 Arterial vasospasm: major complication of rupture

o Can lead to extensive cerebral infarction
(↓ blood flow to rest of brain)

Treatment: clips or coils

Arteriovenous Malformations (AVMs)

Tangled masses of markedly abnormal blood vessels in parenchyma, meninges, or both

 Arise from early embryo (when cerebral blood vessels form)

 Include nidus, feeding artery / arteries, and draining veins

o Arteries feed directly into veins  high flow shunt
(drain blood away from parenchyma)

 Produce subarachnoid and/or intraparenchymal hemorrhages

o sometimes focal ischemia too

18
Symptoms
 Early / middle adulthood
 Seizures or headaches (can have focal symptoms too)

Treatment: surgery, endovascular embolization (sacrifice vessels for surrounding veins), radiosurgery (gamma knife)
 Can re-form if abnormal vessels remain

DDx: multiple hemorrhages in unusual sites

Esp in hospitalized patients
 Platelet disorders (leukemia – no platelets!)
 Clotting factor abnormalities
 Vasculopathies (fungal infection: aspergillis)

Sample cases (for practice)

Notes:
 Case #2: swelling tells you it’s a few days ago
 Case #2, flip side: older, because of contraction / shrinking in affected area

19
 CNS Tumors
Classification & Grading
 Classified by how they resemble a normal precursor cell (although origin not actually clear)
 Molecular characterization useful for some (oligodendroglioma, glioblastoma, medulloblastoma)

Grading
 Numerical index: degree of malignancy, biological aggressiveness
 Descriptions below can vary with treatment, type of tumor
o little Tx effect for glioblastoma; ½ cured in Grade IV medulloblastoma
Description Life expectancy (if untreated)
Grade I Well circumscribed, “non-invasive”, slow-growing, little malignant potential
Grade II Often infiltrative; prone to malignant degeneration variable, often ≤ 10 yrs
Grade III Mitotically active, usually infiltrative ≤ 5yrs
Grade IV Overtly malignant (anaplastic) ≤ 2yrs

Benign vs Malignant
 Vary; generally malignant for grade III-IV gliomas; is it really “benign” if grade II kills you in 10 yrs (astrocytoma)?
 Some malignant neoplasms (choroid plexus carcinoma) – cured by excision alone
 “Well-differentiated” vs “anaplastic” is more precise
o but still need to take type, grade, location, Tx available into account

Staging
 Only used rarely in CNS tumors; CNS tumors rarely spread outside of nervous system
Intra/extra-axial
 Meningiomas are usually extraaxial; the others here are usually intraaxial
Clinical expressions
Produced by:
 Bulk of neoplasm itself
Mass effect  Peritumoral edema, hemorrhage
 Obstruction of CSF pathway
 Rare: choroid plexus papillomas – actually secrete CSF
Common presentation in tumors involving cerebral cortex
Seizures
 Temporal lobe is most frequent site of epileptogenic tumors
Varies with location
 Some are very stereotypic
Focal neurological defect
 Mostly need MR, Sx and biopsy to make diagnosis
 but sometimes can use neuro sx + imaging alone

Spinal Cord Lesions

Epi- (extra-) dural Can be bad if it’s invading bone!
Intradural extramedullary Often easier to resolve
Intramedullary: Bad – don’t want to be inside the cord!

Pics:
 meningioma is intradural extramedullary (left)
 astrocytoma: intramedullary, diffusely infiltrating
(right)

20
 Meningioma
Feature Description
Arachnoid meningothelial cells (cranial, spinal meninges)
Origin  can be intraventricular (meningothelial cells in choroid plexus)
Spontaneous mostly, also prior radiotherapy or inherited syndromes (Neurofibromatosis 2)

 ADULTS, slightly F>M

Clinical  ↑ ICP and/or focal neurological deficit (depends on site)
Features  Seizures are less common than intra-axial neoplasms
 Can be discovered incidentally, usually well-circumscribed

