Review of the pathophysiology, presentations and management strategies for PSP (Progressive Supranuclear Palsy)

1. PROGRESSIVE SUPRANUCLEAR
PALSY RICHARDSON SYNDROME
Randy M Rosenberg MD FAAN FACP
Associate Professor of Neurology
Lewis Katz School of Medicine at Temple University

2. TAU PROTEIN
• Tau protein promotes assembly
of and stabilizes microtubules
• One of the major structural
components of the axonal
transport and
neurotransmission
machinery.
• Abnormal phosphorylation of
tau decreases its binding
capacity to tubulin, leading to
microtubule disorganization
with protein self-
polymerization and
aggregation.
• Tau phosphorylation is
regulated by tau kinases,
phosphatases and changes in
its conformational state.

3. TYPES OF TAUOPATHIES
 Progressive supranuclear palsy (PSP)
 Frontotemporal dementia (FTD) with parkinsonism
 Corticobasal degeneration (CBD)
 Agyrophilic grain disease
 ALS/Parkinson-dementia complex of Guam
 Niemann-Pick C (NPC)
 Pick’s disease
 Post-encephalitic Parkinsonism
 Chronic traumatic encencephalopathy

4. PROGRESSIVE SUPRANUCLEAR PALSY:
CLINICAL PRESENTATION
The cardinal manifestations of PSP are as follows:
 Supranuclear ophthalmoplegia
 Pseudobulbar palsy
 Prominent neck dystonia (often dystonia in extension)
 Parkinsonism
Frequent falls/impaired postural reflexes
 Severe disruption of circadian rhythm with sleep
deprivation

5. COGNITIVE DYSFUNCTION IN PSP
• Slowed cognitive processing, sequencing and planning
difficulties, mild memory difficulty, and apathy (generally
more prominent in late disease)
• High apathy scores coupled with low agitation and
anxiety scale scores on Neuropsychiatric Inventory
testing

6. PSP: OCULAR MOTILITY DISTURBANCE
Slow vertical saccades and square wave jerks on
ocular examination (early signs)
Supranuclear ophthalmoplegia (classic gaze palsy
in PSP)
Downgaze typically involved before upgaze
Eyelid retraction, apraxia, blepharospasm or lid
lag
Complete ophthalmoparesis in advanced PSP

7. EYE MOVEMENT IN PSP

8. APRAXIA AND BELPHAROSPASM OF EYELIDS

9. PROGRESSIVE SUPRANUCLEAR PALSY (PSP)

10. MRI IN PROGRESSIVE
SUPRANUCLEAR PALSY
Atrophy of the midbrain. “Hummingbird sign”
(Mickey Mouse ears in axial projection)

11. HUMMINGBIRDS AND MICKEY MOUSE
PSP Normal

13. CRITERIA FOR DIAGNOSTIC VARIANTS OF PSP

14. TAU GENETICS IN PSP
Typical PSP Richardson’s syndrome is a
primary sporadic 4-repeat tauopathy
because, at autopsy, most of the tau that
is deposited is primarily 4-repeat tau.
In a normal brain or in a brain that has
Alzheimer’s disease, there is an equal
ratio of 3-repeat to 4-repeat tau.
In Pick’s disease, 3R>4R
In PSP and corticobasal (CBD)
degeneration, 3R<4R
For some reason, there is a strong
genetic link to 4-repeat tau in PSP
 many therapies that are being
developed for PSP are focusing on the
tau gene, and in particular on this 4-
repeat type of tau

15. BIOMARKERS IN PSP
• Despite PSP is very strongly related
to tau pathology, PSP patients have
normal or slightly low levels of tau
protein as compared with normal
controls.
• Neurofilament light chain level is
strongly related to the rate of
progression over time.
• Patients with low levels of
neurofilament have the slowest or
most indolent course of disease,
but those with higher levels have a
much more rapid progression of
disease over time.

16. TREATMENT FOR PSP
Some patients with PSP actually will respond to levodopa.
Usually, the response is less than what you would see in
typical Parkinson’s patients
A small number of patients who have severe difficulty with
opening their eyes due to apraxia of eyelid opening will respond
to botulinum toxin injections in the pretarsal muscles.
intensive physical, occupational, and speech therapy.
A small trial that was done over 6 weeks initially showed a very
modest benefit on the PSP rating scale with coenzyme Q10
supplementation.
A longer 1-year trial failed to replicate this benefit.
However, in examining the data, there was a suggestion that
possibly there might be a small benefit from coenzyme Q10

17. TOXIC GAIN OF FUNCTION IN TAUOPATHIES
The current research
community believes that the
cause of neurodegeneration, is
due to toxic gain of function.
Aggregation of tau into those
insoluble deposits and
possibly from what’s called a
prion-like spread of tau.
It is possible that the
aggregates may form in one
cell, and then they template
other forms of tau that will
spread to neighboring neurons
and glia
Gain-of-function
mutation=A mutation
that confers new or
enhanced activity on a
protein.
Loss-of-function
mutation=which are more
common, result in
reduced or abolished
protein function

18. EXPERIMENTAL AND THEORETICAL APPROACHES
Toxic gain

19. Many thanks for your attention
Applause is always welcome!