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Paper
Factors associated with survival probability in
autopsy-proven frontotemporal lobar degeneration
S X Xie,1 M S Forman,2 J Farmer,2 P Moore,3 Y Wang,1 X Wang,1 C M Clark,3
H B Coslett,3 A Chatterjee,3 S E Arnold,4 H Rosen,5 J H T Karlawish,6 V M Van Deerlin,2
V M-Y Lee,2 J Q Trojanowski,2 M Grossman3
1
Department of Biostatistics
and Epidemiology, University of
Pennsylvania School of Medicine
Philadelphia, PA, USA;
2
Pathology and Laboratory
Medicine and Center for
Neurodegenerative Disease
Research University of
Pennsylvania School of Medicine
Philadelphia, PA, USA;
3
Department of Neurology,
University of Pennsylvania
School of Medicine, Philadelphia,
PA, USA; 4 Department of
Psychiatry, University of
Pennsylvania School of
Medicine, Philadelphia, PA, USA;
5
Department of Neurology,
University of California, San
Francisco, CA, USA;
6
Department of Geriatrics,
University of Pennsylvania
School of Medicine, Philadelphia,
PA, USA
Correspondence to:
Murray Grossman, Department
of Neurology—2 Gibson,
Hospital of the University of
Pennsylvania, 3400 Spruce St,
Philadelphia, PA 19104-4283,
USA; [email protected].
upenn.edu
Portions of this work were
presented at the annual meeting
of the American Academy of
Neurology, San Diego, April
2006.
Received 3 November 2006
Revised 18 June 2007
Accepted 19 June 2007
Published Online First
5 July 2007
ABSTRACT
Objective: To examine the clinical and pathological
factors associated with survival in autopsy-confirmed
frontotemporal lobar degeneration (FTLD).
Methods: The final analysis cohort included 71 patients
with pathologically proven FTLD, excluding patients with
clinical motor neuron disease (MND), evaluated at the
University of Pennsylvania or at the University of
California, San Francisco. We assessed clinical and
demographic features; cognitive functioning at presentation; genetic markers of disease; and graded anatomical
distribution of tau, ubiquitin and amyloid pathology.
Results: The tau-negative group (n = 35) had a median
survival time of 96 months (95% CI: 72–114 months),
whereas the tau-positive group (n = 36) had a median
survival time of 72 months (95% CI: 60–84 months).
Patients with tau-positive pathology across all brain
regions had shorter survival than those with tau-negative
pathology in univariate Cox regression analyses (Hazard
ratio of dying = 2.003, 95% CI = 1.209–3.318,
p = 0.007).
Conclusions: Tau-positive pathology represents a significant risk to survival in FTLD, whereas tau-negative
pathology is associated with a longer survival time when
clinical MND is excluded.
Frontotemporal lobar degeneration (FTLD) is a
progressive neurodegenerative condition that manifests clinically as a disorder of social comportment,
personality and executive functioning (ie behavioural change), or as a progressive form of aphasia
(ie language change). Although FTLD may progress
to death more rapidly than Alzheimer’s disease
(AD),1 there has been little consensus on the
factors contributing to the rapid decline of these
patients. A recent consensus group distinguished
between tau-positive and tau-negative pathologies.2 Two reports associate tau-positive pathology
with a longer survival,3 4 whereas others have
found equal survival in tau-negative and taupositive pathologies.1 5 6 We examined clinical and
pathological characteristics contributing to survival
in a relatively large cohort of autopsy-proven
FTLD.