Discrete contrast-enhancing lesions

Radiology  Short extensions along dural surface (“DURAL TAILS”)
 Most arise along meninges & compress instead of infiltrating brain (malignant variants can invade)
Most well-differentiated; cells resemble normal leptomininges
Histology  WHORLS and CALCIFIED CONCRETIONS (“PSAMMOMA BODIES”) are classic
Grade I (well diff) > grade II (atypical) > grade III (anaplastic)
Loss of chromosome 22 (in region of NF2 gene; ½ -2/3)
Molecular
Losses on 1p and 14q = tumor progression (↑ in grade II/III)

Simple excision (often truly benign) or just follow

Treatment
 Harder to excise if infiltrate bone or surround critical fessels
Prognosis
 Can recur if less well differentiated (anaplastic)

L: Normal meningothelial cells; Classic whorls & psammoma body Meningioma (lower left); expands &
R: meningioma (very similar) (central calcification of whorl) causes mass effect here

Most are spontaneous; here radiation-induced (L, in path of Common locations (bad if
DURAL TAILS on MRI
beam) and from NF2 (multiple lesions) around ICA, etc)

Left: meningioma invading skull

(rare)

Right: Grade II meningioma

(more mitoses, prominent nucleoli)

21
 Gliomas (Glioblastoma Multiforme, GBM)
Note that gliomas include astrocytomas, oligodendrogliomas, ependymomas: here focusing on GBM
Feature Description
Astrocytes (precise origin often obscure)
Origin
Mostly spontaneous (rarely: prior radiotherapy, Turcot’s syndrome – DNA mismatch repair, colon + brain tumors)

Adults mostly (can happen in kids, esp. in pons)

Clinical
 Throughout CNS; most common in cerebral hemispheres
Features
 Recent onset symptoms (fast grower): seizures, headaches, focal neuro defects

Ring or rim of contrast around dark central necrotic area

Radiology
 Broad zone of edema on T2 MRI

Variable (multiforme), composed of malignant glia (generally astrocytes)

 2° features: NECROSIS and VASCULAR PROLIFERATION
 Necrosis with PSEUDOPALISAIDING (rows of cells around it)
Histology  GLOMERULOID VASCULAR PROLIFERATION
o (VEGF released from ischemic cells  pericyte, endothelial cell hyperplasia  looks like glomerulus!)
Malignant: ↑ cellularity, ↑ mitotic rate, ↑ invasion & infiltration
 Often pass through corpus callosum to opposite hemisphere

Primary pathway: more common, no obvious precursor: ↑ EGFR, deletion of p16, PTEN mutations
Molecular Secondary pathway: from better differentiated astrocytoma precursor  develops p53 mutation
Loss of chr 10 common in both; distinguishing feature from grade III anaplastic astrocytoma

Curative surgical excision impossible except in rare cases

Treatment
 Inevitable residual tumor, rapid growth, resistance to other therapies
Prognosis
Rarely survive past 3 years; median survival 15 months

Normal: Astrocytoma: H&E (L, kind of looks Glioblastoma (L, MRI with contrast; R, T2)
O = oligodendrocyte, like astrocytes) & IHC for GFAP Note ring around central area of necrosis
A= astrocyte (R, see astrocytes & processes w/ contrast

More glioblastomas (MRI with contrast) – see ring of No distinguishing path features;
Gross: large necrotic area; here
contrast enhancement around central necrosis here tiny cells but can have tons
producing herniation (mass effect)
Lesion on right is in brainstem of forms

22
 More glioblastomas

Vascular proliferation (left) and Highly invasive: infiltrating corpus callosum

pseudopalisaiding (cells crowding
together & kind of lining up around
area of necrosis)
Glomeruloid vascular proliferation:
(left; myelin stain, see cell bodies); crossing
kind of looks like a glomerulus if you
corpus callosum (right) to contra. hemisphere
squint just right

Medulloblastomas
Feature Description
Mostly unknown / spontaneous
Origin
Some have sonic hedgehog pathway mutations  external granular cell layer mutations

Children mostly (can happen in adults too)

