Neuropathology of neurodegenerative disorders
Dr. C. Bergeron
Slow neuronal death preceded by long period of dysfunction. This provides a window of opportunity to protect the neurons and prolong their survival. Thus, importance of early diagnosis.
Early diagnosis can be made with functional imaging. Degeneration begins in the temporal-parietal area with relative sparing of the frontal lobes.
In diffuse Lewy body disease and in Parkinson disease.
Alpha-synuclein is a synaptic protein that is in the presynaptic area, important in neuroplasticity, involved in traffic of synaptic vesicles.
Lewy bodies occur in substantia nigra, nucleus basalis, locus ceruleus, serotonin neurons, limbic system, autonomic neurons, enteric neurons, and cortex. They give rise to parkinsonism, abnormal behaviour, visual hallucinations, autonomic symptoms, abnormal GI motility, and dementia. They develop in an unpredictable manner leading to variability of the clinical symptoms.
Structural correlation is unknown. No atrophy in the brain. Very little neuronal loss.
No correlation between load of Lewy bodies and severity of disease (debated).
DLB patients may respond better to cholinergic agents than AD. Their M1 muscarinic receptors are upregulated. This improves attention and consciousness, not memory. ACh plays a role in sleep, dreams, attention, and consciousness in the basal and pedonculopontine nuclei.
Circumscribed cortical atrophy, neuronal loss and gliosis, microvascularization, status spongiosus, pale swollen neurons.
Deposition of abnormal tau, Pick bodies, ubiquitin inclusions and profiles.
CBGD – tau + (neuronal and glial)
Pick’s – tau + and Pick bodies
FTD – Pick body negative
Pick’s disease – “dried walnut” type atrophy
- status spongiosus
- balloon neurons
- Pick bodies
CBD – more subtle atrophy, circumscribed in perirolandic distribution
- loss of pigment in S. nigra
- neuronal loss and gliosis, swollen neurons
- tau + tangles, neuropil threads
FTD – cortical changes in frontal +/- temporal areas
- tau negative
- ubiquitin inclusions (nuclear or cytoplasmic)
- inclusions similar to motor neuron disease with dementia
Relative incidence of frontotemporal dementias:
15% Pick’s disease
Pathogenesis of FTD – tau dysfunction? Relationship to motor neuron disease?
IPD - In longstanding disease, Lewy bodies can be hard to find. Look for them in exotic places. Also easier to look for pale bodies, precursors of Lewy bodies. If seen, look carefully for Lewy bodies.
PSP – atrophy of brainstem, STN, SCP, STN, GP, loss of nigral pigment is _uniform_. Glial tau present in the intermediate compartment – “tufted astrocyte”.
Tau – AD is 3 bands, PSP and PD is 2 bands.
- progressive striatal atrophy, relative sparing of the nucleus accumbens
- neuronal loss and gliosis, relative sparing of large neurons
- secondary atrophy as disease duration increases – globus pallidum lateral>medial, S. nigra pars reticulate, brainstem
- brain is not shriveled, but actually small, thinning of cortex and white matter, large ventricles, thinning of corpus callosum
- oligodendroglial inclusions
- alpha-Synuclein positive
OPCA – flattened basis pontis
In pure cerebellar degeneration, you get Purkinje cell loss, with cortical atrophy. In OPCA, you lose afferent fibers, so the white matter is atrophic.
Hard to detect cerebellar atrophy. The cerebellum should weight 1/10th of the cerebral hemispheres.
In cerebellar degeneration, loss of Purkinje cells and decreased granular cell layer. In OPCA, Purkinje cells preserved. Silver stain in loss of Purkinje cells shows “empty baskets” in early disease, or torpedoes later on (“axonal spheroid”).
The olivary nucleus in OPCA is sick.
DRPLA – dentato-rubro-pallido-luysian atrophy
- CAG repeats on chr 12
- Ataxic-choreathetoid, pseudo-Huntington, myoclonus epilepsy
- Autosomal dominant
- GAA extention in the Frataxin gene
- Autosomal recessive
- microvascuolation in type I (dementia)
- confluent spongy degeneration in type II (cerebellar)
- demented type gets diffuse synaptic loss, plaques in the cerebellar type
- florid plaques in vCJD with surrounding spongiosis
- western blot is different in the different types