METHODS
Study cohort
Inclusion criteria included all patients with FTLD
spectrum neuropathology identified at the
University of Pennsylvania (UPenn) between
1995 and 2005, following clinical assessments at
UPenn or University of California, San Francisco
126
(UCSF), who did not have significant non-neurological co-morbidities such as cancer or pulmonary
disease (n = 91). Patients without adequately
detailed clinical evaluations were excluded
(n = 15), and patients with a clinical diagnosis of
motor neuron disease (MND) were excluded due to
their known shorter lifespan and known pathology
(n = 5). Table 1 summarises the final analysis
cohort, including 71 subjects with a pathological
diagnosis of FTLD. All subjects in the final analysis
cohort had a primary pathological diagnosis related
to a disorder of tau. However, four subjects had a
secondary pathological diagnosis, suggesting some
features of AD. Not all subjects had information
for all variables (see table 1 for more details). Some
of these patients were previously reported.7
Clinical evaluations and survival time
Clinical diagnosis was based on informant interview, medical history, neurological examination,
neuropsychological evaluation, laboratory screening and brain imaging, when available (including
MRI, SPECT and/or PET). The clinical diagnosis
was consistent with published criteria.2 8
Survival time was computed from the approximated time of symptom onset until the time of
death. Symptom onset estimation was based on a
family report of the earliest persistently abnormal
clinical feature in the domains of language, social
function or personality change, memory, executive, visual–spatial functioning, movement disorder or weakness.
Symptoms at presentation included (coded as
present or not present): Social/behavioural change;
language dysfunction; other cognitive deficits;
movement disorder; and focal weakness. Specific
clinical signs from the neurological exam included:
Social dysfunction; aphasia; extrapyramidal features; and pyramidal signs. A limited battery of
cognitive tests was available across the accrual
period at the referring sites, including: MiniMental State Examination (MMSE); Boston
Naming Test; Animal Fluency; Word List Recall;
and Digit Span Forward. Family history was coded
as: Present or absent. Tau haplotype and
Apolipoprotein E genotypic information were also
available for analyses.
Pathology evaluation
To establish a neuropathological diagnosis, representative blocks were examined from the brain, as
described previously.7 All cases were reviewed by
two board-certified neuropathologists (MSF and
J Neurol Neurosurg Psychiatry 2008;79:126–129. doi:10.1136/jnnp.2006.110288
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Paper
Table 1 Clinical and demographic characteristics of participants
Characteristics
Whole cohort1 (n = 71)
Tau-negative group (n = 35)
Tau-positive group (n = 36)
Male, n (%)
Age at symptom onset (years)*
Education (years)*,{
MMSE at initial clinic visit*,{
Presence of family history, n (%){
Clinical diagnosis
Frontotemporal dementia
Corticobasal degeneration
Progressive supranuclear palsy
Alzheimer’s disease
Unclassified dementia
Average tau pathology density
34 (48)
61.0¡9.5 (30–80)
15.0¡2.8 (10–20)
23.0¡6.8 (4–30)
30 (47)
16 (46)
60.4¡9.5 (43–80)
14.8¡2.6 (10–20)
22.8¡6.2 (8–30)
16 (52)
18 (50)
61.5¡9.7 (30–80)
15.1¡3.0 (10–20)
23.2¡7.3 (4–30)
14 (42)
47
10
3
6
5
1.38
28
0
1
3
3
0.34
19
10
2
3
2
2.39
*Mean ¡ SD (range)
Known in 56 subjects
{
Known in 64 subjects
1
Pathologic diagnoses in the whole cohort included Pick’s disease (n = 8), corticobasal degeneration (n = 21), frontotemporal
degeneration with Parkinsonism due to a mutation on chromosome 17 (n = 3), progressive supranuclear palsy (n = 5),
frontotemporal lobar degeneration with ubiquitin-positive inclusions (n = 24), dementia lacking distinctive histopathology (n = 4),
and other primary tauopathies (n = 6, ie argyrophylic grain disease, tangle-predominant senile dementia, and tauopathy not
otherwise specified).
{
JQT) blinded to clinical diagnosis, and consensus pathological
diagnoses were established according to the Workgroup on
frontotemporal dementia and Pick’s disease (PiD).2 Examined
brain regions included: mid-frontal gyrus, inferior parietal
lobule, superior and middle temporal gyri, anterior cingulate
gyrus, hippocampus, amygdala with entorhinal cortex, thalamus, and basal ganglia. Examined proteins used in the analysis
included: tau, amyloid and ubiquitin. Based on the density of
immunostained pathology, semi-quantitative grading was
assigned (0 = no or rare pathology, 1 = low pathology, 2 = moderate pathology, 3 = high pathology) in each analysed brain
region. We considered several summary neuropathology variables, including: average pathology across all regions for each
ascertained protein; and average pathology reading across tau,
ubiquitin and amyloid for a single brain region. We dichotomised these neuropathology variables into low pathology
(grading = 0 or 1) and abundant pathology (grading = 2 or 3)
categories. We refer to cases with low tau pathology as taunegative (average tau pathology rating (1), and cases with
abundant tau pathology as tau-positive (average tau pathology
rating >2).