Clinical
 Sx: CSF flow obstruction: headaches, nausea, vomiting
Features
 Cerebellar neuro deficits too

 Discrete, contrast-enhancing masses in vermis or cerebellar hemisphere

Radiology
 CSF pathways can be seeded at presentation

From neuronal precursor

 NEUROBLASTIC (Homer Wright) ROSETTES
 Immunoreactive for synapse-associated protein (synaptophysin)
Histology
If from SHH pathway: nodular architecture (neoplasm & developing CNS tissue)
 Called desmoplastic medulloblastomas
Densely cellular; grade IV by def’n, variation in differentiation; some respond (↓ mitosis) better than others (↑)

Heterogeneous; ¼ have SHH mutations, ¼ have WNT mutations; 17p involved too
Molecular
↑ MYC = bad prognosis, ↑ TRKC = better prognosis

60% cured overall; mostly by total excision of well differentiated tumors

Treatment
 Bad prognosis for anaplastic tumors or disseminated at Dx
Prognosis
 Get radio & chemo-therapy in both cases

B
P

I I

Normally: Left: cells migrate down from external granular cell Medulloblastoma: densely Medulloblastoma with
layer (E) through Bergmann astrocyte layer (B) and Purkinje cell cellular, proliferative, rapid neuroblastic (Homer-Wright)
layer (P) to establish internal granular cell layer (I). progression without treatment rosettes
Right picture: the end result in an adult

23
Nodular / Desmoplastic meduloblastoma What’s going on? Kind of recapitulating the normal development of the EGLIGL.
Most likely to be external granule cell layer Some % is normal, some % is mildly abnormal, some % is very abnormal
(SHH) – derived; area to left is a little more Depends on how many hits each part of cell pop has had
well differentiated (see neuropil)

CSF Seeding: multiple white areas in spinal cord

Some young kids might not actually need

treatment; others will seed down the neuroaxis

This is why Tx of both cerebellum and rest of

neuroaxis is needed (major implications for kid,
but necessary)

Anaplastic medulloblastoma: much Chemo + Rad to neuroaxis too!

poorer prognosis; really bad looking cells

24
 Peripheral Neuropathy

Normal Peripheral Nerves: Pathology & Pathophysiology

The peripheral nerve
 Peripheral nerves are painful when you touch them
 Most common biopsy site: sural nerve behind lateral malleolus
 See trichrome, drawing, schematic below

Epineurium Perineurium Endoneurium

around whole nerve around each fascicle, thick (up to 12 layers thick) inside (pink stains myelin here)
fatty yellow  Not present in root  Green is collagen
 Inside of nerve is immunologically privileged space (gives nerve stretchiness)

Dorsal root (see EM above): paucity of collagen (vs peripheral nerve)

Fiber Speed Other
Large, myelinated axons (Aβ) 120 m/s
Small, myelinated axons (Aδ) 15 m/s “first pain” (immediate after burning hand)
Pale gray circles: unmyelinated axons (C-fibers) 1 m/s “second pain” (later; slower; really hurts)

Node of Ranvier axon narrows as Schwann cell processes interfold

 Where almost all ionic exchange occurs
 saltatory conduction relies on N of R
 diameter of axon ↓ at nodes
 Lots of Na channels (inflow of Na) in node itself

+
K channels ↑ on either side (K out, termination of flow) Node of Ranvier: axon stained (L), myelin stained (R)

C-fiber axons (no myelin)

 Lots of collagen (in peripheral nerve); Schwann cells wrapped around axons
 C-fiber: light gray axoplasm with neurofilaments & MTs
 In unmyelinated state, can have several axons per Schwann cell
o In neuropathy, axons missing! Schwann cells will actually wrap collagen

Left: normal C-fibers, several wrapped by Schwann cell.

