Movement Disorders
Vol. 18, Suppl. 6, 2003, pp. S43–S50
© 2003 Movement Disorder Society
Update on Epidemiological Aspects of Progressive
Supranuclear Palsy
Irene Litvan, MD*
Movement Disorder Program, University of Louisville School of Medicine, Louisville, Kentucky, USA
Abstract: The cause of progressive supranuclear palsy (PSP),
the most common form of the atypical parkinsonian disorders,
is unknown. PSP is characterized by four-repeat tau aggregates
in neurons (neurofibrillary tangles) and glia in specific basal
ganglia and brainstem areas. A thorough literature review led
us to hypothesize that genetic and/or environmental factors
contribute to its development. It is likely that inheritance of the
H1/H1 tau genotype represents a predisposition to develop PSP
Progressive supranuclear palsy (PSP) was first de-
scribed by Steele and colleagues1 as a discrete clinico-
pathological entity in 1964. Clinically, it is characterized
by prominent postural instability, supranuclear vertical
gaze palsy, pseudobulbar palsy, frontal cognitive distur-
bances, and levodopa-unresponsive parkinsonism pre-
senting in middle-to-late age.1– 4 Neuropathologically,
PSP is characterized by the presence of neurofibrillary
tangles in neurons and glia in specific basal ganglia and
brainstem areas.5 Neuropathological and clinical criteria
for the diagnosis of PSP have been standardized and
validated and are widely accepted.3,5–7 Neurofibrillary
tangles are abnormal aggregates of tau protein that are
also the main pathological feature in Alzheimer’s disease
(AD), corticobasal degeneration (CBD), Pick’s disease,
and frontotemporal dementia with parkinsonism linked
to chromosome 17 abnormalities (FTDP-17). Neurode-
generative disorders recently have been grouped by the
protein that aggregates, which is tau in the above-men-
*Correspondence to: Dr. Irene Litvan, University of Louisville
School of Medicine, Department of Neurology, A Building, Room 113,
500 South Preston, Louisville, KY 40202.
E-mail: i.litvan@louisville.edu
Published online in Wiley InterScience (www.interscience.wiley.
com). DOI 10.1002/mds.10562
S43
requiring other environmental or genetic factors. Less likely, a
relatively rare mutation with low penetrance could contribute to
the abnormal tau aggregation present in this disorder. The
possible role of chemicals in the diet or occupation, hyperten-
sion, traumatic brain injury, coffee, and inflammation or oxi-
dative injury are reviewed. © 2003 Movement Disorder Soci-
ety
Key words: parkinsonism; tau; genetic factors; epidemiology
tioned diseases; thus, these disorders are classified as
“tauopathies.”
In the normal adult human brain, there are six
different tau isoforms with different microtubule-bind-
ing domains, and the ratio of tau isoforms with three-
(3-R) and four-repeat (4-R) microtubule binding do-
mains is 1:1. In AD, there is amyloid deposition and
the six tau isoforms aggregate mainly in neurons, but
the 1:1 ratio is maintained. By contrast, in PSP and
CBD, there is no amyloid deposition and tau aggre-
gates in neurons and glia, mainly as a 4-R isoform,
thereby altering the 3-R:4-R ratio.5,8 –10
PSP and CBD have much in common from a clinical,
pathological, and genetic perspective.8,9,11 Besides both
being sporadic 4-R tauopathies, they both may present
with frontal cognitive disturbances, parkinsonism not
responding to levodopa therapy, and ocular motor,
speech, and swallowing disturbances.11,12 The similari-
ties between PSP and CBD have led investigators to
question whether the two disorders are distinct nosolog-
ical entities or different phenotypes of the same disor-
der.13 Recently validated neuropathological diagnostic
criteria14 emphasize the presence of tau-immunoreactive
lesions in neurons, glia, and cell processes in these dis-
orders and also provide good differentiation between
PSP and CBD.14
S44
TABLE 1. Past and present progressive supranuclear palsy prevalence and incidence estimates
Past
Prevalence 1.39/100,000 inhabitants
Incidence 0.3–0.4 per 100,000 person/yr
Clinical Diagnosis Easy
Survival ⬍10 yr
EPIDEMIOLOGY
PSP is the most common form of the atypical parkin-
sonian disorders.15,16 Early reports of the incidence and
prevalence were very low (Table 1). Early crude inci-
dence rates ranged from 0.3 to 0.4 per 100,000 per
year.17 More recent studies on PSP have resulted in much
higher incidence rate estimations. An incidence study of
PSP and all types of parkinsonism in Olmsted County,
Minnesota, from 1976 to 199015,18 found a crude inci-
dence rate for PSP of 1.1 per 100,000 per year, which
increased exponentially from 1.7 cases per 100,000 per
year at ages 50 to 59 years to 14.7 per 100,000 per year
at ages 80 to 99 years.15 The incidence of PSP is close to
10% of incidence of Parkinson’s disease (PD),18 making
it much more common than previously recognized. It is
thought that these figures are higher because of better
methodological case finding and increased recognition of
the disorder by neurologists and non-neurologists.15 Sim-
ilarly, the earlier underestimated prevalence of 1.39 per
100,000, approximately 1% of the prevalence of PD,19
has been found recently to be 6.0 to 6.4/100,000 in two
population-based prevalence studies using currently ac-
cepted diagnostic criteria for PSP conducted in the
United Kingdom.16,20 Of note, most of the PSP cases
identified in the London area had not been diagnosed as
PSP until this study, suggesting that PSP continues to be
under-diagnosed.16
The natural history of PSP was evaluated by surveying
caregivers of 318 living and 119 deceased patients with
PSP21 and by retrospectively evaluating the medical
records of 24 autopsy-confirmed cases.2 Both methods
have limitations. The survey included a large study sam-
ple, but only considered caregivers’ responses and in-
cluded a few autopsy-confirmed cases. On the other
hand, the autopsy-confirmed study included a small
study sample, was retrospective, and included nonstand-
ardized evaluations. The autopsy-confirmed studies22
found that onset of falls during the first year, early
dysphagia, and incontinence predicted a shorter survival
time. Age at onset, gender, early onset of dementia,
vertical supranuclear gaze palsy, or axial rigidity had no
effect on survival. Similar predictors of survival were
identified in a recently published record-based study of
Movement Disorders, Vol. 18, Suppl. 6, 2003
I. LITVAN
Present
6.4/100,000 inhabitants
5.4 new cases per 100,000 person/yr Incidence rising with aging population
⬎25% of patients are never diagnosed by specialists
5–6 yr
Shortened if early falls, dysphagia, or supranuclear gaze palsy are present
187 PSP patients of which 62 (33%) were examined by
the investigators, of which 49 (79%) underwent stan-
dardized clinical assessment, and 75 (40%) died during
follow-up but did not undergo autopsy-confirmation.23
These investigators found that classification as probable
PSP according to the NIND-SPSP criteria was associated
with a poorer survival. In particular, they found that
onset of falls, speech problems, or diplopia within 1 year
and swallowing problems within 2 years of onset, were
associated with a worse prognosis.23
Several important findings extending the results of
prior research2,19,22,24,25 emerged from the survey.21 PSP
affects men more frequently than women and we noted
that men were diagnosed later than women and that, once
diagnosed, they died earlier than women. Although the
results of the survey are relevant, they must be viewed
cautiously, because the patients self-reported their symp-
toms, the study did not include a systematic evaluation
of features by experts, and there was no autopsy
confirmation.