Statistical analyses
The Kaplan–Meier method was used to generate survival
probabilities. Single and multiple covariate Cox proportional
hazards regression models examined factors associated with
survival. A forward model selection procedure was used,
following model building guidelines.9 Potential independent
variables included demographic features, clinical features at the
initial visit, cognitive variables, family history, genetic information and neuropathology features. Statistical analyses used SAS
software (SAS Institute, Cary, NC). All statistical tests used
two-sided p-values. Statistical significance was set at the 0.05
level.
RESULTS
The proportion of males and presence of family history, mean
years of education, mean age at onset, as well as MMSE score at
the initial visit, were similar between tau-negative and taupositive groups (p.0.05, table 1). The discrepancy between
J Neurol Neurosurg Psychiatry 2008;79:126–129. doi:10.1136/jnnp.2006.110288
estimated symptom onset and initial diagnosis (mean = 39 months, standard deviation = 37 months) differed between taupositive and tau-negative groups (Wilcoxon rank sum test,
z = 2.056, p = 0.040). Median survival from symptom onset for
the entire cohort was 80 months (95% confidence interval
(CI) = 72–84 months). The tau-negative group had a median
survival time of 96 months (95% CI: 72–114 months), whereas
the tau-positive group had a median survival time of 72 months
(95% CI: 60–84 months). In the univariate Cox regression
analyses, patients with tau-positive pathology had shorter
survival than those with tau-negative pathology (Hazard ratio
(HR) of dying = 2.003, 95% CI: 1.209–3.318; Wald x2 = 7.278,
df = 1, p = 0.007). A shorter survival time in the univariate
analysis was associated with abundant pathology of any sort in
the basal ganglia region (HR = 1.874, 95% CI: 1.054–3.332;
Wald x2 = 4.569, df = 1, p = 0.033). Shorter survival in the
univariate analysis was also associated with abundant pathology of any sort in the anterior cingulate region (HR = 1.782,
95% CI: 1.037–3.062; Wald x2 = 4.372, df = 1, p = 0.037).
Finally, shorter survival in the univariate analysis was associated with tau-positive pathology in an averaged cortical
region, including midfrontal, parietal, temporal and anterior
cingulate regions (HR = 1.637, 95% CI: 1.009–2.656; Wald
x2 = 3.983, df = 1, p = 0.046). Other characteristics were not
significantly associated with the survival probability.
The forward model selection procedure generated a preliminary model with only one significant predictor: status of
tau-positive versus tau-negative pathology across all regions.
Inspection of the remaining candidate variables revealed that
education produced the largest important change to the
regression coefficient of the tau pathology factor across all
regions (32%). A comparison of higher education levels (>15
years) to lower education levels (,15 years) in FTLD demonstrated a hazard ratio of 0.736 (95% CI = 0.425, 1.274), although
this effect did not reach statistical significance. Pathology of any
sort in the basal ganglia region also substantially changed the
regression coefficient of the model, including both tau
pathology status and education (44%). The association between
tau pathology status and survival probability was strengthened
after adjusting for years of education and pathology of any sort
in the basal ganglia region (HR = 3.750, 95% CI: 1.694–8.303;
127
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Paper
Wald x2 = 10.627, df = 1, p = 0.001). Figure 1 displays the
corresponding survival curve.
DISCUSSION
Median survival time from symptom onset in our cohort was
80 months, resembling previous studies of autopsy-proven
FTLD, with median survival ranging from 72 months to
104 months.3–6 Tau-positive pathology was associated with
shorter survival time in FTLD. Factors contributing to survival
included education and disease in the basal ganglia.