Right: Schwann cells wrapping collagen! (neuropathic)

25
 Pathology
Major categories
Wallerian degeneration Axonal degeneration
Demyelination Schwann cell loss
Vasculitis / amyloid Endothelial dysfunction
Immune mediated Mϕ / Abs
Connective tissue disorder fibroblast  collagen
Metabolic disorder Systemic effects

Wallerian Degeneration
 time-delayed, actively-mediated, axonal degradation distal to a nerve injury
o Cut off from soma, so axon degenerates distally

Early phase WD little visible change in nerve

Mid phase WD  neurofilaments and microtubules quickly dissolve
(48-96h post  myelin ovoids form
transection)  responder cells synthesize DNA
 macrophages proliferate and digest myelin
Late phase WD
 Schwann cells proliferate, axons may sprout

MTs, neurofilaments losing structure Myelin ovoids; also ↓ #axons Foamy Mϕ (fat-filled with myelin) at work
(L: normal, R: mid-phase WD) (shouldn’t see individual axons) Also ↑cellularity (more blue) but no axons

Demyelination

Segmental in nature (one or more Schwann cells / internodes may degenerate)

 Schwann cell is target!
 (vs Wallerian degeneration, which occurs everywhere distal to injury)

Acute phase demyelination: immune-targeted Mϕ invade

 begin myelin digestion (foamy Mϕ)
 Acquired demyelination

Subacute phase demyelination: “naked” axons & thinly myelinated axons

 Big axons without myelin are ABNORMAL: myelination should be proportional to axon diameter!
 Acquired or inherited

Repeated demyelination / re-myelination  “onion bulbs”

26
 Mϕ in nerve; some axons normal; Onion bulbs from demyelination /
others being pathologically changed “Naked axons” – shouldn’t see remyelination cycles
big axons without myelin! (visible hypertrophy of nerves on PE!)

Vascular Pathology

Vasculitis: inflammation and occlusion of vessels

 Vasculitic damage is often patchy but may be confluent.
First phase vasculitis Peri-vascular inflammation and ↑ Mϕ inside vessel
Second phase vasculitis Fibrinoid necrosis and invasion of the vessel wall
Third phase vasculitis shows vessel occlusion

Nerve appearance with vasculitis:

Fasicle-fasicle variation and
 Centro-fascicular axon loss and fascicle-to-fascicle variation centrofasicular axonal depletion

Amyloid: deposition of amyloid in vessel wall; distorts vessel wall

 Congo red & apple-green birefringence with polarized light
 Small, myelinated axons depleted, large axons preserved

Immune-mediated disorders
Multiple variants of Guillain-Barre syndrome
AIDP/CIDP/AMAN
 AMAN = motor variant
Sensory>motor
Anti-MAG
 Myelin Associated Glycoprotein
Pure motor block (looks like ALS!)
MMN (multifocal motor neuropathy)
 IgM to GM
Pure sensory
Hu
 paraneoplastic, neuronal Ab

Connective tissue & metabolic

Collagen disorders  nerve injury

Metabolic forms
 Diabetes: multiple forms of PN associated
 Renal: painful burning, cold, numbness
o ↓ with ↑ Epo supplementation in renal failure
o Epo receptors on nerve fibers!

27
 Clinical Approach to Peripheral Neuropathy
Prevalence
 5% medicare patients have it as 1° diagnosis; 8.5% as 1st or 2nd 3 diagnostic questions:
 Most common starting in middle age  Focal or diffuse?
 Diabetes is #1, others important too  Axonal or demyelinating?
 Heritable or acquired?
Patient questions:
 What is neuropathy? A disease of the peripheral nerves (connect legs/arms to SC/brain). Like wiring!
 Is there a treatment? Depends on the cause.
 Will I wind up in a wheelchair? Probably not.

Focal or Diffuse?
 Numbness: legs  arms   forehead (C2 wraps up –
sort of long!)
 Can tell on physical exam

Options:
 Radicular pattern?
 Named nerve?
 Diffuse & symmetrical?

Axonal or Demyelinating?

 Use EMG / nerve conduction study to figure it out!

