Tauopathies
A contemporary way to consider a set
of neurodegenerative diseases based
on their molecular signature
John Growdon, M.D.
Neurofilament tangles are composed
of paired helical filaments in AD, and
straight filaments in conditions such
as PSP.
Electron microscopy of
neurofilament fibers, labeled by
polyclonal anti-tau.
Tau Protein
• A microtubule associated protein largely localized
to neuronal axons
• Important biological role in stabilizing
microtubules and thereby aiding neuronal
structure and axonal transport
• Hyperphosphorylation of tau at specific serine &
threonine epitopes impairs it normal function; this
process either leads to neuronal dysfunction &
death, or is a marker of neuronal death.
Tauopathies: Clinical Diseases
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•
•
•
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Alzheimer’s disease
Dementia pugilistica
Guam ALS/PD
Pick Disease
Argyrophilic grain
dementia
• Nieman-Pick, type C
• SSPE
• PSP
• MSA
• Corticobasoganglionic
degeneration
• FTDP-17
• Postencephalitic PD
• Autosomal recessive
PD
History of LT
born: 6/26/05
died: 11/16/87
1977: 72 y.o. woman with subtle onset of difficulty finding words in speaking.
1980: MGH examination. No focal neurologic signs. Speaking greatly impaired
with anomia & circumlocutions (pen=“something you write with”); intact
memory; no apraxia; preserved personality; independent ADLs. BDS = 2.
1982: worsening expressive language; sings better than she speaks. Recent onset
of apraxia. Stopped driving a car. Sweet personality. BDS = 12.
1983: expressive & receptive aphasia. Withdrawn personality with apathetic mood.
BDS = 16 .
1984: mute, but occasional non-verbal communication. No housework, but still
cares for personal hygiene.
ICD-10 Diagnostic Criteria for Pick’s Disease
1. Dementia.
2. Slow steady deterioration.
3. Two or more of the following:
a. Emotional blunting
b. Apathy or restlessness
c. Coarsening of social behavior
d. Aphasia
4. Relative preservation of memory & parietal-lobe functions.
Caregiver Report of Initial Symptoms in Pick Disease (PiD) and
Alzheimer Disease (AD) Patients: Mean Prevalence (%)
Symptom
PiD n=34
Memory
61.8
Speech
29.4 p<0.05
AD n=78
93.6
9.1
Use of objects
0.6
2.6
Socializing
2.9
2.6
Personality
53.3
Irritability/aggressiveness
11.8
3.9
Reasoning
5.9
6.5
Sense of direction
0.0
7.8
Vision
0.0
1.3
p=0.07
14.1
p<0.001
Mean Cognitive Test Scores (+/- SD) at Initial Examination for PiD, AD, and
Normal Control Subject (NCS) Groups
Test
PiD
AD
NCS
NYU Immediate Recall
3.1 (2.7)
2.5 (1.9)
8.4 (3.1)
NYU Delayed Recall
2.3 (3.1)
0.7 (1.3)
7.8 (3.2)
Geometric Figure Recall
4.0 (3.6)
2.2 (2.9)
7.2 (2.6)
Benton Visual Retention
9.2 (3.0)
8.3 (2.8)
11.9 (1.7)
Boston Naming
24.6 (9.7)
25.8 (9.1)
37.1 (5.0)
Stroop Color Naming
13.3 (10.1)
11.2 (7.6)
29.3 (10.9)
Luria Mental Rotation
8.1 (1.9)
6.0 (2.8)
8.3 (2.4)
Picture Arrangement
5.9 (4.3)
4.4 (3.1)
10.5 (5.1)
NCS scores were significantly superior to AD scores on all tests (p<0.05), and to PiD on all
tests (p<0.05) on all tests except the Luria. PiD scores were significantly superior to AD
scores on the NYU Delayed Recall and Luria tests (p<0.001).
Cognitive test scores over time: AD open circles; Pick black circles
As judged by global measures of
dementia severity, PiD (black circles)
progresses faster than AD (open circles).
Clinical Aspects: PcD vs. AD
Initial Symptoms: Personality change & language
impairments are more commonly reported in PcD;
memory loss reported in both, but was more
common in AD.
Cognitive Tests: PcD superior to AD in explicit
memory & visuospatial functions. Over time,
dementia worsened in both. PcD dclined more
rapidly than AD on language tests and measures of
global dementia severity.
Alzheimer’s disease is more prevalent
than Pick’s disease
At the Massachusetts General Hospital between 1985 and 1996,
63% of the patients examined in the Memory Disorders Unit had a
clinical diagnosis of AD. During the same period of time, only 2%
of the patients had a clinical diagnosis of Pick’s disease.
Of autopsied cases (n=696), 52% had AD and 3% had Pick’s
disease.
Six tau isoforms that are expressed in human brain:
alternatively splicd exons 2,3 & 10 are shown in white;
black bars indicate the microtubular-binding repeats.
Electrophoretic tau profiles
distinguish AD from Pick’s
disease (PiD).