Our findings differ from the results of two previous studies
charting survival in FTLD.3 4 These investigators reported that taunegative pathology results in shorter survival time. It is well
established that tau-negative pathology—in particular, frontotemporal lobar degeneration with ubiquitin/TDP-43 inclusions
(FTLD-U)—is identical to the pathology underlying MND.10 11
However, a second analysis (excluding MND) replicated the basic
finding that tau-negative pathology is associated with shorter
survival time.3 4 Factors potentially contributing to the discrepancy
between these findings and ours include that the pathologies
contributing to the cohorts may not be the same across studies:
Our cohort had many corticobasal degeneration (CBD) patients,
whereas other studies had many tau-positive patients with PiD.3 4
Previous studies performed only univariate analyses, and did not
adjust for other covariates. Finally, our study used the actual
empirical burden of tau pathology to establish tau-positive and
tau-negative groups, whereas previous studies inferred the amount
of tau pathology based on the pathological diagnosis.3 4
Three other reports described equivalent survival in taupositive and tau-negative patients.1 5 6 One study compared
survival in carefully defined pathological cohorts of 15 taunegative patients with clinical MND, 18 FTLD patients without
MND and 12 cases with PiD,5 finding no difference between
FTLD-U without MND and PiD. We attempted to replicate this
finding by excluding CBD from our analysis, but the remaining
sample was too small to yield interpretable results. Another
study comparing 19 tau-positive patients primarily with PiD
and 24 tau-negative cases found a trend towards more rapid
decline in tau-negative cases, but did not exclude clinical MND
cases from the tau-negative cohort.1 Another report of 60
autopsy-proven FTLD patients showed a trend toward shorter
survival in tau-positive cases.6
In our multivariate survival model, additional factors
influencing prognosis in FTLD may include significant basal
ganglia pathology. Although this variable did not reach
statistical significance in the final multivariate model, it did
change the magnitude of the regression coefficient of tau
pathology across all regions by .20%, indicating that the
burden of basal ganglia pathology may contribute to survival.
This may be related, in part, to the large number of CBD
patients. Clinical assessments of survival in non-autopsy studies
of FTLD have reported that parkinsonism, a marker of basal
ganglia disease, contributes to rapid disease progression.12
Parkinsonism and dementia have independent and additive
effects on mortality in Parkinson’s disease13 and in AD.14 We
may not have observed the direct contribution of extrapyramidal features to mortality because we ascertained extrapyramidal features only at the onset of disease when all subjects
were mildly impaired.
Education also changed the magnitude of the regression
coefficient by .20%, although this factor was not significantly
associated with survival probability in the multivariate analysis.
One previous report found no significant effect of education on
survival in FTLD,4 but these investigators did not consider the
contribution of demographic factors in a multivariate account
of survival in FTLD. It is difficult to assess the effect of
education in our highly educated cohort as variance was not
sufficiently broad.
Our study did not otherwise demonstrate a relationship
between survival and clinical features at presentation.
Conclusions about clinical factors such as aphasia or a social
disorder have been conflicting.3 4 12 As syndromic subgroup
classification may change during the natural history of FTLD,6
we elected to evaluate the presence of a specific clinical
abnormality in the model rather than the presence of a
particular syndrome.3 4 Although some studies investigated
many neuropsychological variables on smaller autopsy samples,4
we evaluated a small number of neuropsychological measures to
maximise the size of the autopsy-confirmed cohort. It is
unfortunate that inattention and apathy were not ascertained
in enough patients because these features may be associated
with anterior cingulate disease,15 and pathology in this region
may contribute to survival.
Although patients were recruited early in their disease when
there is little sense of progression rate, we cannot exclude the
possibility that an inadvertent selection bias was introduced
because subjects enrolled in an autopsy program may be sicker
or have a higher level of education. Because we performed a
relatively large number of analyses, the readers should bear in
mind that there may exist false-positive findings. With these
caveats in mind, our findings indicate that several factors
predispose FTLD patients to a limited survival. The principal
contributing factor is the presence of tau pathology. This
observation emphasises the importance of developing biomarkers that reflect the presence of tau pathology.16
Acknowledgements: This work was supported in part by funds from the US National
Institutes of Health (AG17586, AG15116, NS44266, AG09215, AG10124, AG19724
and AG23501) and the Dana Foundation.
