Content uploaded by Marcel O. Pontón
Author content
All content in this area was uploaded by Marcel O. Pontón on Dec 08, 2017
Content may be subject to copyright.
5.
Marshall JC, Halligan PW. Seeing the forest but only half the
trees? Nature 1995;373:521-523.
6. Navon D. Forest before trees: the precedence
of
global features
in visual perception. Cogn Psychol 1977;9:353-383.
7. Delis DC, Robertson LC, Efron R. Hemispheric specialization
of memory for visual hierarchical stimuli. Neuropsychologia
8.
Robertson LC, Delis DC. Part-whole processing in unilateral
brain damaged patients: dysfunction of hierarchical organiza-
tion.
Neuropsychologia 1986;24:363-370.
9. Levy J, Trevarthen CB, Spew RW. Reception of bilateral
chimeric figures following hemisphere disconnexion. Brain
1972;95:61-78.
1986;24:205-214.
10. Bryden MP. Laterality. New York: Academic Press, 1982.
11.
Doyon J, Milner
B.
Right temporal-lobe contribution
to
global
visual processing. Neuropsychologia 1991;29:343-360.
12. Sergent J. The cerebral balance of power: confrontation or
cooperation?
J
Exp Psychol 1982;8:253-272.
13. Robertson LC, Lamb
MR,
Knight RT. Effects of lesions of
temporal-parietal junction on perceptual and attentional pro-
cessing in humans.
J
Neurosci 1988;8:3757-3769.
14. Benton
AL,
Hamsher K deS. Multilingual aphasia examina-
tion. Iowa City, Iowa: AJA Associates, 1989.
15. Kertesz A. Western Aphasia Battery. San Antonio,
‘IX
The
Psychological Corporation, 1982.
16. Grailet JM, Seron
X,
Bruyer R, Coyette
F,
Frederix M. Case
report of a visual integrative agnosia. Cogn Neuropsychol
17. Humphreys GW, Riddoch MJ.
To
see but not to see:
a
case
study of visual agnosia. London: Lawrence Erlbaum, 1987.
18. Hochberg J, McAlister
E.
A quantitative approach
to
figural
goodness.
J
Exp Psychol 1953;46:361-364.
19. Dinnerstein D, Wertheimer
M.
Some determinants
of
phe-
nomenal overlapping.
Am
J
Psychol 1957;70:21-37.
20. Kosslyn SM, Koenig
0.
Visual perception. In: Wet mind. New
York:
MacMillan, 1992:73-77.
1990;7( 4):275-309.
Emergence
of
artistic talent
in
frontotemporal dementia
B.L.
Miller, MD;
J.
Cummings, MD;
F.
Mishkin, MD;
K.
Boone, PhD; F. Prince, PhD;
M. Ponton, PhD; and C. Cotman, PhD
Article
abstract-objectiue:
To
describe the clinical, neuropsychological, and imaging features of five patients with
frontotemporal dementia (FTD) who acquired new artistic skills in the setting of dementia.
Background:
Creativity in the
setting of dementia has recently been reported. We describe five patients who became visual artists in the setting of FTD.
Methods:
Sixty-nine FTD patients were interviewed regarding visual abilities. Five became artists in the early stages of
FTD. Their history, artistic process, neuropsychology, and anatomy are described.
Results:
On SPECT or pathology, four of
the five patients had the temporal variant of FTD in which anterior temporal lobes are involved but the dorsolateral
frontal cortex is spared. Visual
skills
were spared but language and social skills were devastated.
Conclusions:
Loss
of
function in the anterior temporal lobes may lead to the “facilitation” of artistic skills. Patients with the temporal lobe
variant of FTD offer a window into creativity.