ETIOPATHOGENESIS
The cause of PSP is unknown but it is hypothesized
that genetic and/or environmental factors contribute to its
development26,27 (Fig. 1). Environmental and genetic
factors have also been linked to other neurodegenerative
disorders such as PD and AD.28,29
Genetic
PSP is associated with a specific form of the tau gene
(H1 tau haplotype)30 –32 (Table 2). However, because the
H1/H1 genotype is present in approximately 90% of
patients with this disorder, but also in approximately
60% of healthy Caucasians, it is unclear whether inher-
itance of the H1/H1 tau genotype represents a predispo-
sition to develop PSP (requiring other environmental or
genetic factors) or whether a relatively rare mutation
with low penetrance (rather than an inherited suscepti-
bility variant) could contribute to the abnormal tau ag-
gregation present in this disorder. It is likely that differ-
ential environmental or genetic factors may lead to
different cell vulnerability, phenotypes, and rate of dis-
ease progression observed in PSP patients. CBD is also
 UPDATE ON EPIDEMIOLOGICAL ASPECTS OF PSP S45

FIG. 1. Genetics, environment, mitochondrial abnormalities, oxidative damage, and inflammation are hypothesized to be involved in the pathogenesis
of progressive supranuclear palsy. TIQ, tetrahydroisoquinolones HTN, hypertension.

associated with the inheritance of the H1 haplotype.30,31 not influence age at onset, severity, or survival of PSP
The observation that coding and splice-site mutations in patients,40 in contrast to what is observed with APOE⑀4
the tau gene cause FTDP-17 demonstrates that tau dys- in AD.
function is sufficient to induce neurodegeneration.8,33–36
The parallels between FTDP-17 and PSP/CBD also in- Environmental Factors
clude that there are FTDP-17 patients with defined tau
Caparros-Lefebvre and Elbaz reported the results of a
mutations (e.g., P-301, N279K) who share many clinical
case-control study on atypical parkinsonism in Guade-
and pathological features with PSP and CBD37–39 such as
loupe.41 They found an association with consumption of
selective deposition of 4-R tau. However, because highly
tropical fruits (pawpaw) or herbal teas (boldo) in 31
penetrant tau mutations are not found in PSP and CBD,
patients with PSP and 30 patients with atypical parkin-
it is likely that other genetic or environmental factors
sonism compared to controls (odd ratio [OR], 4.35; 95%
contribute to the development of these disorders. A re-
confidence interval [CI], 1.25–15.2 for PSP; OR, 4.27;
cent pilot study showed that H1 haplotype dosage does
95% CI, 1.22–14.91, for atypical parkinsonism). These
investigators suggested that chronic exposure to the tet-
TABLE 2. Tau haplotype/genotype in PSP patients rahydroisoquinolones (TIQs), present in these herbal teas
and controls and fruits could be linked to developing PSP and atypical
PSP Controls parkinsonism.41 Biochemical analysis of the central ner-
vous system of 3 of those atypical parkinsonian patients
Haplotype
H1 94 77 with a PSP phenotype who recently died showed a 4-R
H2 6 23 tauopathy.42 There is evidence that TIQs are potentially
Genotype
H1/H1 88 60
neurotoxic.43– 46 TIQs have been found in parkinsonian
H1/H2 12 33 brains47 and levels of 1-benzyl-TIQs are elevated in the
H2/H2 0 7 cerebrospinal fluid of PD patients.48 Injections of TIQs
From Houlden et al., 2001.32 Values are expressed as percentages. have caused parkinsonism in mice48 –50 and in pri-
PSP, progressive supranuclear palsy. mates.51–53 In addition, cellular studies showed that TIQs

Movement Disorders, Vol. 18, Suppl. 6, 2003

S46 I. LITVAN
exert a direct toxicity to dopaminergic neurons through
inhibition of complex I enzymes, a mitochondrial mech-
anism similar to that of MPTP or rotenone exposure.54,55
A similar cytotoxic mechanism has been reported as a
consequence of the administration of beta-carbolines,
which have been hypothesized as a possible cause of
PD.56 – 61 This further suggests that environmental factors
may be relevant for developing PSP. It is unlikely that
PSP patients seen in the United States are past consumers
of the tropical fruits and herbal teas that have been linked
to PSP in Guadeloupe. However, TIQs have been found
in foods that are common in the Western diet; specifi-
cally, in cheese, milk, eggs, cocoa, and bananas.62,63
Although the amounts of TIQs in these foods vary, they
may accumulate in the brain over many years.62 There
have also been reports of other toxins causing atypical
parkinsonism. There is some evidence of an environmen-
tal effect in Lytico-Bodig disease,64 and ecological cor-
relations support the cycad hypothesis.65,66
McCrank and Rabheru reported environmental expo-
sure to organic solvents in 12 of 13 patients with
PSP.67,68 Petroleum waste ingestion has been linked to
parkinsonism in a 20-year-old man.69 N-Hexane has
been shown to induce parkinsonism in rats70 and was
linked to parkinsonism in a 49-year-old Italian leather
worker.71 Patients with multiple system atrophy had sig-
nificantly more exposure to metal dusts and fumes, plas-
tic monomers and additives, organic solvents, and pesti-
cides than controls.72 Although PSP patients were not
found to have an association with any occupation or
toxin exposure in the two previous case-control stud-
ies,73,74 these studies were not powered to test this
hypothesis.
