doi:10.1093/brain/awl268Brain (2006) Page 1 of 12
Frontotemporal dementia and parkinsonism
associated with the IVS1+1G!A mutation in
progranulin: a clinicopathologic study
Bradley F. Boeve,1,8Matt Baker,6Dennis W. Dickson,5,8Joseph E. Parisi,1,2,8Caterina Giannini,2
Keith A. Josephs,1,8Michael Hutton,6,8Stuart M. Pickering-Brown,6Rosa Rademakers,6
David Tang-Wai,7Clifford R. Jack Jr,3,8Kejal Kantarci,3Maria M. Shiung,3Todd Golde,6,8
Glenn E. Smith,4,8Yonas E. Geda,4,8David S. Knopman1,8and Ronald C. Petersen1,8
1Departments of Neurology,2Laboratory Medicine and Pathology,3Diagnostic Radiology—Neuroradiology and4Psychiatry
and Psychology, Mayo Clinic, Rochester, MN,5Neuropathology Laboratory and6Neurogenetics Laboratory, Mayo Clinic,
Jacksonville, FL, USA,7Department of Medicine, University of Toronto, Toronto, Ontario, Canada and8Robert H. and
Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program of the Mayo Foundation, USA
Correspondence to: Bradley F. Boeve, MD, Department of Neurology, Mayo Clinic, 200 First Street SW,
Rochester, MN 55905, USA
We previously reported a kindred with three cases of dementia, in which the proband exhibited features typical
of frontotemporal dementia and parkinsonism (FTDP). An arginine insertion at codon 352 (insR352) in the
of neurodegeneration not directly related to amyloid pathophysiology. The proband was followed with yearly
evaluations of functional, clinical, neuropsychologic, neuropsychiatric and radiologic status, which showed
relatively linear change over the initial 4 years of assessment. Upon the proband’s death at age 63, neuro-
pathologic examination revealed frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions
(FTLD-U). We recently identified several kindreds with familial FTDP associated with mutations in the pro-
granulin (PGRN) gene, particularly in those cases with neuronal intranuclear inclusions. Our proband was
indeed found to have such inclusions, and PGRN analysis in this proband revealed the G to A mutation in
the exon 1 splice donor site (IVS1+1G!A) which is predicted to destroy the 50-splice site of exon 1 and remove
the start methionine codon and hence completely block any PGRN protein from being generated. These
findings suggest that the insR352 PSEN1 is not pathogenic, and the IVS1+1G!A mutation in PGRN
causes FTDP associated with FTLD-U pathology and represents a new class of neurodegenerative disease—
Keywords: frontotemporal dementia; progranulin; presenilin; neurodegenerative disease; neurogenetics
Abbreviations: Ab ¼ beta-amyloid; FTD ¼ frontotemporal dementia; NFT ¼ neurofibrillary tangles; SP ¼ senile plaques;
VV ¼ ventricular volume; WBV ¼ whole-brain volume
Received July 31, 2005. Revised August 29, 2006. Accepted August 30, 2006
Over 60 mutations in the presenilin-1 gene (PSEN1)
located on chromosome 14q24.3 have been identified in
autosomal dominant Alzheimer’s disease. Although the
clinical phenotype associated with most mutations has been
progressive memory impairment followed by progressive
impairment in other cognitive domains, atypical features
have been present in many, including spastic paraparesis
(Crook et al., 1998), seizures, prominent ‘psychiatric’
symptoms(Tedde et al., 2000), and frontotemporal
dementia (FTD) (Raux et al., 2000a, b). Almost all cases
have had elevations in plasma and/or cerebrospinal fluid
beta-amyloid (Ab) levels (Borchelt et al., 1996), particularly
of the Ab40 and Ab42 fractions, as well as characteristic
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examination (Crook et al., 1998; Dermaut et al., 2001),
strongly implicating the direct causal role of abnormal
amyloid protein processing in the pathogenesis of PSEN1-
associated mutations regardless of clinical phenotype.
