Slowly Progressive (Death 5-10 Yrs)
Disease / Signs & Symptoms / Pathogenesis / Histology
Disease
Alzheimers / -
- slowly progressive (death 5-10 yrs)
- disease of aging
- 90% sporadic (familial have an earlier onset 50 – 60 or earlier)
- Familial – Amyloid Precursor protein/ presenilin 1 (14)/ presenilin 2 (1)
- Sporadic ApoE e 4 (19)/ IL-1A & B
- AB amyloid deposition (cortex- plaques / vessel walls-angiopathy)
- Hyperphosphorylated tau protein in neurons
- Microglial reaction to amyloid (toxicity to neurons – cytokines and oxidative stress)
- Vascular insufficiency
- Neurofibrillary tangles (begin in mesial temporal lobe- spread throughout cerebral cortex)
- Tau-opathy
Frontotemporal dementia with parkinsonism – chr 17
-(FT dementia) / Dementia
Parkinsonian symptoms / Mutations in tau gene
Cerebral cortical atrophy with tau- containing neurofibrillary tangles, but no AB plaques
Degeneration of substantia nigra.
Tau- opathy
Pick Disease
-(FT dementia)
Progressive supranuclear palsy /
- Rare cause of dementia
- Usually sporadic
- Onset age 50-80, death in 5-7 yrs
- Difficulties with eye movements, speech, and a movement disorder resembling parkinsonism
- Dementia develops later in the disease
- Severe atrophy of frontal lobes with sparing of parietal and occipital lobes
- Numerous Pick bodies in neurons (round)
- Tau-opathy
- Neuronal and glial tau pathology
- – tau neurofibrillary tangles in basal ganglia and brainstem
- – tau glial inclusions in basal ganglia and brainstem
Tau -opathy / “knife edge gyri”
Corticobasal Degeneration
-(FT dementia) /
- movement disorders, often asymmetrical, and dementia
- atrophy of the motor cortex and of parietal cortex, also asymmetrical
- ballooned neurons
- tau inclusions in glia, and less commonly, in neurons in affected cortex and in the brainstem.
- Tau-opathy
Motor neuron disease inclusion dementia
-(FT dementia) /
- may or may not have clinical motor neuron disease
- may or may not be genetic
- In familial cases some family members may have dementia, while others may have motor neuron disease
- small ubiquitin positive neuronal inclusions with no other pathology
(picture in notes)
Dementia lacking distinctive histology
-(FT dementia) / / / Superficial cortical microvasculization is common to many FTDs
Vascular dementia /
- Clinically distinguished by a “stepwise” progression. Although not always reliable
- Generally caused by numerous small strokes
- Synergistic with alzheimers: less AD path required for dementia if vascular disease present
Parkinson’s Disease /
- Slowed movements and rigidity
- Tremor
- Preservation of higher cortical functions in most cases
- Some pts. Show psychiatric changes and progressive dementia: Dementia with Lewy bodies
- Most cases sporadic
- Familial -> genes-> a-synuclein / Parkin
- Lewy bodies in substantia nigra
- Death of substantia nigra dopaminergic neurons
- Loss of normal balance in basal ganglia circuits
- A-syncleinopathy
Dementia with Lewy bodies /
- Dementing disease similar to Alzheimer’s, but often with hallucinations and fluctuations in symptoms
- Overlap with Alz. Disease: most (60-70%) DLB cases also show ALZ. pathology
- Always Lewy bodies in SN, but there is not always parkinsonism
- A-synucleinopathy
Multiple system atrophy /
- Three normally separate diseases now united under the term MSA b/c of their common a-synuclein pathology
- – striatonigral degeneration
- –olivepontocerebellar atrophy
- shy-drager syndrome
- The common pathology is a-synuclein inclusions in affected areas. The inclusions are primarily in Oligodendrocytes.