Inflammation
It has been demonstrated that neurodegeneration in
AD is accompanied by specific inflammatory mecha-
nisms, including activation of the complement cascade
and accumulation and activation of microglia.75,76 Al-
though there is limited information about a decreased
inflammatory reaction after treatment with anti-inflam-
matory medication in autopsy-confirmed AD cases,77,78
because there is strong evidence that, in PSP, there are
activated glia,79 – 83 there may be augmented complement
activation in the brain (higher cerebrospinal fluid levels
of C4 in PSP compared to controls and PD),84 and active
glial involvement in PSP is as severe as (or more so than)
that found in AD,85 it is appropriate to wonder if inflam-
mation plays a role in the etiopathogenesis of PSP. This
role is particularly relevant as several epidemiological
studies have shown that anti-inflammatory agents may
delay the onset and slow the progression of AD.86 – 88
Movement Disorders, Vol. 18, Suppl. 6, 2003
Hypertension
The role of hypertension (HTN) in PSP is controver-
sial. Dubinsky and Jankovic proposed a “vascular” eti-
ology for some of the cases diagnosed as clinical PSP.89
They found that 19 of 58 PSP patients (32.8%) had
radiological evidence of cortical, subcortical, or brain-
stem strokes, compared with 25 of 426 (5.9%) patients
with PD (P ⬍ 0.001). The same group of investigators90
found that 30 of 128 (23.3%) PSP patients satisfied
criteria for vascular PSP. However, there have been few
autopsy-confirmed cases of exclusively vascular PSP.
Frequently, PSP is associated with strokes or pathologi-
cal features of other neurodegenerative diseases.91
Two studies looked at the presence of presymptomatic
HTN in patients with PSP.92,93 Ghika and colleagues
excluded clear-cut cases of vascular parkinsonism by
omitting cases with obvious multilacunar state on com-
puted tomography or magnetic resonance imaging, se-
vere hypertensive leukoencephalopathy, Binswanger dis-
ease, pseudo-PSP due to small vessel disease, and
vascular dementia. They found that the prevalence of
presymptomatic HTN in patients with clinically diag-
nosed PSP was 34 of 42 (81%). Because the vascular
cases were excluded, they did not believe that HTN was
a marker for a vascular form of PSP. They proposed that
HTN may be the first symptom of PSP, arising from
degeneration of adrenergic nuclei in the brainstem. How-
ever, Fabbrini and coworkers92 and a previous case-
control study conducted by Davis and colleagues,73
found no increased frequency of HTN in PSP patients.
Further studies are needed to evaluate whether HTN is
simply acting as a risk factor for vascular parkinsonism.
Traumatic Brain Injury
A possible role for traumatic brain injury (TBI) as a
risk factor in the development of 4-R tauopathies such as
PSP is supported by several observations. First, it is well
known that repetitive TBI induces the formation of neu-
rofibrillary tangles,94 which are found in PSP. Second,
posttraumatic parkinsonism may occur after cumulative
head trauma in contact sports and infrequently after a
single severe closed head injury.95,96 However, it is un-
clear whether TBI should be considered as a risk factor
in the pathogenesis of PD.97 Third, several epidemiolog-
ical studies have demonstrated that TBI is a risk factor
for developing another tauopathy, AD,98 –100 although
controversy exists over the extent to which TBI and
genetics contribute to the development of AD. A recent
large cross-sectional multicenter study of first-degree
relatives of AD patients suggest that the influence of TBI
on developing AD is greater among persons lacking
APOE-⑀4 compared with those having one or two ⑀4
 UPDATE ON EPIDEMIOLOGICAL ASPECTS OF PSP
alleles.100 These findings were confirmed in a retrospec-
tive study that evaluated two autopsy-confirmed cohorts
of patients with AD with known APOE-⑀4 genotype.101
On the other hand, two recent large European prospec-
tive clinical epidemiological studies suggest that a his-
tory of TBI, with or without an association with
APOE⑀4, is not a risk factor for developing AD,102,103
although major or many TBIs may increase the risk of
cognitive decline.104 Lastly, a large number of experi-
mental animal studies support the role of TBI in the onset
or progression of AD. Unfortunately, a previous epide-
miological study in PSP had limited power to study this
issue but interestingly, it found high ORs for boxing
(OR, 4.0), TBI with loss of consciousness (OR, 2.4), and
TBI with memory loss (OR, 1.8), although none of them
reached statistical significance.73
Education
Two case-control studies from the same institution
resulted in conflicting conclusions on the role of educa-
tion as a risk factor for PSP. Davis and colleagues found
that cases of PSP had a significantly higher educational
level than controls in two of three categories tested (OR,
3.1 for completing high school and 2.9 for completing
college; P ⬍ 0.05).73 Golbe and coworkers however,
found that patients with PSP were less likely to have
completed at least 12 years of school (OR, 0.35; 95% CI,
0.12– 0.95; P ⫽ 0.022).74 They attributed this disparity to
methodological differences in control selection.74 AD is
another neurodegenerative disorder where, like in PD,
many case-control studies were conducted. These studies
may offer clues as to possible risk factors for PSP as PSP
shares with AD the deposition of abnormal tau protein.