Understanding the aetiologic mechanisms underlying
some of the more recently described cases with PSEN1
mutations has been perplexing. The initially described cases
withthe phenotypeof FTD
identified—Leu113Pro (Raux et al., 2000a, b; Rogaeva
et al., 2001)and insArg352
‘insR352’) (Rogaeva et al., 2001; Amtul et al., 2002; Tang-
Wai et al., 2002), but no neuropathological findings have
been reported on affected individuals to date. Two more
recently described kindreds showing some clinical features
suggesting FTD, but with different PSEN1 mutations—
G183V (Dermaut et al., 2004) and M146L (Halliday et al.,
2005)—have interestingly had Pick bodies, with Alzheimer-
type pathology coexisting in one kindred (Halliday et al.,
2005). Biochemical studies in the G183V kindred failed to
show any increase in the presumed neurotoxic Ab species,
suggesting that this specific mutation did not cause the
disease via amyloidogenic mechanisms. Additional data on
such ‘PSEN1 mutation/non-amyloid pathology’ kindreds are
clearly desired to better understand the role of PSEN1
mutations in neurodegeneration.
We and others very recently identified mutations in the
progranulin (PGRN) gene in several kindreds of familial
FTD associated with frontotemporal lobar degeneration with
ubiquitin-positive inclusions (FTLD-U) pathology (Baker
et al., 2006; Cruts et al., 2006). Only scant data exists on the
normal role of progranulin and on pathologic states relating
to progranulin dysfunction (He and Bateman, 2003; Ong
and Bateman, 2003). Progranulin is involved in epithelial
cell growth and promotes tumour growth (He and Bateman,
2003; Ong and Bateman, 2003). Mutations resulting in
frame shift or stop codons in PGRN likely form null alleles
such that no progranulin protein is expressed (Baker et al.,
2006; Cruts et al., 2006). We suspect that the lack of
progranulin production leads to neurodegeneration, but the
precise mechanisms underlying
changes are not yet known.
We previously reported the pedigree, clinical and
radiologic features (Tang-Wai et al., 2002), and biochemical
findings (Amtul et al., 2002), in the small kindred noted
above with FTD associated with the novel arginine insertion
at codon 352 (insR352) in PSEN1 gene identified in the
proband. The proband has been followed longitudinally with
serial functional assessments, clinical examinations, neuro-
laboratory measurements and radiologic studies, and has
subsequently come to autopsy. The neuropathologic findings
led us to sequence the proband’s PGRN gene, and a
mutation was identified. Because of the longitudinal nature
of the comprehensive assessments on this proband, the
intriguing neuropathological and genetic findings, and the
scant longitudinal data on FTD subjects in general, we now
report these clinical, genetic and pathologic findings and
review our results in the context of the evolving literature.
Material and methods
All available clinical records and neuroimaging studies on the
proband since our original report were reviewed and analysed,
and no additional members of this kindred have since become
symptomatic. The proband was enrolled in the Mayo Alzheimer’s
Disease Research Center, which is a Mayo Foundation Institutional
Review Board-approved protocol, and was followed longitudinally
with a standardized battery of functional, neuropsychologic,
neuropsychiatric, clinical, laboratory and radiologic studies at
?12-month intervals until death. The neurologists who performed
the neurologic evaluations and completed several functional
measures (B.F.B. and D.T.W.) were blinded to scores and ratings
from prior evaluations. Genetic analyses, serial MRI scans and
eventual autopsy were performed after the family provided written
All data on the Clinical Dementia Rating (CDR) scale (Morris,
1993), Global Deterioration Scale (GDS) (Reisberg et al., 1988), and
Record of Independent Living—part A (ROIL-A) (Weintraub,
1986) were tabulated and analysed.
Testing included assessments of screening and global cognitive
functioning [Mini-Mental State Examination (MMSE; Folstein etal.,
1975)], Short Test of Mental Status (STMS; Kokmen et al., 1991;
Tang-Wai et al., 2003), Mattis Dementia Rating Scale (DRS; Mattis,
1988),learning andmemory[logicalmemory (WMS-LM)andvisual
reproductions (WMS-VR) of the Wechsler Memory Scale—Revised
(WMS-R) (Wechsler, 1987), Auditory Verbal Learning Test (AVLT;
Rey, 1964)], language functioning [Boston Naming Test (BNT;
Kaplan et al., 1983), Controlled Oral Word Association Test
(COWAT; Benton and Hamsher, 1978), Multilingual Aphasia
Examination Token Test (TOKEN; Benton and Hamsher, 1978),
and Category/Semantic Fluency (animals, fruit, vegetables) (CAT
FLU)], attention/executive functioning [Trail-Making Test (TMT;
Reitan, 1958), digit span (WAIS-DS) of the revised Wechsler Adult
Intelligence Scale (WAIS-R; Wechsler, 1981), and Wisconsin Card
Sorting Test (WCST; Heaton, 1981)], and visuospatial skills [block
design (WAIS-BD) and picture completion (WAIS-PC) subtests of
the WAIS-R (Wechsler, 1981), and Rey–Osterreith complex figure
(REY-O; Rey, 1941; Osterrieth, 1944)]. Mayo Older American
Normative Studies (MOANS) norms were used to determine scaled
scores for these tests, in which 10 represents the mean and the SD is 3
(Ivnik et al., 1992, 1996, 1997; Lucas et al., 1998a, b).