Axonal Demyelinating Both

 Severe compression  Mild compression  Diabetic
 Toxicity  Autoimmune (GBS, CIDP)  Severe GBS
 Nutritional  Heritable  Nutritional

What’s in the peripheral nerve? Those are the things that could be affected!
 Axons (neuronal processes)
 Schwann cells (myelinating & non-myelinating)
 Mϕ, fibroblasts, mast cells, endothelial cells, etc.

Nerve conduction studies EMG

 Motor / sensory  Extent of denervation
 Demyelinating  Evidence of intrinsic mm disease
 axonal, patchy vs diffuse  Really painful!
 acquired vs. inherited esp. abductor pollicus (carpal tunnel) / biceps

Skin biopsy: small fiber assessment

 Essential for small fiber neuropathies
 Well-tolerated, easily repeated, great clinical marker

Skin biopsy: C-fibers (small fibers)

28
Heritable or Acquired?

Heritable Acquired
 Axonal  Sensory / autonomic  Compression  Toxicity
 Demyelinating  Motor  Autoimmune  Viral

Lab studies:
 Basics: metabolic, TSH  PN extra: autoimmune, ANA, SS-A
 PN special: 2h glucose tolerance test (diabetes)  PN CSF: protein, cells (GBS, etc)

Diagnosis & Treatment

Summary of diagnostic tests:

Test Used for…

NCS/EMG Large fibers
Skin biopsy Small fibers*
Lab studies Disease markers
Nerve biopsy Vessels, inflammation (vasculitis, amyloid, leprosy, sarcoid)
*Note that NCS/EMG DOESN’T tell you anything about small fibers!
nd
* do a muscle biopsy too for vasculitis: don’t want to miss it & subject pt to 2 Bx

Nerve biopsy: generally the last stop for diagnosis

Treatment
 Anti-depressants, narcotics / atypical agents, anticonvulsants, ± topical
 NSAIDS ARE NOT EFFECTIVE for neuropathic pain
o If not responding to ibuprofen, etc – think NEUROPATHIC!

29
 Pathology of Neurodegenerative Disease
Alzheimer Disease (AD)
 Most common neurodegenerative disease, #1 cause of dementia
o Usually elderly, F>M
o 10% have strong FHx

 Slowly progressive course (years)

o Early: memory loss (esp. short-term)
o Loss of other cortical functions:
language, judgment, abstract reasoning, impaired visuospatial skills
o Average survival 5-10 yrs after onset

Gross:
 Diffuse cortical atrophy & hippocampal atrophy
 Narrowed gyri & widened sulci result

Microscopic: Plaques & Tangles

Neuritic plaques: Extracellular Amyloid-β, abnormal neurites (organelles plus tau), reactive microglia
Neurofibrillary tangles Cytoplasmic inclusions made out of tau protein

Plaques
 Neuritic plaques: Amyloid-β peptide+ abnormal neurites
o Most important for AD Dx

o Neurites come from multiple surrounding neurons

 Swollen because tau & abnormal organelles accumulate
o May or may not have dark spot in center seen in pic L: close-up neuritic plaque, R: zoomed out
o Reactive microglia too (inflammatory component)
o ↓ # synapses within plaque

 Diffuse plaques: seen in other situations too

 Amyloid-β can accumulate in blood vessels also

Amyloid-β (Aβ)
 Key component of plaques, can see in vessels too

 From Amyloid precursor protein (AP) via abnormal cleavage (β-, γ- secretases)
o AP is normal transmembrane protein

 Peptides of varying lengths

 smaller > larger oligomers for toxicity

30
Familial AD (autosomal dominant form)
 APP is replicated in Down Syndrome (trisomy 21)  AD in pts with Down’s!

 Presinilin 1 in ≈ 40% of early onset cases, but small % of overall cases

o Presinilin – component of γ-secretase, also involved in NOTCH signalling

 ApoE4 is a risk factor (in late onset forms)

Gene Chromosome Age of Onset % of Early Onset Cases % of All Cases

APP 21 45-66 <1 <0.1
Presenilin 1 14 28-62 40 1-2
Presenilin 2 1 40-85 <1 <0.1
ApoE4 19 >60 (late onset) (risk factor)
What do these genes do? ↑ levels of Aβ42 (pathogenic)