However, in AD, tau mainly aggregates as neurofibril-
lary tangles in neurons that contain all six isoforms;
whereas in PSP, selected tau isoforms (4R tau) aggregate
in neurons and glia. For AD, one explanation for an
association is the brain reserve hypothesis, i.e., education
leads to increased cortical thickness and synaptic density,
and thus more-educated people can tolerate the impair-
ment caused by progressive neurodegeneration.105–108
This hypothesis may not be applicable to primarily motor
disorders like PSP. Other hypotheses that could explain
this risk factor include the possibility that lower educational
attainment is a proxy for poor early-life nutrition or expo-
sure to neurotoxic substances.74 Alternatively, subtle cog-
nitive changes of PSP begin early in life so as to impair
intellectual or educational motivation.74
Coffee/Tobacco
Davis and colleagues found that heavy coffee drinking
(⬎5 cups/day) and cigarette smoking were inversely
S47
associated with PSP but that the results of their case-
control study were statistically insignificant.73 Vanacore
and coworkers found no difference in tobacco use be-
tween PSP cases and controls.109 The number of cases in
both PSP studies, however, was small (50 and 55). Risk
factors that occur with low frequency in the population
may not be detected, thus resulting in type II error. These
findings contrast with those in PD. A recent analysis
from the Honolulu–Asia Aging Study based on a large
sample size suggest, that midlife coffee consumption is
significantly inversely associated with PD independent
of the effect of tobacco use.110 Similarly, a significant
inverse association between heavy coffee drinking (⬎5
cups/day) before or at age 40 years and PD111 and that
tobacco use is inversely associated with PD has been
confirmed in several studies.112
Whether these factors are also operational in the
pathogenetic or protective mechanisms involved in 4-R
tauopathies, provide a clue to a common pathogenesis, or
whether the epidemiological data support the notion that
different risks factors may be associated with different
groups of neurodegenerative disorders needs to be inves-
tigated further. Although the literature on PSP is defi-
nitely limited, it is reasonable to consider that there may
be different risk factors for PSP than for PD.
REFERENCES
1. Steele JC, Richardson JC, Olszewski J. Progressive supranuclear
palsy. Arch Neurol 1964;10:333–359.
2. Litvan I, Mangone CA, McKee A, Verny M, Parsa A, Jellinger K,
et al. Natural history of progressive supranuclear palsy (Steele-
Richardson- Olszewski syndrome) and clinical predictors of sur-
vival: a clinicopathological study. J Neurol Neurosurg Psychiatry
1996;60:615– 620.
3. Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC,
et al. Clinical research criteria for the diagnosis of progressive
supranuclear palsy (Steele-Richardson-Olszewski syndrome): re-
port of the NINDS-SPSP international workshop. Neurology 1996;
47:1–9.
4. Litvan I. Diagnosis and management of progressive supranuclear
palsy. Semin Neurol 2001;21:41– 48.
5. Hauw JJ, Daniel SE, Dickson D, Horoupian DS, Jellinger K,
Lantos PL, et al. Preliminary NINDS neuropathologic criteria for
Steele-Richardson-Olszewski syndrome (progressive supranuclear
palsy). Neurology 1994;44:2015–2019.
6. Litvan I, Hauw JJ, Bartko JJ, Lantos PL, Daniel SE, Horoupian
DS, et al. Validity and reliability of the preliminary NINDS neu-
ropathologic criteria for progressive supranuclear palsy and related
disorders. J Neuropathol Exp Neurol 1996;55:97–105.
7. Lopez OL, Litvan I, Catt KE, Stowe R, Klunk W, Kaufer DI, et al.
Accuracy of four clinical diagnostic criteria for the diagnosis of
neurodegenerative dementias. Neurology 1999;53:1292–1299.
8. Spillantini MG, Goedert M. Tau protein pathology in neurodegen-
erative diseases. Trends Neurosci 1998;21:428 – 433.
9. Sergeant N, Wattez A, Delacourte A. Neurofibrillary degeneration
in progressive supranuclear palsy and corticobasal degeneration:
tau pathologies with exclusively “exon 10” isoforms. J Neurochem
1999;72:1243–1249.
10. Chambers CB, Lee JM, Troncoso JC, Reich S, Muma NA. Over-
expression of four-repeat tau mRNA isoforms in progressive su-
Movement Disorders, Vol. 18, Suppl. 6, 2003
S48 I. LITVAN
pranuclear palsy but not in Alzheimer’s disease. Ann Neurol
1999;46:325–332.
11. Litvan I, Agid Y, Goetz C, Jankovic J, Wenning GK, Brandel JP,
et al. Accuracy of the clinical diagnosis of corticobasal degenera-
tion: a clinicopathologic study. Neurology 1997;48:119 –125.
12. Litvan I, Agid Y, Jankovic J, Goetz C, Brandel JP, Lai EC, et al.
Accuracy of clinical criteria for the diagnosis of progressive su-
pranuclear palsy (Steele-Richardson-Olszewski syndrome). Neu-
rology 1996;46:922–930.
13. Boeve BF, Lang AE, Litvan I. Corticobasal degeneration and
progressive supranuclear palsy: The relationship between the syn-
drome and the disease to FTD. Ann Neurol 2003;54(Suppl. 5):
515–519.