Characteristic western
immunoblots using
phosphorylation-dependent
monoclonal antibodies. In AD,
all isoforms are phosphorylated;
in PiD, only 3R isoforms.
MGH cases, courtesy of Andre Delacourte
Do defects in alternative exon 10 splicing of
the tau gene underlie Pick disease?
• Missense mutations and splice variants of tau,
many near exon 10, account for hereditary FTDP17, a condition similar to Pick.
• Antibodies to exon 10 fail to immunostain Pick
bodies.
• Mostly 3R tau (55 & 64 kD bands) in Pick.
• Vulnerability to 3R tau, or altered 3R:4R ratio, in
frontal & temporal cortices may account for the
regional distribution of degeneration in Pick.
Frontotemporal Lobar Degeneration
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•
•
•
•
•
Pick’s Disease
Frontal Lobe Dementia +/- ALS
Primary Progressive Aphasia
Semantic Dementia
FTD with Parkinsonism linked to chr. 17
Corticobasalganglionic Degeneration
History of Mr. GSC
born: 3/17/26
died: 1/27/95
1979: Insidious onset of difficulty arising from a chair.
1982: Hypophonia.
1985: Postural instability, with falling backward. Hip fracture.
1986: Difficulty focusing eyes and looking down when reading a page in a book.
1989: MGH Examination. Slow fractionated saccades; 3 mm vertical gaze. PD
stage 3 stigmata: akinesia, limb rigidity, en bloc turns. BDS = 2 (normal).
1991: Absent vertical saccades. Blepharospasms. Dsyphagia. Micrographia.
1992: Neck rigidity. Dysarthria. Requires assistance to stand; multiple falls with
fractured collarbone. Stage 4 PD.
1993: Eyes fixed…no volitional movement but intact oculocephalic reflex. Fell
with resultant skull fracture.
NINDS-SPSP Criteria for Dx PSP
• Gradually progressive disorder.
• Onset at age 40 years old or later.
• Either vertical supranuclear (up or down)
gaze palsy or
• Both slowing of vertical saccades and
prominent postural stability with falls in the
first year on disease onset.
Supportive Criteria for Dx PSP
• Symmetric akinesia or rigidity.
• Abnormal neck posture, especially retrocollis.
• Poor or absent response of parkinsonism to
levodopa therapy.
• Early dysphagia and dsyarthria.
• Early onset of cognitive impairment, including at
least 2 of these: apathy, decreased verbal fluency,
impaired abstract reasoning, & utilization
behavior.
Memory is less affected in PSP than in classic
dementing illnesses such as AD
Clinical Characteristics of PSP Patients and
Separate Groups of Normal Control Subjects (NCS)
Studied with Cognitive Tests & SPECT
Subjects
Age, yrs.
Duration, yrs.
H&Y stage
PSP n=11
67.5
4.6
3.6
NCS- SPECT n=10
70.8
na
na
NCS-Cognition n=16
66.5
na
na
Cognitive Test Scores of PSP Patients and Normal Control Subjects
Cognitive Test
Delayed Story Recall
PSP
Control Subjects
5.8 (3.0)
8.3 (2.5)
Boston Naming
33.5 (2.3)**
38.2 (3.9)
Verbal Fluency “S”
4.1 (2.2)***
18.8 (7.0)
Stroop
39.9 (23.7)***
Raven’s Matrices
23.6 (5.2)***
32.5 (3.3)
Picture Arrangement
4.0 (2.8)**
11.4 (4.5)
** = p<.01
***= p<0.001
106.3 (9.0)
Tau doublet at 69 & 64kD that is characteristic of PSP
 Gel 8-15 %
Load: 20µL
 AD2 at 1/10 000e
74
69
64
64
.
Alzheimer
Cortex
Cortex
Cortex
Cortex
Cortex
Cortex
White
Caudate
(Wat)
Temporal
Frontal
Frontal
Central
Central
Occipital
matter
nucleus
(1/5)
10182
10179
10185
10177
10184
10178
10183
10180
97 083
Thalam.
10181
Cere
Alzheimer
bellum
(1/1)
10186
Quantification of pathological tau proteins
In PSP, aggregated filaments are
largely hyperphosphorylated tau 4R
isoforms encoded by exon 10
100
80
60
40
20
W 6
at
1/
1
1
18
10
0
18
10
3
18
10
8
18
10
4
17
10
7
18
10
5
17
10
9
18
10
2
17
10
18
10
1/
5
0
W
at
60
:
74
MGH case, courtesy of Andre
Delacourte
The Search for Genetic Causes of PSP: 2004 Update
1. Hyperphosphorylated 4R tau in tangles
2. The tau gene A0 allele (a dinucleotide repeat in the intron
following exon 10) is over represented in PSP.
3. The tau H1 haplotype has high sensitivity (98%) but only
modest specificy as a marker for PSP
4. There are rare families with atypical PSP apparently caused by
mutations in the tau gene.
5. Mutations in the tau gene have not been found in most
sporadic PSP cases.
6. Some tau smoke, but no fire…more to follow!