- A- synucleinopathy
Huntington’s disease /
- Age of onset varies (30-50)
- Autosomal Dominant
- Large, involuntary, “dance-like” movements(chorea) loss of regulation of cortical motor neurons
- Later, dementia
- CAG trinucleotide repeats in Huntington gene (chr 4)
- – abnormal Huntington protein with glutamine repeats at one end
- – impairs mitochondrial function and axonal transport
- – worsening in successive generations
- Degeneration of straite nuclei (caudate / putamen)
- – loss of neurons, inhib GABA neurons are particularly affected
- –leads to disruption of normal inhib/excit balance in basal ganglia circuits
- Later, cortical atrophy with loss of neurons
Spinocerebellar ataxia /
- A group of diseases all genetic
- Most are dominant, some recessive
- degeneration of spinal cord and cerebellar neurons and tracts
- Friedrich ataxia begins in childhood, death w/in 5 yrs. Associated with heart disease and diabetes. GAA repeats in frataxin gene
- Ataxia-telangiectasis begins in early childhood, death by age 20. telangiectasias of conjunctiva, skin and CNS. Abnormal response to DNA damage: continued replication w/o repair or apoptosis (immunodef. w/ recurrent infections and various cancers.
Leucodystrophies /
- Long tract signs – ataxia/ pyramidal signs.
- Clinical presentation is dominated bny motor signs rather than cognitive decline: spasticity, hypotonia, ataxia
- Most have onset in early childhood: an exception is adrenoleucodystrophy
- Diffuse degeneration of CNS whire matter due to malformed myelin
- Krabbe (globoid cell) leucodystrophy
- --- deficiency of galactocerebroside B-galactosidase
- --- inability to degrade galactocerebroside
- --- alternate catabolism generates galactosphingosine, wh/ is toxic to oligodendrocytes
- --- macrophages collect undigested cerebroside, and form multinucleated giant cells around the blood vessel
- Metachromatic leucodystrophy
- ---arylsulfatase A deficiency
- --- defective degeneration of sulfatides
- – there is a (rare) adult form that can present with psych. Symp or with progressive dementia
- --- Accumulated sulfatides stain red-brown w/ cresyl violet
- Adrenoleucodystrophy
- --- peroxismal defect, x-linked
- --- inability to degrade fatty acids with more than 22 carbons (very long chain fatty acids)
- --- there is also atrophy of the adrenal glands with accum. Of VLCFA
- ---most common in 5-9yro children
- adult form with progressive paraplegic of legs (adrenomyeloneuropathy)
Clefts in Macrophages in ALD
Mitochondrial diseases
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Leigh disease /
- involve tissues with high aerobic demands muscle, heart, retina, and brain
- primarily diseases of young adults
MELAS
KEARNS SAYRE
Fatal disease of early childhood / Caused by various mutations affecting cytochrome c
Peculiar degeneration of brain tissue adj. to CSF pathways with sparing of neurons
Pathology resembles Wernicke-Korsakoff although the clinical setting is entirely different.
Vit Def: Thiamine (B1) /
- wernike encephalopathy: an acute psychotic/opthalmoplegic syndrome
- korsakoff syndrome: chronic memory disturbances with confabulation
- May cause peripheral neuropathy (beri beri)
- May cause degeneration of mamillary bodies and of brain tissue adj. to CSF pathways (WK synd) that resembles Leigh disease
- W-K syndrome is most commonly seen in association with cachexia or poor nutrition: alcoholism/ GI disease/cancer
Vit. Deficiencies: B12 /
- Numbness and tingling of legs, proceeding to spastic weakness and paraplegia
- Folate def can cause a similar syndrome
- Degeneration of both ascending and descending tracts of spinal cord: subacute combined degeneration of the spinal cord
Metabolic disorders / /
- hypoglycemia similar to hypoxic injury
- hyperglycemia dehydration affects brain function/ overly rapid rehydration can cause cerebral edema
- Hepatic encephalopathy hyperammonenia leads to confusion progressing o coma/ Histologically there are altered astrocytes (alz. Type 2 glia) in the cerebral cortex
Toxic disorders / /
- Carbon Monoxide similar to hypoxic injury/ bilateral necrosis of globus pallidus can occur/ delayed demyelination can occur
- Methanol retinal degeneration/ bilateral necrosis of putamen
- Ethanol massive, acute ethanol intoxication can cause cerebral swelling and death/ it is unclear alone has any chronic effects on CNS/ associated with nutritional deficiencies can cause cerebellar vermal atrophy or Wk syndrome/ fetal exposure results in severe deficits
- Radiation radionecrosis of brain is due to endothelial injury with fibrinoid degeneration of vessel and thrombosis/ this can follow radiotherapy for malignant brain tumor
- Combined methotrexate and radiation injury white matter necrosis/ may occur months after exposure