14. Dickson DW, Bergeron C, Chin SS, Duyckaerts C, Horoupian D,
Ikeda K, et al. Office of Rare Diseases neuropathologic criteria for
corticobasal degeneration. J Neuropathol Exp Neurol 2002;61:
935–946.
15. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Inci-
dence of progressive supranuclear palsy and multiple system atro-
phy in Olmsted County, Minnesota, 1976 to 1990. Neurology
1997;49:1284 –1288.
16. Schrag A, Ben-Shlomo Y, Quinn NP. Prevalence of progressive
supranuclear palsy and multiple system atrophy: a cross-sectional
study. Lancet 1999;354:1771–1775.
17. Mastaglia FL, Grainger K, Kee F, Sadka M, Lefroy R. Progressive
supranuclear palsy (the Steele-Richarson-Olszewski Syndrome)
clinical and electrophysiological observations in eleven cases. Proc
Aust Assoc Neurol 1973;10:35– 44.
18. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Inci-
dence and distribution of parkinsonism in Olmsted County, Min-
nesota, 1976 –1990. Neurology 1999;52:1214 –1220.
19. Golbe LI, Davis PH, Schoenberg BS, Duvoisin RC. Prevalence and
natural history of progressive supranuclear palsy. Neurology 1988;
38:1031–1034.
20. Nath U, Ben-Shlomo Y, Thomson RG, Morris HR, Wood NW,
Lees AJ, et al. The prevalence of progressive supranuclear palsy
(Steele-Richardson-Olszewski syndrome) in the UK. Brain 2001;
124(Pt 7):1438 –1449.
21. Santacruz P, Uttl B, Litvan I, Grafman J. Progressive supranuclear
palsy: a survey of the disease course. Neurology 1998;50:1637–
1647.
22. Wenning GK, Litvan I, Jankovic J, Granata R, Mangone CA,
McKee A, et al. Natural history and survival of 14 patients with
corticobasal degeneration confirmed at postmortem examination.
J Neurol Neurosurg Psychiatry 1998;64:184 –189.
23. Nath U, Ben-Shlomo Y, Thomson RG, Lees AJ, Burn DJ. Clinical
features and natural history of progressive supranuclear palsy: a
clinical cohort study. Neurology 2003;60:910 –916.
24. Maher ER, Lees AJ. The clinical features and natural history of the
Steele-Richardson-Olszewski syndrome (progressive supranuclear
palsy). Neurology 1986;36:1005–1008.
25. Collins SJ, Ahlskog JE, Parisi JE, Maraganore DM. Progressive
supranuclear palsy: neuropathologically based diagnostic clinical
criteria. J Neurol Neurosurg Psychiatry 1995;58:167–173.
26. Litvan I, Dickson DW, Buttner-Ennever JA, Delacourte A, Hutton
M, Dubois B, et al. Research goals in progressive supranuclear
palsy: a brainstorming conference. Mov Disord 2000;15:446 – 458.
27. Golbe L. Progressive supranuclear palsy in the molecular age.
Lancet 2000;356:870 – 871.
28. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov
AV, Greenamyre JT. Chronic systemic pesticide exposure repro-
duces features of Parkinson’s disease. Nat Neurosci 2000;3(12):
1301–1306.
29. Saunders AM, Hulette O, Welsh-Bohmer KA, Schmechel DE,
Crain B, Burke JR, et al. Specificity, sensitivity, and predictive
value of apolipoprotein-E genotyping for sporadic Alzheimer’s
disease. Lancet 1996;348:90 –93.
Movement Disorders, Vol. 18, Suppl. 6, 2003
30. Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez-Tur
J, et al. Association of an extended haplotype in the tau gene with
progressive supranuclear palsy. Hum Mol Genet 1999;8:711–715.
31. Di Maria E, Tabaton M, Vigo T, Abbruzzese G, Bellone E, Donati
C, et al. Corticobasal degeneration shares a common genetic back-
ground with progressive supranuclear palsy. Ann Neurol 2000;47:
374 –377.
32. Houlden H, Baker M, Morris HR, MacDonald N, Pickering-Brown
S, Adamson J, et al. Corticobasal degeneration and progressive
supranuclear palsy share a common tau haplotype. Neurology
2001;56:1702–1706.
33. D’Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM, Bird TD, et
al. Missense and silent tau gene mutations cause frontotemporal
dementia with parkinsonism-chromosome 17 type, by affecting
multiple alternative RNA splicing regulatory elements. Proc Natl
Acad Sci U S A 1999;96:5598 –5603.
34. Iijima M, Tabira T, Poorkaj P, Schellenberg GD, Trojanowski JQ,
Lee VM, et al. A distinct familial presenile dementia with a novel
missense mutation in the tau gene. Neuroreport 1999;10:497–501.
35. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H,
et al. Association of missense and 5⬘-splice-site mutations in tau
with the inherited dementia FTDP-17. Nature 1998;393:702–705.
36. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Ander-
son L, et al. Tau is a candidate gene for chromosome 17 fronto-
temporal dementia. Ann Neurol 1998;43:815– 825.
37. Bird TD, Nochlin D, Poorkaj P, Cherrier M, Kaye J, Payami H, et
al. A clinical pathological comparison of three families with fron-
totemporal dementia and identical mutations in the tau gene
(P301L). Brain 1999;122(Pt 4):741–756.
38. Bugiani O, Murrell JR, Giaccone G, Hasegawa M, Ghigo G,
Tabaton M, et al. Frontotemporal dementia and corticobasal de-
generation in a family with a P301S mutation in tau. J Neuropathol
Exp Neurol 1999;58:667– 677.
39. van Swieten JC, Stevens M, Rosso SM, Rizzu P, Joosse M, de
Koning I, et al. Phenotypic variation in hereditary frontotemporal
dementia with tau mutations. Ann Neurol 1999;46:617– 626.
