Pathology Of Neurodegenerative Disorders Flashcards
Neurodegenerative diseases that involve the hippocampus and cortices present with what symptoms?
Cognitive , memory, behavior and language dysfunctions
includes Alzheimer’s and FTLD as the most common ones
Neurodegenerative diseases that affect the basal ganglia present with what symptoms?
Movement disorders (hyper/hypokinetic)
includes Parkinson’s and Huntington’s
Alzheimer’s disease background
most common cause of dementia in older patients
Most Alzheimer’s disease is sporadic
- 5-10% is genetic
Usually only presents after 50 yrs of age
Alzheimer’s disease symptoms
Insidious onset
Early stage Symptoms:
- impaired higher intellectual intellectual functions
- memory impairment
- altered mood and behavior
Late stage symptoms:
- severe aphasia
- profound motor and cognitive disabilities
- mute and immobile patients
*patients usually die from inter current infections during the late stage phases
Alzheimer’s pathogenesis
Over production and accumulation of AB plaques and tau protein tangles throughout the brain
- causes inflammation and neuronal cell death overtime
AB and tau proteins are misformed peptides usually used to from microtubules
- the AB plaque aggregations replace normal synaptic locations overtime
- tau aggregates prevent neuronal synapses as well
*AB generation is the critical initiating event for developing Alzheimer’s
** The APP gene on chromosome 21 is directly linked to production of AB plaques, so patients with this gene have higher risk (also because of this down syndrome patients are at even higher risk due to potentially having 3 copies of this gene)
- ** The apolipoproteinE (ApoE) has a direct link to developing AD
- specifically the e4 alleles on chromosome 19
Alzheimer’s disease morphology
Shows cortical atrophy w/ widening cerebral sulci
- affects frontal/temporal and parietal lobes the most
Also shows hydrocephalus ex vacuo
- compensatory ventricular enlargement due to cortical atrophy
AB plaques vs tau tangles morphology
neuritis plaques
- focal, spherical collections of dilated processes
- most common found in the hippocampus, amygdala and the neocortex
- core contains the AB protein aggregates
Neurofibrillary tangles
- paired helical filaments that are basophilic structures in the cytoplasm.
- the tau proteins are hyper phosphorylated
- most commonly found in the cortical neurons, pyramidal cells in the hippocampus, amygdala, basal forebrain and raphe nuclei
Frontotemporal lobar degeneration (FTLD)
Includes several disorders that affect primarily the frontal and temporal lobes
- often referred to as frontotemporal dementias
Occurs in younger than 50 yrs of age patients
Clinical features
- progressive deterioration of language behavior (comes first usually)
- personality changes
- memory disturbances (usually last)
Shows atrophy of frontal and temporal lobes and neuronal loss/gliosis in these regions
Two subtypes of FTLD
Picks disease
- Contains FTLD-tau proteins that aggregate together and form smooth round inclusions that are called “Pick bodies”
FTLD-TDP43
- contains aggregates of DNA/RNA-binding protein TDP43
Parkinson disease background
Marked by a hypokinetic movement disorder that is caused by a loss of dopaminergic neurons in the substantia Nigra
-pars reticulata is affected first usually
Caused by Lewy body inclusions within dopaminergic neurons of the substantial Nigra
- contain a-synuclein proteins
- causes defects in Autophagy and lysosomal degradation as well
Shows Parkinsonism symptoms
- ridigity
- tremor
- bradykinesia
- instability
Other symptoms:
- diminished facial expression (masked facies)
- stooped posture
- slowing of voluntary movement
- destinations gait
- pill-rolling tremors
Usually takes 10-15 yrs to progress and then eventually generate immobility In the patient
- patient dies from pneumonia or secondary infection
Morphology of Parkinson’s disease
Pallor of the substantia Nigra and locus ceruleus
- Loss of pigmented neurons in these regions that is replaced with gliosis
Lewy bodies are seen which are single/multiple rounded elongated inclusions that stain eosinophilic
Treatment of Parkinson’s
L-DOPA is maintain
- best initially but overtime becomes resistant to
- also only slows disease does not cure
Deep brain stimulation
- used for extreme tremors (especially action tremors)
Huntington’s disease background
Inherited (autosomal dominant) disease that degenerates GABAergic neurons in the stratum (caudate and putamen)
Relentlessly progressive and death usually occurs within 15yrs after early symptoms
Symptoms
- involuntary jerky movements
- early cognitive symptoms (forgetfulness, short term memory, etc.)
- suicidal ideology
Huntington’s disease pathogenesis
CAG trinucleotide repeat expansions in gene 4p16.3 on chromosome 4.
- encodes for Huntingtin proteins which gains a toxic function of the protein huntingtin
- the larger the number of repeats, the early the onset of the disease is
the number of repeats does not speed up the course of the illness (15 yrs approximately), only speeds up when the disease initiates
Huntington’s disease morphology
Striking atrophy of the putamen and caudate
Atrophy of the globus pallidus and frontal lobe
Dilated 3rd and lateral ventricles (4th remains normal)
*rarely shows atrophy in the parietal lobe
Gliosis and loss of neuronal cell bodies in the striatum
