CPC #7: Pathology Barbara J. Crain, MD, PhD February 25, 2009

Gross brain findings Lacunar infarct, left putamenNO hippocampal atrophy Well pigmented substantia nigra

No evidence of Alzheimer disease No neuritic plaquesFrequent neurofibrillary tangles in hippocampus (above) and entorhinal cortex; sparse tangles in temporal cortex Silver

Evidence of Parkinson disease?  Lewy bodies in brainstem or cortex?  α-synuclein stains? ?

Evidence of Parkinson disease? NO  Lewy bodies in brainstem or cortex? NO  α-synuclein stains? Negative

Globose tangles (cytoplasmic inclusions) in neurons of substantia nigra Globose tangles displacing neuromelaninTau-positive H&ETau

Similar tangles in multiple brainstem and deep gray areas Base of ponsGlobus pallidus

Tau-positive inclusions in glia Thorn-shaped astrocyte Smaller inclusions in astrocytes and oligos Tufted astrocytes

Frontal and temporal neocortex Spongiosis in outer layers of cortex Occasional astrocytic plaques TauH&E

“TAUOPATHY”: Progressive supranuclear palsy (PSP  High density of tangles and threads in at least 3: -Substantia nigra -Basis pontis -Globus pallidus -Subthalamic nucleus  Low to high density of tangles or threads in at least 3: -Striatum -Oculomotor complex -Medulla -Dentate nucleus AND

Progressive supranuclear palsy (PSP)  Classic syndrome -Akinetic / rigid parkinsonism and falls -Tremors mild or absent -Symptoms poorly responsive to L-DOPA -Supranuclear gaze palsy, particularly vertical -Cognitive change, dementia late if at all  More recently -Dementia (FTD-type) can predominate (behavioral and/or language problems) -Not all patients have eye findings  Gross brain changes -Pallor of substantia nigra -Brainstem atrophy -Variable cortical atrophy Dudley Moore

“Protein-based” classification system: Ubiquitin-positive Tau-negative (most TDP-43+)  FTLD-U  FTLD-U / MND (ALS+dementia) Ubiquitin-negative Tau-negative  Dementia lacking distinctive histology  Miscellaneous specific types Tau-positive  Pick disease  Corticobasal degeneration  PSP  FTDP-17 FRONTOTEMPORAL DEMENTIAS Behavioral / personality changes Progressive nonfluent aphasia, semantic dementia

Progressive supranuclear palsy without PSP PSP with “PSP” All PSP as defined by tau + We probably need a new name….

PSP illustrates two general principles of neurodegenerative disease  Importance of protein aggregation -Characteristic inclusions / deposits in different diseases -Current basis for histologic classification / diagnosis throughout the neurodegenerative diseases  “Neurodegenerative” diseases involve glia, too You see what you look for!