NEUROLOGY
1998;51:978-982
Previously learned skills or talents can be conserved
in the setting of dementia, and demented individuals
have been described who maintained card-playing
skills,l musical skills,’ painting
talent^,^-^
and word
game skills.’ Even more remarkable
is
the business-
man who became an artist in the setting of dementia
and whose paintings steadily improved despite pro-
gressive cognitive decline.8 The anatomic substrate
for
these unique patients is unknown, although
evi-
dence is emerging that indicates that enhancement
of visual
or
musical abilities is more common with
newly characterized subtypes of frontotemporal de-
mentia (FTD).6-X
FTD accounts
for
as
much as
258
of the presenile
dementias,‘j and has anatomic and chemical deficits
that differ from those seen with
AD
and other de-
mentia~.~ The clinical manifestations
of
FTD are di-
verse in part because the regional distribution of
pathology
is
heterogeneous. Many patients show bi-
lateral frontotemporal degeneration6a9J0; but, in
some, pathology
is
asymmetric and it affects the
or the right side.15 The temporal lobe variant
is an
FTD
subtype in which anterior temporal and
basal frontal lobes atrophy slowly while dorsolateral
frontal areas remain inta~t.~ We describe the clinical,
neuropsychological, and imaging features of five
FTD patients who acquired new artistic skills in the
setting of dementia.
From the Departments of Neurology
(Drs.
Miller and Cummings), Radiology
t
Dr.
Mishkin), and Psychiatry (Drs. Boone and Ponton), University
of
California
Los Angeles School
of
Medicine; and the Department of Psychobiology
(Dr.
Cotman), University
of
California
at
Irvine, CA.
F.
Prince is in private practice.
Supported by the University
of
California
Los
Angeles Alzheimer Disease Center
AG-10123,
the Christine Risse Award, and the Sidell-Kagan Research
Foundation through the University
of
California
Los
Angeles Medical School.
Received November
5,
1997.
Accepted in final form June
5,
1998.
Address correspondence and reprint requests to
Dr.
Bruce Miller, Professor of Neurology UCSFMt. Zion Hospital,
1600
Divisadero, Room
663,
San
Francisco, CA
94115.
978
Copyright
0
1998
by the American Academy
of
Neurology
Figure
3.
This painting of horses was made at a time
when the patient was disinhibited. She was approximately
64
years old.
Figure
1.
This church was painted by the artist
in
his
late
50s.
He remembered the building from his childhood.
Patient histories.
Patient
5
was described previo~sly.~,~
At
53
years
of
age, a left-handed man with a
tenth-grade education and no prior interest in art took a
short course in drawing at a local park and began to paint.
Soon afterward he was dismissed from a job changing car
stereos and began to have trouble speaking. By age
58
he
was disinhibited and irritable. He developed a compulsion
to find coins and searched
for
money in the street. His first
drawings were simple still lifes of vases and bridges. His
precision improved and he began painting pictures of Indi-
ans and buildings recalled from his youth (figure
1).
His
final paintings were churches and haciendas remembered
from childhood. In the year before evaluation, after
5
years
of intense artistic activity, he stopped painting. At
59
years he was pleasant but smiled inappropriately. His
Mini-Mental State Examination
(MMSE)
score was
16
of
30.
He was oriented to the date, and copied the intersect-
ing pentagons correctly. He was unable
to
name any words
on the Boston Naming Test. He generated seven novel
designs (novel designs touching four clots in five-dot
squares in
1
minute) and two
“d”
words
(“d”
words exclud-
ing proper nouns produced in
1
minute). He showed multi-
Patient
1.
ple perseverations on the Wisconsin Card Sorting and
Stroop tasks, and his modified Rey-Osterrieth Complex
Figure Copy results were normal. Bulbar weakness, dysar-
thria, hypophonia, and a weak gag reflex were present.
Muscle fasciculations and wasting of the hand muscles
were noted. SPECT showed bitemporal hypoperfusion (left
more than right) and mild left frontal hypoperfusion.
FTD
with motor neuron disease was diagnosed.
Patient
2.
At
51
years
of
age, a left-handed housewife
without previous artistic training took art classes. She be-
came uncomfortable coping with social engagements and
withdrew socially. At age
55,
she completed her first paint-
ings, which depicted rivers, ponds, and rural scenes re-
called from childhood (figure
2).