Neuropsychiatric Inventory (NPI; Cummings et al., 1994) data were
provided by the proband’s husband. The total score (sum of the
products of frequency and severity for the 12 neuropsychiatric
neuropsychiatric burden, with increasing values reflecting increasing
burden. The product of (frequency · severity) for each item over all
evaluations was also presented graphically and analysed.
Page 2 of 12Brain (2006)B. F. Boeve et al.
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All comprehensive neurobehavioural clinical data (Members of
the Department of Neurology, 1998) were reviewed and summar-
ized. The modified motor subtest of the United Parkinson’s Disease
Rating Scale (UPDRS) was used to assess the degree of
parkinsonism (range 0–44); increasing values reflect greater degrees
of parkinsonism (Fahn et al., 1987).
Sequence analysis of PSEN1, amyloid precursor protein (APP),
microtubule-associated tau protein (MAPT), and PGRN from
patient genomic DNA was performed as described previously
(Hutton et al., 1996, 1998; Tang-Wai et al., 2002; Baker et al.,
MRI was performed using a GE scanner at 1.5 T, and images of the
brain were obtained in the sagittal (T1-weighted), axial [proton-
density, T2-weighted, and fluid attenuation inversion recovery
(FLAIR)], and coronal (T1-weighted) planes. Changes in whole-
brain volume (WBV) and ventricular volume (VV) were measured
from serial MRI studies using the boundary shift integral (BSI)
method as described (Gunter et al., 2003; Boeve et al., 2005).
1H magnetic resonance spectroscopy (1H MRS) studies were
performed with the automated single voxel MRS package: Proton
Brain Examination/Single Voxel (PROBE/SV). Point resolved
spectroscopy (PRESS) pulse sequence with TR = 2000 ms, TE =
30 ms, 2048 data points and 128 excitations were used for the
examinations. An 8 cm3(2 · 2 · 2 cm3) voxel, prescribed on a
mid-sagittal T1-weighted image, included right and left posterior
cingulate gyri and inferior precunei. The anterior border of
splenium, the superior border of corpus callosum and the cingulate
sulcus were the anatomical landmarks to define the anterior
inferior and the anterior superior border of the 8 cm3voxel as
described previously (Kantarci et al., 2004). We analysed the
metabolite intensity ratios, using creatine (Cr) as an internal
reference metabolite to control for acquisition and scanner related
Sections of neocortex, hippocampus, amygdala, basal ganglia,
thalamus, midbrain, pons, medulla and cerebellum were stained
with haematoxylin and eosin. Sections of cortex, hippocampus and
amygdala are studied with Bielschowsky and thioflavin-S fluor-
escent microscopy. Sections of cortex and hippocampus were
immunostained for Ab (6F/3D, 1:10; DAKO, Carpinteria, CA),
phospho-tau (AT8, 1:1000; Endogen, Woburn, MA, USA),
ubiquitin (Ubi-1, 1:40 000; Chemicon, Temecula, CA, USA), and
alpha-synuclein (LB509, 1:100; Zymed, South San Francisco, CA,
USA). Brainstem sections were studied for Lewy bodies with a-
synuclein immunohistochemistry. Brainstem sections were studied
for tract degeneration and motor neuron disease with Luxol fast
blue and immunohistochemistry for neurofilament (SMI-31, 1:20
000; Luterville, MD, USA), aB-crystallin (1:10 000; NovoCastra,
Newcastle, UK), HLA-DR (LN3; 1:100) and ubiquitin. For
immunohistochemistry 5-mm thick paraffin sections were depar-
affinized and rehydrated and stained with a DAKO Autostainer
(DAKO, Carpinteria, CA) using 3,30-diaminobenzidine (DAB) as
the chromogen. For Ab and a-synuclein, the sections were
pretreated with 95% formic acid for 30 min and then steamed in
distilled water for 30 min. After immunostaining, the sections were
counterstained with haematoxylin.