Competing interests: None declared.
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Historical note
A note on X linked
adrenoleukodystrophy (Addison–
Schilder syndrome)
In one of the unsurpassed medical works of the nineteenth
century,1 2 Thomas Addison (1793–1860) when investigating a
‘‘peculiar form of anaemia’’ described the classic symptoms of
adrenal cortical failure and found pathological changes in both
‘‘suprarenal glands’’—Addison’s disease. The ill-fatedi Paul
Ferdinand Schilder (1886–1940) in 1913 reported3 three cases of
‘‘encephalitis periaxialis diffusa’’, characterised by diffuse involvement of the cerebral white matter in children with severe myelin
loss, fat-laden phagocytes and gliosis, which resembled multiple
sclerosis, and was named Schilder’s disease. The two conditions
appeared unrelated until Haberfeld and Spieler reported the
combination of bronzed skin with leukodystrophy in 1910, but
the findings in the adrenal gland were not reported.4
‘‘A previously normal boy developed disturbances in eye
movement and vision at the age of 6 years, became apathetic,
and his schoolwork deteriorated. Four months later his gait
became spastic, and this progressed to an inability to walk.
He was hospitalised at 7 years. Dark skin was noted, but
otherwise not discussed. He had a spastic paraparesis, severe
apathy alternating with irritability, did not speak, and was
incontinent. He died 8 months later. An older brother had
died of a similar illness at 8.5 years. The postmortem brain
was studied by Schilder in 1913 who confirmed epidermal
pigmentation and diffuse demyelination of the brain..’’
Siemerling (1857–1931) and Creutzfeldt (1885–1964) in 1923
reported a similar case and deserve credit for proving adrenal
involvement,5 and thereby founding adrenoleukodystrophy, the
term first introduced in 1970.6
Hoefnagel et al summarised the literature and described an
afflicted family.7 It included a boy aged 7 years at death with no
melanoderma but with diffuse demyelination, absence of
pituitary basophils, interstitial cell testicular tumour and
adrenal atrophy. Similar abnormalities of the pituitary and
adrenal were present in his brother, although neither had
clinical hypoadrenocorticism. In contradiction to Poser and van
Bogaert in 1956, they believed
‘‘the coexistence of these lesions is not merely coincidental,’’
but the nature of ‘‘the interrelation of these lesions remains
entirely conjectural.’’
In 1963, Guido Fanconi (1892–1979) and colleagues8 explained
the full clinical picture suggesting an X linked hereditary
disorder. Mosser et al subsequently proved this by positional
cloning, located at the ABCD1 gene (chromosomal Xq28 locus).9
The defect is in a protein, ABCD1, that has a role in peroxisomal
beta oxidation. The resulting impaired function of adrenoleukodystrophy protein causes accumulation of very long chain
fatty acids.
There are three resulting phenotypes: (1) a childhood cerebral
form; (2) an adult adrenomyeloneuropathy and (3) a form with
later childhood onset, symptoms of Addison disease but no
clinically evident cerebral disorder. The plasma concentration of
very long chain fatty acids is elevated in more than 99% of
males with X linked adrenoleukodystrophy of all ages,
irrespective of symptoms, and is valuable in establishing carrier
status and prenatal diagnosis.
Correspondence to: Dr J M S Pearce, Department of Neurology, Hull Royal Infirmary
and Hull York Medical School, 304 Beverley Road Anlaby, East Yorks HU10 7BG, UK;
[email protected]
Competing interests: None.
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129
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Factors associated with survival probability
in autopsy-proven frontotemporal lobar
degeneration
S X Xie, M S Forman, J Farmer, et al.
J Neurol Neurosurg Psychiatry 2008 79: 126-129 originally published
online July 5, 2007
doi: 10.1136/jnnp.2006.110288
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