From
59
to
63
years of
age, she produced realistic copies
of
paintings. At age
65
she gained weight, became incontinent, and spoke in
a
disinhibited fashion. Brown and yellow became dominant
colors in her paintings (figure
3).
Her speech became repet-
itive and rambling. By age
66
she was expelled from her
art class due to wandering, and she stopped painting. Her
last paintings were slightly distorted family portraits. At
age
71
she died of advanced dementia. Autopsy showed
Figure
2.
This rural scene was painted by the artist
ap-
proximately
6
years after she started taking art classes.
She was approximately
56
years
of
age.
Figure
4.
This is a photograph taken by the patient
in
Guatemala. It represents work early in the course of his
illness.
October
1998
NEUROLOGY
51
979
gliosis and microvacuolization of the cortex, most severe in
the right temporal lobe. Both inferior temporal
gyri
were
severely atrophic. There was mild frontal lobe atrophy and
little posterior atrophy.
No
plaques or tangles were found.
FTD was diagnosed.
A
57-year-old, right-handed man developed
a successful advertising agency between the ages of 29 to
35 years. At age 35 he decided to write a novel and quit
work.
No
significant writing was produced, and he was
supported by his wife’s income. Between the ages of
38
and
40
he left his family
for
trips to remote areas of Central
America, where he photographed buildings and people.
The locations were dangerous; on one occasion he was ar-
rested by the military. Pictures were acquired in a compul-
sive manner, and he photographed them from multiple
angles
to
achieve the “perfect” image (figure
4).
Between
44 and 48 years of age this patient carved wax miniature
animals using candle drippings. He photographed until the
age of
50.
At 53 he had several traffic accidents, started
cheating at card games, stole, berated his mother-in-law,
and masturbated in public.
At
age 54 he was fidgety and
stared inappropriately at strangers. His MMSE score was
26,
Comprehension, fluency, naming, and constructions
were normal. His executive abilities were impaired, as ev-
idenced by his inability to perform the Wisconsin Card
Sorting, Stroop, or Trails tasks. His basic neurologic exam-
ination was normal. SPECT showed bifrontal hypoperfu-
sion (right worse than left) with mild right temporal
involvement.
At
age 56 he was placed in a nursing facility.
Fourteen years earlier, a 59-year-old woman
divorced her husband and remarried. Always interested in
art, she quit her job as a business manager and started a
handicraft business with two friends. She sold gourds with
paintings
of
Santa Claus and sculpted small wooded
scenes. Her work steadily improved for
3
years and then
declined.
At
age 53 she stopped working and became apa-
thetic and inactive. She complained of fatigue and with-
drew socially. She showed mild disinhibition, stopped
flushing the toilet, and lost interest in her hygiene. She
gained approximately 27 kg and shunned vegetables, pre-
ferring sweets. She had odd compulsions-after meals she
folded paper plates into small triangles. Her ability to use
appropriate words worsened and she stopped talking. On
examination she was passive and stared inappropriately.
She giggled frequently and responded
“I
don’t know” to
many questions. Her MMSE score was
9.
She could not
name a pencil, but got
1
point for the intersecting penta-
gons. Digit span was six forward. She correctly named one
of
15
items (“bed) and was not helped with clues. Her
comprehension was mildly impaired. She failed memory
testing, but found her way easily back to her car. There
was mild impairment on three-dimensional drawing. She
could produce no
“d”
words
or
novel designs. Her basic
neurologic examination was normal. MRI showed moder-
ate left and mild right frontal atrophy with dilatation of
the ventricles anteriorly. The temporal lobe on the left was
slightly atrophic. SPECT showed left frontal and bitempo-
ral hypoperfusion.
A
68-year-old right-handed man was seen
for a dementing illness of a 12-year duration. Previously a
successful businessman without interest in art, at age 56
he began
to
describe “open” and “closed” periods. When
“closed,” he was dysphoric, and experienced lights and
980
NEUROLOGY
51
October
1998
Patient
3.
Patient
4.
