Neuroanatomy Block 4 Neurodegenerative Diseases

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neurodegenerative diseases characterized by:

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progressive loss of neurons
• No identifiable inciting event
• Only selected groups of neurons
• Only selected groups of neurons involved
• Primarily cerebral cortex: dementia
• Primarily subcortical: movement disorders

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Abeta peptide found in

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plaques, tangles, amyloid angiopathy

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pathological changes identical to alzheimers occur in almost all trisomy 21 pts who live

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beyond 45

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mutations of what gene is implicated in some cases familial AD, gene dosage phenomenon in Down syndrome

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APP (amyloid precursor protein) gene

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what is the most common cause of dementia?

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Alzheimer's disease

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how does alzheimer's start? onset and progression

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• Insidious onset of higher level intellectual impairment, mood/behavior changes → progressive memory loss, disorientation, aphasia → mute, immobile

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onset of Alzheimers is generally after

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age 50 with increasing incidence with increasing age

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AD involves atrophy of what?

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frontal, temporal, parietal lobes
may have hydrocephalus ex-vacuo

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who has AD features to a lesser degree?

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elderly non-demented brains

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flame cells
bundls of intracytoplasmic filaments that displace or encircle nucleus remain visible after death of neuron
primary components: microtubule
assoc with tau protein, ubiquitin, amyloid, β-peptide

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neurofibrillary tangles

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EC spherical collections of dilated, tortuous, neuritic processes, 20-200 microns

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neuritic plaques

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what is often seen at the perimeter of neuritic plaques?

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microglia and astrocytes

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what is the primary component of neuritic plaques?

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Aβ peptide

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deposition of Aβ peptide in cerebral vessel walls

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amyloid angiopathy

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neuronal intracytoplasmic vacuoles containing granules

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granulovacuolar degeneration

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ovoid pink EC bodies containing paracrystalline arrays of beaded filaments

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Hirano bodies

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amyloid is encoded by what chr?

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21

Front 18

amyloid found in plaques, tangles, amyloid angiopathy get there how?

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endocytosed by b- and g-secretase

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apolipoprotein E (Apo E) is encoded by chr

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19

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mutation of ApoE causes

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increased risk of developing AD
decrease age of onset

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rare disease with progressive dementia, behavioral, personality changes, language disturbances

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Pick disease

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Pick disease has what morphological characteristics?

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severe "knife edge" atrophy of frontal and temporal lobes
neuron loss is most severe in cortex of these lobes surviving neurons often swelling (Pick cells)
or cytoplasmic inclusions (Pick bodies)

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decreased facial expression, stooped posture, festinating gait, rigidity, "pill-rolling" tremor

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Parkinsonism

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Parkinsonism is due to damage to

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nigro-striatal dopaminergic system

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what can cause Parkinsonism?

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absence of any other known cause (idiopathic)
sporadic but can be AD (mutation of alpha-synuclein)

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ovoid pink EC bodies containing paracrystalline arrays of beaded filaments

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Hirano bodies

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amyloid is encoded by what chr?

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21

Front 28

amyloid found in plaques, tangles, amyloid angiopathy get there how?

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endocytosed by b- and g-secretase

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apolipoprotein E (Apo E) is encoded by chr

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19

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mutation of ApoE causes

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increased risk of developing AD
decrease age of onset

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rare disease with progressive dementia, behavioral, personality changes, language disturbances

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Pick disease

Front 32

Pick disease has what morphological characteristics?

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severe "knife edge" atrophy of frontal and temporal lobes
neuron loss is most severe in cortex of these lobes surviving neurons often swelling (Pick cells)
or cytoplasmic inclusions (Pick bodies)

Front 33

decreased facial expression, stooped posture, festinating gait, rigidity, "pill-rolling" tremor

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Parkinsonism

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Parkinsonism is due to damage to

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nigro-striatal dopaminergic system

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what can cause Parkinsonism?

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absence of any other known cause (idiopathic)
sporadic but can be AD (mutation of alpha-synuclein)

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morphological changes in Parkinsonism

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Pallor of SN and LC due to loss of pigmented neurons in nuclei
Lewy bodies - large round eosinophilic inclusion with a halo in cytoplasm of neuons

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morphological changes in Parkinsonism

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Pallor of SN and LC due to loss of pigmented neurons in nuclei
Lewy bodies - large round eosinophilic inclusion with a halo in cytoplasm of neuons

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Lewy bodies contain

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NF, alpha-synuclein, ubiquitin

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Lewy bodies contain

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NF, alpha-synuclein, ubiquitin

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what is the tx of Parkinsonism?

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L-dopa helpful but some pt become refractory over time
stereotactic transplantations of fetal mesencephalic tissue into striatum can be effective

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what is the tx of Parkinsonism?

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L-dopa helpful but some pt become refractory over time
stereotactic transplantations of fetal mesencephalic tissue into striatum can be effective

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what percentage of PD pts develop dementia?

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10-15%

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what percentage of PD pts develop dementia?