Tangles:
 Start in medial temporal lobe (incl. hippocampus), spread throughout cortex
o Sterotyped spread (unlike diffuse neuritic plaques)
 Primary sensory / motor areas are affected last

Hippocampus:
 Normal circuitry: Neocortex → Entorhinal cortex → Dentate gyrus → CA3 → CA1 → Subiculum
 Hippocampus crucial for short-term memories
 Earliest tangles appear in entorhinal cortex and CA1
o Taking out afferent and efferent circuitry to/from hippocampus!

Tau
 Microtubule-associated protein that’s main component of tangles

 Hyperphosphorylated in AD  dissociates from MTs 

 Self-aggregates into paired helical filaments (PHF)
 Abnormal tau accumulates in cyto as
o neurofibrillary tangles (cell body)
o neuropil threads (neuronal processes/axons)

Tau / amyloid- β relationship is controversial & unclear!

 Mutations in tau itself cause NON-AD degenerative disease!

Parkinson Disease

#2 neurodegenerative disease
 1% of pop > 65 yo  Usual onset 40-70 yo  Slight M>F

Clinical features
 Rigidity, bradykinesia, resting tremor
 Postural instability, mask-like facies, festinating gait
 Some cognitive impairment in late stages

Gross:
 Pallor in substantia nigra of midbrain (lose cells  lose black pigmentation!)
31
  Other brainstem nuclei affected too:
o locus ceruleus (adrenergic to forebrain)
o dorsal nucleus of vagus (parasymps to viscera)

Microscopic:
 Loss of DA neurons in substantia nigra

 LEWY BODIES: α-synuclein (in pigmented DAergic SN neurons)

o Round, cytoplasmic inclusions with clear halos
 LEWY NEURITES: α-synuclein again
o In neuropil around Lewy bodies

α-synuclein: normal presynaptic protein

 Misfolded in Lewy bodies & Lewy neurites
 Protofibrils (not large aggregates) may be toxic

Mutations in familial Parkinson dz (not as common as familial AD

Gene Inheritance Function Lewy Bodies Age of Onset

α-Synuclein Autosomal dominant Synaptic function(?) Yes 30-60
Parkin Autosomal recessive E3 ligase (ubiquitin-proteasome) Rarely ~30
LRRK2 (most common) Autosomal dominant Protein kinase Variable 40-80

 Parkin: early onset Parkinson Dz

 α-synuclein: removed by parkin through Ub-proteosome system
 Nobody really knows how these genes are linked together

Dementia in Parkinson’s Disease

 Most people with PD don’t have dementia

Causes:
 Severe, end-stage PD itself
 Co-existing disorders (Lots of overlap between AD and PD – consider AD in PD pt!)
 Dementia with Lewy bodies (cortical Lewy body disease)

Dementia with Lewy Bodies (DLB)

#2 neurodegenerative dementia Distinguishing Features of DLB

 Age of onset similar to AD; average survival 8 years  Visual hallucination
 Onset of dementia prior to PD or within 2 years  Parkinsonism
 Clinical / pathologic overlap with both AD and PD  Marked fluctuation in symptoms
Pathology:
 Cortical Lewy bodies: limbic & association areas of cortex
o No halos (can’t see in H&E)
 Lewy neurites in hippocampal area CA2

Relationship of dementia with Lewy bodies to PD?