Patient
5.
sounds as exquisitely intense. When “open,” lights and
sounds produced a pleasant feeling that allowed him to
think creatively. He painted images experienced during
“open” and “closed” periods. At 58 years he became anomic
and disinhibited. Language and memory deteriorated, but
he showed heightened visual and auditory awareness. Odd
compulsions developed, and despite
his
considerable
wealth, he cajoled his caregivers to walk with him to look
for coins.
At
56 years he began painting. During the next
decade he created paintings with increasing precision and
detail. The first featured brightly colored ellipses. Soon his
work became realistic, and he drew animals. Later works
were crafted with care, and he took hours to complete
single lines. Between 63 and 66 years his paintings won
several art show awards. By age
68
he drew oddly shaped
doll-like figures. On examination he was remote and irrita-
ble, showing little facial emotion. He displayed heightened
interest in his environment, commenting extensively on
color and sound. His MMSE score was 15, and his verbal
output was fluent.
A
mild comprehension deficit and a
semantic anomia were present. Word list generation was
two “d” words but
17
novel designs were produced.
MRI
showed bitemporal atrophy (worse on the left than the
right
),
and SPECT revealed bilateral temporal hypoperfu-
sion (worse on the right than the left). Frontal perfusion
was normal. Regions with highest perfusion were the right
primary visual cortex and the right posterior parietal lobe.
Discussion.
Although
AD
is more common than
FTD,‘j all patients we have seen who developed
or
maintained artistic talents carried a diagnosis of
FTD. The artistic products were diverse but shared
many features. The creativity was visual but never
verbal. Similarly, the paintings, photographs, and
sculptures were realistic copies lacking an abstract
or
symbolic component. The painters remembered re-
alistic landscapes, animals,
or
people; one woman
hand-crafted small figures; and a photographer cap-
tured scenes in rural Guatemala. The painters
seemed to recall images that were then mentally
reconstructed
as
pictures without the mediation
of
language.
Also,
despite progressive cognitive and
so-
cial impairment, they showed increasing interest in
the fine detail of faces, objects, shapes, and sounds.
Lastly, there was an intense preoccupation with
art
in all patients, and their willingness
to
repeat the
work until
a
perfect product was obtained enhanced
the quality
of
their
art.
FTD
causes selective anterior frontotemporal cor-
tical degeneration, whereas in
AD,
early pathology
involves the posterior parietal and medial temporal
areas.9 In
AD,
visuoconstructive abilities dissipate in
conjunction with the progressive
loss
of function in
posterior parietal and posterior temporal regions-
the brain areas responsible for visuoconstructive
skill^.^
In contrast, in FTD, copying skills are often
n0rma1,6.~ and posterior pathology is minimaL9J5
Sparing of these brain areas seemed to allow our
subjects to paint and photograph despite the ad-
vances
of
their dementia. Yet even though copying
skills are preserved in FTD,16 diminished-not en-
hanced-creativity is more common with this ill-
ness,6 suggesting that those who become artistic are
atypical or unusual.
On SPECT
or
pathology, four of the five patients
had the temporal variant of FTD.7 Planning, organi-
zation, and motivation are mediated through dorso-
lateral and medial frontal lobe~’~-areas that are
preserved in the temporal lobe variant. The painters’
capacity
to
draw scenes remembered from the past
suggests that components of episodic and working
memory are spared. In contrast, semantic memory
(which relies on the integrity of the left inferior tem-
poral 10bel~~~) was devastated,
as
evidenced by ab-
normal performance on word recall and naming.
Goldman-Rakic observed that “Visuospatial pro-
cesses engaged in humans by activities such as
.
.
.
painting and drawing from memory.
. .
rely on the
dorsolateral prefrontal convexity
.
.
.
”
(reference 18,
p.
13473).
The dorsolateral prefrontal cortex is
spared in the temporal lobe variant of FTD.
Also,
there was
a
disproportionate representation
of patients with dominant-hemisphere dysfunction.