40. Litvan I, Baker M, Hutton M. Tau haplotype does not affect the
onset, symptom severity, or survival in progressive supranuclear
palsy. Neurology 2001;57:138 –140.
41. Caparros-Lefebvre D, Elbaz A. Possible relation of atypical par-
kinsonism in the French West Indies with consumption of tropical
plants: a case-control study. Caribbean Parkinsonism Study Group.
Lancet 1999;354:281–286.
42. Caparros-Lefebvre D. Doparesistant parkinsonism in Guadeloupe
and possible relation with the toxicity of isoquinolone derivates.
Mov Disord 2001;16:394 –395.
43. Kikuchi K, Nagatsu Y, Makino Y, Mashino T, Ohta S, Hirobe M.
Metabolism and penetration through blood-brain barrier of parkin-
sonism- related compounds. 1,2,3,4-Tetrahydroisoquinoline and
1-methyl-1,2,3,4- tetrahydroisoquinoline. Drug Metab Dispos
1991;19:257–262.
44. Makino Y, Ohta S, Tasaki Y, Tachikawa O, Kashiwasake M,
Hirobe M. A novel and neurotoxic tetrahydroisoquinoline deriva-
tive in vivo: formation of 1,3-dimethyl-1,2,3,4-tetrahydroisoquino-
line, a condensation product of amphetamines, in brains of rats
under chronic ethanol treatment. J Neurochem 1990;55:963–969.
45. Niwa T, Takeda N, Tatematsu A, Matsuura S, Yoshida M, Nagatsu
T. Migration of tetrahydroisoquinoline, a possible parkinsonian
neurotoxin, into monkey brain from blood as proved by gas chro-
matography-mass spectrometry. J Chromatogr 1988;452:85–91.
46. Soto-Otero R, Mendez-Alvarez E, Sanchez-Sellero I, Cruz-Land-
eira A, Lopez-Rivadulla Lamas M. Reduction of rat brain levels of
the endogenous dopaminergic proneurotoxins 1,2,3,4-tetrahy-
droisoquinoline and 1,2,3,4-tetrahydro- beta-carboline by cigarette
smoke. Neurosci Lett 2001;298:187–190.
47. Niwa T, Takeda N, Sasaoka T, Kaneda T, et al. Detection of
tetrahydroisoquinoline, in parkinsonian brain as an endogenous
amine by use of gas chromatography-mass spectrometry. J Chro-
matogr 1989;491:397– 403.
 UPDATE ON EPIDEMIOLOGICAL ASPECTS OF PSP
48. Kotake Y, Tasaki Y, Makino Yea. 1-Benzyl-1,2,3,4-tetrahydroiso-
quinoline as a parkinsonism-inducing agent: a novel endogenous
amine in mouse brain and parkinsonian CSF. J Neurochem 1995;
65:2633–2638.
49. Kawai H, Makino Y, Hirobe M, Ohta S. Novel endogenous
1,2,3,4-tetrahydroisoquinoline derivative: uptake by dopamine
transporter and activity to induce parkinsonism. J Neurochem
1998;70:745–751.
50. Tasaki Y, Makino Y, Ohta S, Hirobe M. 1-Methyl-1,2,3,4-tetra-
hydroisoquioline, decreasing in 1-methyl-4-phenyl-1,2,3,6-tetra-
hydropyridine-treated mouse, prevents parkinsonism-like behavior
abnormalities. J Neurochem 1991;57:1940 –1943.
51. Kotake T, Yoshida M, Ogawa M, Tasaki Y, Hirobe M, Ohta S.
Chronic administration of 1-benzyl-1,2,3,4-tetrahydroisoquinoline,
an endogenous amine in the brain, induces parkinsonism in a
primate. Neurosci Lett 1996;217:69 –71.
52. Nagatsu T, Yoshida M. An endogenous substance of the brain,
tetrahydroisoquinoline, produces parkinsonism in primates with
decreased dopamine, tyrosine hydroxylase and biopterin in the
nigrostriatal regions. Neurosci Lett 1988;87:178 –182.
53. Yoshida M, Niwa T, Nagatsu T. Parkinsonism in monkeys pro-
duced by chronic administration of an endogenous substance of the
brain, tetrahydroisoquinoline: the behavioral and biochemical
changes. Neurosci Lett 1990;119:109 –113.
54. Lannuzel A, Michel PP, Abaul MJ, Caparros-Lefebvre D, Ruberg
M. Neurotoxic effects of alkaloids from Annona muricata (sour-
sop) on dopaminergic neurons: potential role in etiology of atypical
parkinsonism in French West Indies [abstract]. Mov Disord 2000;
13(Suppl. 3):28.
55. Friedrich MJ. Pesticide study aids Parkinson research. JAMA
1999;282:2200.
56. Cobuzzi RJ Jr, Neafsey EJ, Collins MA. Differential cytotoxicities
of N-methyl-beta-carbolinium analogues of MPP⫹ in PC12 cells:
insights into potential neurotoxicants in Parkinson’s disease.
J Neurochem 1994;62:1503–1510.
57. Collins MA, Neafsey EJ, Matsubara K, et al, editors. Indole-N-
methylation of beta-carbolines: The brain’s bioactivation route to
toxins in Parkinson’s disease? Ann NY Acad Sci 1992;648:263–
265.
58. Drucker G, Raikoff K, Neafsey EJ, Collins MA. Dopamine uptake
inhibitory capacities of beta-carboline and 3,4-dihydro- beta-car-
boline analogs of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) oxidation products. Brain Res 1990;509:125–133.
59. Kuhn W, Muller T, Grosse H, Rommelspacher H. Elevated levels
of harman and norharman in cerebrospinal fluid of parkinsonian
patients. J Neural Transm 1996;103:1435–1440.