 2 diseases or continuum?
o Continuum: Lewy bodies: medullaponsmidbrainlimbic ares of cortex  association areas
o Different: Most PD pts won’t get cortical Lewy bodies or dementia; pts with DLB generally don’t have full PD

32
 Amyotrophic Lateral Sclerosis (ALS)
 “Motor neuron disease” (most famous: Stephen Hawking, Lou Gehrig)
o Both upper motor neurons and lower motor neurons (spinal cord, medulla)

Clinical Course: Progressive weakness and atrophy, eventually involving respiratory muscles

Epidemiology:
 40-60 years of age  Usual duration 3-5 years  5-10% familial
 male > female  10% > 10 years

Gross findings
 ATROPHY of VENTRAL ROOTS of SPINAL CORD
o Compare size of anterior & posterior roots!
 Rarely: atrophy of motor cortex

Microscopic findings:
 Lose myelinated axons in CST,
ventral roots, motor nerves

 Lose motor neurons

Neuronal inclusions containing ubiquitin, TDP-43

 Ub seen in a bunch of neurodegenerative inclusions
 “Skein inclusions” – have TDP-43 (ALS-specific)

TDP-43: Transactivation response DNA-binding Protein 43

 Normal: found diffusely throughout nucleus
 Sporadic/familial ALS: see cytoplasmic ± nuclear
inclusions in motor neurons

TDP-43, ALS, and frontotemporal dementia (FTLD-U form)

 TDP-43 inclusions also found in most common form of frontotemporal dementia

o FTLD-U = “frontotemporal lobar degeneration with Ub inclusions”

 SPECTRUM: ALS  ALS + dementia  FTLD-U (without ALS!)

o Pathogenic & clinical overlap

Genes in familial ALS

 Superoxide dismutase
o 1st “ALS gene” in familial ALS, 10% familial cases, aut-dom
o no TDP-43 inclusions: maybe not relevant to sporadic ALS?

 TDBP: gene for TDP-43

o but only a few ALS families have been described with mutations in TDBP

 Other mutations associated with TDP-43 deposition in FTLD-U

o but not yet linked to ALS itself

33
 Huntington Disease
Epidemiology
 Age of onset usually 30-50 years, but onset in infancy through old age is well documented
 Duration typically 10-30 years
 Autosomal dominant inheritance (polyglutamine repeat)

Clinical Features
 Chorea; also an akinetic-rigid form
 Personality change, depression and psychosis; progressing to dementia

Gross findings:
 ATROPHY of STRIATUM, esp. CAUDATE NUCLEUS
 Dilation of ventricles results; cortical atrophy later

Microscopic:
 Neuronal loss and reactive astrocytosis
 Loss of 50% of striatal (spiny) neurons: onset Sx

 Intranuclear inclusions: HUNTINGTIN

 Similar inclusions in other polyglutamine diseases

Polyglutamine repeats: Left: control; Middle: HD, ↓ neurons & ↑ astrocytes

 Huntingtin, on chr. 4p Right: Huntingtin inclusion in nucleus (zoomed in)
 Expressed throughout body; function unknown in neurons
# Phenotype
<27 Normal
Repeat expansion numbers are important clinically
27-35 Unstable, prone to expansion /
 Anticipation (esp. paternal) contraction but no disease
 ↑ repeat # in successive generations 36-39 Variable penetrance
>40 Clinical disease (can be much higher)
Repeat length is important too:
 Longer repeat length: earlier onset and more severe disease
 Shorter repeat length: later onset and milder; may present as dementia

Proteins in Neurodegenerative Disease

 Good for study of pathogenesis, good place to start, but don’t know if they’re markers, harmful, protective?
 Mechanisms still not worked out

Summary table
Disease Gross findings Neuronal loss Inclusions / deposits Protein(s) Gene(s)
Hippocampal
Alzheimer Hippocampus Neuritic plaques and Aβ peptide APP, presenilins 1&2,
and cortical
disease and neocortex neurofibrillary tangles tau ApoE4
atrophy
Parkinson
Substantia nigra, α-synuclein
disease / Pallor of Lewy bodies
other brainstem α-synuclein parkin
dementia with substantia nigra Lewy neurites
nuclei LRRK2
Lewy bodies
Ventral horns;
Atrophy of Skeins SOD-1
ALS hypoglossal TDP-43
ventral roots rounded inclusions TDBP
nucleus
Striatal
Huntington
(especially Striatum Nuclear inclusions huntingtin huntingtin
disease
caudate) atrophy
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