Nondominant-hemisphere injury devastates artistic
skills, even in previously talented artists,lg but in-
jury
to
the dominant hemisphere can leave drawing
relatively intact.20 KaczmarekZ1 described
a
Polish
painter who suffered a left-hemisphere stroke associ-
ated with aphasia who lost the ability “to create the
highly symbolic pictures” painted before the stroke,
yet he continued drawing realistic pictures without
a
flaw. Kaczmarek noted that there was “impairment
of symbolic processing with fairly well preserved
technical skills” (reference 21, p. 370). This ability to
draw realistically without symbolism or abstraction
was true of our artists.
In
a
recent discussion of the unexpected occur-
rence
of
behavioral improvement following brain in-
jury, KapurZ2 used the term “paradoxical functional
facilitation.” He noted, “in normal subjects, inhibi-
tory and excitatory mechanisms interact in
a
com-
plex harmony.
.
. .
The role of inhibitory processes
may be critical in mediating specific restorative par-
adoxical functional facilitation effects” (reference 22,
p. 1783). It is well accepted that talent in one area,
such as
art,
may be accompanied by dysfunction in
other spheres, such
as
social skills.23 The loss of
so-
cial skills and inhibitions may have facilitated the
art
of our patients. Our photographer traveled to
dangerous areas where he obtained unique photo-
graphs, whereas the willingness of Patient
5
to scorn
social norms led him to take up painting and quit his
work. We hypothesize that selective degeneration
of
the anterior temporal and orbital frontal cortex de-
creased inhibition of the more posteriorly located visual
systems involved with perception, thereby enhancing
these patients’ artistic interest and abilities.
There is an association between bipolar disease
and the visual arts,24 although none of our patients
had
a
history suggestive of mania.
A
break with
so-
cial conventions is common among artists and can
lead
to
a freer more creative output. Van
Gogh’sZ5
and Goya’@ work blossomed in midlife, when they
spurned conventional rules of society. “Outsider
art-
ists” create distinctive paintings despite receiving lit-
tle formal training. Some manifest severe mental
illness and are hospitalized in mental institutions.
Like our patients, they are directed internally with
little interest in the teachings
of
others. Some have
a
history suggesting schizophrenia, but others develop
both talent and
a
behavioral disorder later in life.
Disinhibition, hallucinations, and aphasia are re-
ported in outsider artists. Some may have suffered
from the temporal lobe variant of FTD.27 The mecha-
nism for the enhanced
artistic
skills in these pa-
tients and outsider artists reported previo~sly~~
remains
a
mystery. FTD is an unexpected window
into the artistic process.
References
1.
Beatty W, Winn P, Adams RL, et al. Preserved cognitive skills
in dementia of the Alzheimer type. Arch Neurol
1994;41:
2.
Beatty
WW,
Zavadil
KD,
Bailly RC, et al. Preserved musical
skill in
a
severely demented patient. Int
J
Clin Neuropsychol
3.
Crystal
HA,
Grober E, Masur D. Preservation of musical
memory in Alzheimer’s disease.
J
Neurol Neurosurg Psychia-
4.
Espinel CH. de Kooning’s late colours and forms: dementia,
creativity, and the healing power of art. Lancet
1996;347:
5.
Cummings JL, Zarit JM. Probable Alzheimer’s disease in an
1040-1046.
1988;10:158-164.
try
1989;52:1415-1416.
1096 -1098.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
artist. J&IA
1987;258:2731-2734.
Snowden JS, Neary D, Mann DMA, eds. Fronto-temporal lo-
bar
degeneration. New York: Churchill Livingstone,
1996:99.
Edwards-Lee T, Miller BL, Benson DF, Cummings JL, Russell
G,
Mena
I.
The temporal lobe variant of frontotemporal de-
mentia. Brain
1997;120:1027-1040.
Miller
BL,
Ponton M, Benson DF, Cummings JL, Mena I.
Enhanced artistic creativity with temporal lobe degeneration.
Lancet
1996;348:1744-1755.
Brun A. Frontal lobe dementia of the non-Alzheimer type re-
visited. Dementia
1993;4:126-139.