60. Matsubara K, Senda T, Uezono T, Fukushima S, Ohta S, Igarashi
K, et al. Structural significance of azaheterocyclic amines related to
Parkinson’s disease for dopamine transporter. Eur J Pharmacol
1998;348:77– 84.
61. Neafsey EJ, Drucker G, Raikoff K, Collins MA. Striatal dopami-
nergic toxicity following intranigral injection in rats of 2-methyl-
norharman, a beta-carbolinium analog of N-methyl-4-phenylpyri-
dinium ion (MPP⫹). Neurosci Lett 1989;105:344 –349.
62. Makino Y, Ohta S, Tachikawa O, Hirobe M. Presence of tetrahy-
droisoquinoline and 1-methyl-tetrahydro-isoquinoline in foods:
compounds related to Parkinson’s disease. Life Sci 1988;43:373–
378.
63. Niwa T, Yoshizumi H, Tatematsu Aea. Presence of tetrahydroiso-
quinoline, a parkinsonism-related compound, in foods. J Chro-
matogr 1989;493:347–352.
64. Spencer PS, Kisby GE, Ludolph AC. Slow toxins, biologic mark-
ers, and long-latency neurodegenerative disease in the western
Pacific region. Neurology 1991;41(Suppl. 2):62– 68.
65. Zhang ZX, Anderson DW, Mantel N. Geographic patterns of
parkinsonism-dementia complex on Guam, 1956 through 1985.
Arch Neurol 1990;47:1069 –1074.
S49
66. Zhang ZX, Anderson DW, Lavine L, Mantel N. Patterns of ac-
quiring parkinsonism-dementia complex on Guam, 1944 through
1985. Arch Neurol 1990;47:1019 –1024.
67. McCrank E. PSP risk factors. Neurology 1990;40:1637.
68. McCrank E, Rabheru K. Four cases of progressive supranuclear
palsy in patients exposed to organic solvents. Can J Psychiatry
1989;34:934 –936.
69. Tetrud J, Langston J, Irwin I, Snow B. Parkinsonism caused by
petroleum waste ingestion. Neurology 1994;44:1051–1054.
70. Pezzoli G, Ricciardi S, Masotto C, Mariani CB, Carenzi A. n-
hexane induces parkinsonism in rodents. Brain Res 1990;531:355–
357.
71. Pezzoli G, Barbieri S, Ferrante C, Zecchinelli A, Foa V. Parkin-
sonism due to n-hexane exposure [letter]. Lancet 1989;2:874.
72. Nee L, Gomez M, Dambrosia J, et al. Environmental-occupational
risk factors and familial associations in multiple system atrophy: a
preliminary investigation. Clin Auton Res 1991;1:9 –13.
73. Davis PH, Golbe LI, Duvoisin RC, Schoenberg BS. Risk factors for
progressive supranuclear palsy. Neurology 1988;38:1546–1552.
74. Golbe LI, Rubin RS, Cody RP, Belsh JM, Duvoisin RC, Grosmann
C, et al. Follow-up study of risk factors in progressive supranuclear
palsy. Neurology 1996;47:148 –154.
75. McGeer PL, Rogers J. Anti-inflammatory agents as a therapeutic
approach to Alzheimer’s disease. Neurology 1992;42:447– 449.
76. Halliday G, Robinson SR, Shepherd C, Kril J. Alzheimer’s disease
and inflammation: a review of cellular and therapeutic mecha-
nisms. Clin Exp Pharmacol Physiol 2000;27:1– 8.
77. Halliday GM, Shepherd CE, McCann H, Reid WG, Grayson DA,
Broe GA, et al. Effect of anti-inflammatory medications on neu-
ropathological findings in Alzheimer disease. Arch Neurol 2000;
57:831– 836.
78. Mackenzie IR. Anti-inflammatory drugs and Alzheimer-type pa-
thology in aging. Neurology 2000;54:732–734.
79. Gerhard A, Banati RB, Cagnin A, Brooks DJ. In vivo imaging of
activated microglia with [11C]PK11195 positron emission tomog-
raphy (PET) in idiopathic and atypical Parkinson’s disease. [ab-
stract]. Neurology 2001;56:270.
80. Ishizawa K, Dickson DW. Microglial activation parallels system
degeneration in progressive supranuclear palsy and corticobasal
degeneration. J Neuropathol Exp Neurol 2001;60:647– 657.
81. Lippa CF, Smith TW, Flanders KC. Transforming growth factor-
beta: neuronal and glial expression in CNS degenerative diseases.
Neurodegeneration 1995;4:425– 432.
82. Drache B, Diehl GE, Beyreuther K, Perlmutter LS, Konig G.
Bcl-xl-specific antibody labels activated microglia associated with
Alzheimer’s disease and other pathological states. J Neurosci Res
1997;47:98 –108.
83. Lippa CF, Flanders KC, Kim ES, Croul S. TGF-beta receptors-I
and -II immunoexpression in Alzheimer’s disease: a comparison
with aging and progressive supranuclear palsy. Neurobiol Aging
1998;19:527–533.
84. Yamada T, Moroo I, Koguchi Y, Asahina M, Hirayama K. In-
creased concentration of C4d complement protein in the cerebro-
spinal fluids in progressive supranuclear palsy. Acta Neurol Scand
1994;89:42– 46.
85. Dickson DW. Neuropathologic differentiation of progressive su-
pranuclear palsy and corticobasal degeneration. J Neurol 1999;
246(Suppl. 2):II6 –II15.
86. Li G, Shen YC, Li YT, Chen CH, Zhau YW, Silverman JM. A
case-control study of Alzheimer’s disease in China. Neurology
1992;42:1481–1488.