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10-15%

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truncal rigidity, disquilibrium, abnormal speech, vertical gaze palsy, progresses to difficulty with all eye mvmts, mild progressive dementia

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progressive supranuclear palsy

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truncal rigidity, disquilibrium, abnormal speech, vertical gaze palsy, progresses to difficulty with all eye mvmts, mild progressive dementia

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progressive supranuclear palsy

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age of onset for progressive supranuclear palsy?
male:female ratio?
lethal within...

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onset 5th-7th decades
2:1
5-7 yrs

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age of onset for progressive supranuclear palsy?
male:female ratio?
lethal within...

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onset 5th-7th decades
2:1
5-7 yrs

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hallmark of progressive supranuclear palsy

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widespread midbrain neuron loss and globose neurofibrillary tangle

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hallmark of progressive supranuclear palsy

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widespread midbrain neuron loss and globose neurofibrillary tangle

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neurodegenerative disorders affecting multiple neural pathways
include:

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striatonigral degeneration
Shy-Drager syndrome
olivopontocerebellar atrophy
distinguied by clinical features and distribution of neuron loss--some overlap

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neurodegenerative disorders affecting multiple neural pathways
include:

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striatonigral degeneration
Shy-Drager syndrome
olivopontocerebellar atrophy
distinguied by clinical features and distribution of neuron loss--some overlap

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loss of neurons of pontine nuclei, purkinje cells of cerebellum, inferior olive

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olivopontocerebellar atrophy

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loss of neurons of pontine nuclei, purkinje cells of cerebellum, inferior olive

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olivopontocerebellar atrophy

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what are the symptoms of olivopontocerebellar atrophy?

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ataxia
eye and somatic mvmt disorders
rigidity
dysarthria

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what are the symptoms of olivopontocerebellar atrophy?

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ataxia
eye and somatic mvmt disorders
rigidity
dysarthria

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combined features of IPD or striatonigral degeneration w/ autonomic disturbances due to degeneration in intermediolateral column of SC

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Shy-Drager syndrome

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what are the ANS features of Shy-drager?

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impotence
orthostatic hypotension
sweat and salivary disturbances
pupillary abnormalities

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loss of neurons in SN, target neurons in caudate, putamen, gliosis, no lewy bodies

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striatonigral degeneration

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does striatonigral degeneration respond to L-dopa?

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NO

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Hungtington's contain multiple repeats of

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CAG

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CAG trinucleotide is lengthened during

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spermatogenesis and paternal transmission

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Friedriech Ataxia contain multiple repeats of

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GAA trunucleotide

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the defective gene in Hungtington's is

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huntingin

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the defective gene in Freidreich ataxia is

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frataxin

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relentless progressive AD disease with jerky hyperkinetic mvmt (chorea) and dementia

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Huntington's

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huntington's pt can also develop

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Parkinsonism

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average course for Huntington's

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15yrs

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in huntington's, you lose what neurons and where?

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neurons in BG --> increases inhibition of subthalamic nucleus --> prevents it from regulating motor output

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hydrocephalus ex vacuo is due to

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atrophy of caudate
often dilatation of lateral and 3rd ventricles

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HD gene codes for

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huntingin protein- unknown function

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trinucleotide repeats are expanded during

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spermatogenesis

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atrophy of what in order from most to least?

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caudate>putamen>GP>frontal cortex>parietal cortex

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AR progressive disease beginning in childhood w/ ataxia --> hand clumsiness and dysarthria

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Freidreich Ataxia

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what sensory losses are there in Freidreich ataxia?

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most DTRs (deep tendon reflexes) absent
loss of proprioception, vibratory pain, temp sensation

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most pts with Freidreich Ataxia also have what medical conditions? (5)

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pes cavus
kyphoscholiosis
arrhythmias
CHF
DM in 10%

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in Freidreich ataxia, there is atrophy of neurons and axons where?

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SC
brainstem
cerebellum
+/- motor cortex
DRG

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what heart problems comes w/ Freidreich ataxia?

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enlarged heart
percarditis
myocarditis

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AR disease of childhood, lethal by 2nd decade
recurrent respiratory tract infections --> ataxia, dysarthria, eye mvmt disorders, telangiectasias of skin and conjunctiva

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ataxia telangiectasia

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what comorbidities w/ ataxia telangiectasia?

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lymphoid malignancy
glioms
carcinomas

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ataxia telangectasia has abnormalities of what gene?
what does it do?

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ATM
impairs DNA repair

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heterozygous carriers of ATM abnormalities for ataxia telangiectasia are at increased risk of

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breast cancer

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loss of what and degeneration of what in ataxia telangectasia?

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loss of purkinje, granular cells of cerebellum
degeneration of dorsal columns, spinocerebellar tracts
anterior horn cells
peripheral neuropathy

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what hypoplastic organs in ataxia telangectasia?

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lymph nodes
thymus
gonads

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autosomal dominant in 10%
mutation of SOD1
familial cases earlier onset
motor neuron disease --> loss of upper and lower MN

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Amyotrophic lateral sclerosis

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atrophy of what in ALS?

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precentral gyrus, anterior spinal roots, muscles (denervation atrophy)
loss of anterior horn neurons along entire length of SC with gliosis
loss of neurons in CN nuclei
demyelination from CST to anterior roots