Knopman
DS,
Mastri
AR,
Frey
WH,
Sung JH, Ruston T. Demen-
tia lacking distinctive histologic features:
a
common non-
Alzheimer degenerative dementia. Neurology
1990;40:251-256.
Mesulam MM. Slowly progressive aphasia without general-
ized dementia. Ann Neurol
1982;11:592-598.
Snowden JS, Neary D, Mann DMA, Goulding PJ, Testa HJ.
Progressive language disorder due
to
lobar atrophy. Ann Neu-
rol
1992;31: 174 -183.
Hodges JR, Patterson
K,
Oxbury
S,
Funnel1 F. Semantic de-
mentia. Progressive fluent aphasia with temporal lobe atro-
phy. Brain
1992;115:1783-1806.
Miller BL, Chang L, Mena
I,
Boone
K,
Lesser IM. Progressive
right frontotemporal degeneration: clinical neuropsychological
and SPECT characteristics. Dementia
1993;4:204-213.
Read SL, Miller BL, Mena
I,
Kim R, Darby A.
SPECT
in
dementia: clinical and pathological correlations.
J
Am
Geriatr
Brun A, Englund B, Gustafson L, et al. Clinical and neuro-
pathological criteria for frontotemporal dementia.
J
Neurol
Neurosurg Psychiatry
1994;57:416-418.
Stuss
D,
Benson DF. The frontal lobes. New York: Raven
Press,
1986.
Goldman-Rakic
PS.
Regional and cellular fractionation
of
working memory. Proc Natl Acad Sci USA
1996;93:13473-
13480.
Schnider A, Regard M, Benson DF, Landis
T.
Effects of a right
hemisphere stroke on
an
artist’s performance. Neuropsychia-
try Neuropsychol Behav Neurol
1993;6:249-255.
Alajouanine
T.
Aphasia and artistic realization. Brain
1948;
Kaczmarek
BJ.
Aphasia in an artist: a disorder of symbolic
processing. Aphasiology
1991;4/5:351-371.
October
1998
NEUROLOGY
51
981
SOC
1995;43:1243-1247.
17 :229 -24 1.
22. Kapur
N.
Paradoxical facilitated function in brain-behaviour
23. Gardner
H.
Art, mind and brain: a cognitive approach to cre-
24.
Post
F.
Creativity and psychopathology: a [study of 291 world-
25. Morrant JCA. The wing of madness: the illness
of
Vincent van
26. Cawthorne
T.
Goya’s
Illness. Proc
R
SOC
Med 1962;55:213-
27. Tuchman M, Eliel CS. Parallel visions: modern artists and out-
research. A critical review. Brain 1996;119:1775-1790.
ativity. New York: Basic
Books,
1982.
famous men.
Br
J
Psychiatry 1994;165:22--34.
Gogh. Can
J
Psychiatry 1993;38:480-484.
217.
sider
art.
Princeton,
NJ
Princeton University Press, 1992.
Direct genetic evidence
for
involvement
of
tau in progressive supranuclear palsy
P. Bennett, PhD;
V.
Bonifati, MD;
U..
Bonuccelli, MD; C. Colosimo, MD; M. De Mari, MD; G. Fabbrini, MD;
R.
Marconi, MD;
G.
Meco, MD; D.J. Nicholl, MRCP;
F.
Stocchi, MD;
N.
Vanacore, MD; P. Vieregge, MD; and
A.C. Williams, MD, for the European Study Group on Atypical Parkinsonism Consortium*
Article
abstract-Objective:
To
confinrt whether a dinucleotide repeat sequence in an intron of the microtubule-
associated protein tau is associated with progressive supranuclear palsy
(PSP)
in an independent study population and to
establish an improved methodology for allelotyping. Background: It has recently been reported that a genetic variant
of
tau, known as the
A0
allele, was represented excessively in PSP patients when compared with control subjects. Methods:
In
a
multicenter study, the authors examined the allelic distribution
of
this dinucleotide repeat marker in a set of
clinically ascertained
PSP
patients (n
=
301, multiple system atrophy
(MSA)
patients (n
=
351,
and matched control
subjects (n
=
70). Individuals were allelotyped using automated analysis
of
fluorescently labeled PCR products. Results:
The
A0
allele was significantly overrepresented in the PSP patients (93.3% versus 76.4%;
p
=
0.0067; odds ratio [OR]
=
4.33;
95%
confidence interval
[CI],
1.36
to
13.601, but
not
in the
MSA
patients. Likewise,
A0
homozygotes were overrepre-
sented in the PSP group (86.7% versus 61.1%;~
=
0.02;
OR
=
4.14; 95% CI, 1.19 to 14.48) compared with control subjects.