87. Kawas CH, Clark CM, Farlow MR, Knopman DS, Marson D,
Morris JC, et al. Clinical trials in Alzheimer disease: debate on the
use of placebo controls. Alzheimer Dis Assoc Disord 1999;13:
124 –129.
88. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflam-
matory agents as possible protective factors for Alzheimer’s dis-
ease: a review of 17 epidemiologic studies. Neurology 1996;47:
425– 432.
Movement Disorders, Vol. 18, Suppl. 6, 2003
S50 I. LITVAN
89. Dubinsky RM, Jankovic J. Progressive supranuclear palsy and a
multi-infarct state. Neurology 1987;37:570 –576.
90. Winikates J, Jankovic J. Vascular progressive supranuclear palsy.
J Neural Transm Suppl 1994;42:189 –201.
91. Gearing M, Olson DA, Watts RL, Mirra SS. Progressive supranu-
clear palsy: neuropathologic and clinical heterogeneity. Neurology
1994;44:1015–1024.
92. Fabbrini G, Vanacore N, Bonifati V, Colosimo C, Meco G. Pr-
esymptomatic hypertension in progressive supranuclear palsy.
Study Group on Atypical Parkinsonisms [letter]. Arch Neurol
1998;55:1153–1155.
93. Ghika J, Bogousslavsky J. Presymptomatic hypertension is a major
feature in the diagnosis of progressive supranuclear palsy. Arch
Neurol 1997;54:1104 –1108.
94. Geddes JF, Vowles GH, Nicoll JA, Revesz T. Neuronal cytoskel-
etal changes are an early consequence of repetitive head injury.
Acta Neuropathol (Berl) 1999;98:171–178.
95. Bhatt M, Desai J, Mankodi A, Elias M, Wadia N. Posttraumatic
akinetic-rigid syndrome resembling Parkinson’s disease: a report
on three patients. Mov Disord 2000;15:313–317.
96. Goetz CG, Pappert EJ. Trauma and movement disorders. Neurol
Clin 1992;10:907–919.
97. Newell KL, Boyer P, Gomez-Tortosa E, Hobbs W, Hedley-Whyte
ET, Vonsattel JP, et al. Alpha-synuclein immunoreactivity is
present in axonal swellings in neuroaxonal dystrophy and acute
traumatic brain injury. J Neuropathol Exp Neurol 1999;58:1263–
1268.
98. O’Meara ES, Kukull WA, Sheppard L, Bowen JD, McCormick
WC, Teri L, et al. Head injury and risk of Alzheimer’s disease by
apolipoprotein E genotype. Am J Epidemiol 1997;146:373–384.
99. Nemetz PN, Leibson C, Naessens JM, Beard M, Kokmen E,
Annegers JF, et al. Traumatic brain injury and time to onset of
Alzheimer’s disease: a population-based study. Am J Epidemiol
1999;149:32– 40.
100. Guo Z, Cupples LA, Kurz A, Auerbach SH, Volicer L, Chui H,
et al. Head injury and the risk of AD in the MIRAGE study.
Neurology 2000;54:1316 –1323.
101. Muller J, Wenning GK, Verny M, McKee A, Chaudhuri KR,
Jellinger K, et al. Progression of dysarthria and dysphagia in
Movement Disorders, Vol. 18, Suppl. 6, 2003
postmortem-confirmed parkinsonian disorders. Arch Neurol
2001;58:259 –264.
102. Mehta KM, Ott A, Kalmijn S, Slooter AJ, vanDuijn CM, Hofman
A, et al. Head trauma and risk of dementia and Alzheimer’s
disease: the Rotterdam study. Neurology 1999;53:1959 –1962.
103. Launer LJ, Andersen K, Dewey ME, Letenneur L, Ott A, Ama-
ducci LA, et al. Rates and risk factors for dementia and Alzhei-
mer’s disease: results from EURODEM pooled analyses. EU-
RODEM Incidence Research Group and Work Groups. European
Studies of Dementia. Neurology 1999;52:78 – 84.
104. Luukinen H, Viramo P, Koski K, Laippala P, Kivela SL. Head
injuries and cognitive decline among older adults: a population-
based study. Neurology 1999;52:557–562.
105. Letenneur L, Launder LJ, Andersen K, Dewey ME, Ott A, Cope-
land JR, et al. Education and the risk for Alzheimer’s disease: sex
makes a difference. ERUODEM Pooled Analyses. Am J Epide-
miol 2000;151:1064 –1071.
106. Diamond M. Enriching heredity: the impact of the environment
on the anatomy of the brain. New York: NY Free Press; 1988.
107. Mortimer J. Do psychosocial risk factors contribute to Alzhei-
mer’s disease? In: Henderson AS, Henderson JH, editors. Etiol-
ogy of dementia of Alzheimer’s type. New York, NY: John Wiley
& Sons, Inc; 1988. p 39 –52.
108. Satz P. Brain reserve capacity on symptom onset after brain
injury: a formulation and review of evidence of threshold theory.
Neuropsychology 1993;3:273–293.
109. Vanacore N, Bonifati V, Fabbrini G, Colosimo C, Marconi R,
Nicholl D, et al. Smoking habits in multiple system atrophy and
progressive supranuclear palsy. European Study Group on Atyp-
ical Parkinsonisms. Neurology 2000;54:114 –119.
110. Ross GW, Abbott RD, Petrovitch H, Morens DM, Grandinetti A,
Tung KH, et al. Association of coffee and caffeine intake with the
risk of Parkinson disease. JAMA 2000;283:2674 –2679.
111. Nefzger M, Quadfasel F, Karl V. A retrospective study of smok-
ing in Parkinson’s disease. Am J Epidemiol 1968;88:149 –158.
112. Morens D, Grandinetti A, Reed D, White L, Ross G. Cigarette
smoking and protection from Parkinson’s disease: false associa-
tion or etiologic clue? Neurology 1995;45:1041–1051.