Conclusions: The findings
of
this study, which is the largest to date, support those of a previous investigation that used
pathologically confirmed
PSP
patients. These data provide additional strong evidence that genetic variation at or near the
tau gene plays an important role in the pathogenesis of
PSP.
NEUROLOGY 1998;51:982-985
Progressive supranuclear palsy
(PSP)
was
first
de-
scribed by Steele et
a1.l
in
1964.
Clinically, it
is
a
progressive neurodegenerative disorder presenting
in persons older than
40
years as an akinetic, rigid
syndrome with vertical gaze palsy a,ssociated vari-
ably with dysarthria, dysphagia, axial rigidity, evi-
dence of pyramidal tract dysfunction, and
a
mild
dementia (usually
of
the frontal lobe qype). Patholog-
ically,
PSP
typically shows generalized cerebral atro-
phy with pallor of the substantia nigra and
shrinkage
of
the globus pallidus. There is neuronal
loss and gliosis, as well
as
the presence of numerous
neurofibrillary tangles (NFTs) and neuropil threads.
This occurs predominantly in the superior colliculus,
periaqueductal gray matter, pretectal areas, the
zona compacta
of
the substantia nigra, and the pal-
lidosubthalamic complex.2 In PSP, the NFTs consist
of clusters of straight filaments, compared with those
comprised of paired helical filaments seen in
AD
pa-
tients. However, there
is
a
considerable overlap with
the pathology
of
other tau-related disorders such as
postencephalitic parkinsonism and the ALS-PD de-
mentia complex (APDC) of Guam.3
Because of the frequency of tau pathology in neu-
rodegenerative disease,
a
number
of
hypotheses have
been proposed in an attempt to explain how tau
could lose its normal affinity for microtubules and
associate instead
to
form insoluble
aggregate^.^-^
The
first
direct evidence
for
a
mechanism
was
provided
recently by Conrad et
a17
and indicates that a defect
within the
tau
gene itself may be involved,
at
least in
PSP. This study
first
identified
a
polymorphic GT
repeat in intron nine of the
tau
gene, and subse-
quently demonstrated
a
highly significant overrepre-
sentation of one allele (AO) of this marker in a series
of
22
pathologically confirmed patients with
PSP.
*See the Appendix on page
985
for a listing of additional members of the ESGAP Consortium.
From the University Department of Clinical Neurology (Drs. Bennett, Nicholl, and Williams), Queen Elizabeth Hospital, Birmingham, UK, the Department
of Neurosciences (Drs. Bonifati, Colosimo, Fabbrini, Meco, Stocchi, and Vanacore), “La Sapienza” University, Rome, Italy; the Institute of Neurology (Dr.
Bonuccelli), University of Pisa, Italy; the Institute of Neurology (Dr. De Mari), University of Ban, Italy; the Neurology Section (Dr. Marconi), “Misericordia”
Hospital, Grosseto, Italy; and the Department of Neurology (Dr. Vieregge), Medical University of Lubeck, Germany.
Supported by the Italian Ministry for University, Scientific and Technological Research grants to G.M.
Received February
18,
1998.
Accepted in final form June
27,
1998.
Address correspondence and reprint requests
to
Dr. Phil Bennett, University of Birmingham, Department of Psychiatry, Queen Elizabeth Psychiatric
Hospital, Mindelsohn Way, Edgbaston, Birmingham,
B15
ZQZ
UK.
982
Copyright
0
1998
by the American Academy of Neurology