A PSEN1 mutation analysis in the proband revealed that
there was one normal allele, while the other had a 3 bp
insertion (a repeat of the previous 3 bp) after nt 1055 at
codon 352 in exon 10 (Tang-Wai et al., 2002). No mutation
was identified in APP or MAPT. Genomic sequence analysis
of all PGRN exons revealed a G to A mutation of the first
intronic base following the end of exon 1 [IVS1+1G!A;
exon numbering corresponds to that previously published
by Baker et al. (2006) and Cruts et al. (2006)]. The predicted
effect of this change is to destroy the 50-splice site of exon 1
(leading to the splicing out of exon 1 from the mRNA) and
removal of the start methionine codon, thereby completely
blocking any PGRN protein from being generated.
Analyses of longitudinal clinical and
The proband, proband’s father, and proband’s paternal
grandfather exhibited dementia and prominent neuropsy-
chiatric features, with the onset of symptoms developing in
the early to middle 60s in the proband’s father and
grandfather and at age 56 in the proband (Tang-Wai et al.,
2002). The proband’s initial symptoms included repeated
questioning, forgetting appointments, forgetting financial
matters, taking medication erroneously and excessive
daytime sleepiness. She later developed features consistent
with the Kluver–Bucy syndrome (Lilly et al., 1983) with
prominent hyperphagia and hypersexuality, as well as
illusions, delusions and visual hallucinations. Additional
details of her clinical course through age 59 have been
reported (Tang-Wai et al., 2002), and subsequently her
cognitive impairment progressed such that she was fully
dependent on her husband for activities of daily living. At
age 61, subtle left hemiparkinsonism had evolved, which was
modestly levodopa-responsive; there was no convincing
apraxia. By age 62 she was mute and tended to hold her left
upper extremity in a flexed posture at the elbow and wrist.
She had mild dystonia involving the posterior cervical
muscle group, but no true alien limb phenomenon,
myoclonus or fasciculations. She expired at age 63 from
Changes in her clinical and functional status are shown in
Figs 1 and 2, with the interpretation of the data described in
the figure legend.
Analyses of longitudinal
Changes in her neuropsychological performance are shown
in Figs 3 and 4, with the interpretation of the data described
in the figure legend.
PGRN mutation in FTDPBrain (2006) Page 3 of 12
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Analyses of longitudinal neuropsychiatric
Changes in her neuropsychiatric status are shown in Fig. 5,
with the interpretation of the data described in the
Analyses of longitudinal radiologic data
Representative MRI are shown in Fig. 6, and the longitudinal
WBV and VV calculations are graphically shown in Fig. 7.
The calculated annualized changes in WBV and VV, res-
pectively, were ?43.1 (?3.34%/year) and +37.4 ml/year
(+27.78%). The change in
Evaluations 1–2 compared with control is shown in Fig. 8,
with the interpretation of the data described in the
The fixed right hemibrain weighed 512 g and the calculated
whole-brain weight was 1024 g. The sulci and gyri revealed
marked cortical atrophy over the frontal lobe, with less
marked atrophy affecting the temporal pole. The orbital
frontal had moderate atrophy. The parietal and temporal
convexities and medial temporal lobe had minimal atrophy.
There was sparing of the occipital pole. The corpus callosum
Sequential coronal sections through the supratentorial
tissues (Fig. 9) revealed marked enlargement of the lateral
ventricles, especially the frontal and temporal horns of the
lateral ventricle. The cortical grey mantle was slightly thinner
than usual in the frontal lobe. The subjacent white matter
showed marked atrophy, especially in the frontal and
temporal lobes, with relative sparing of central parts of the
centrum semiovale in the parietal and occipital lobes. The
hippocampal formation and amygdala had minimal atrophy.
Basal ganglia showed marked atrophy of the caudate nucleus
with thinning of the anterior limb of the internal capsule.
The dorsal and medial regions of the thalamus were
Fig. 1 Longitudinal functional scores on the proband on the
Clinical Dementia Rating scale, sum of the boxes on the Clinical
Dementia Rating scale, and the Global Deterioration Scale. Note
the relatively linear change on all three scales over the 5 years of
Fig. 2 Longitudinal scores on the proband on the Record of
Independent Living—part A (ROIL), Neuropsychiatric Inventory
(NPI), and modified Unified Parkinson’s Disease Rating Scale
(UPDRS). Note the relatively linear change over Evaluations 1–4
on the ROIL and floor effect over Evaluations 5 and 6, high degree
of neuropsychiatric morbidity over Evaluations 1–4 with subse-
quent improvement over Evaluations 5 and 6, and relatively linear
increase in the degree of parkinsonism on the UPDRS.
Page 4 of 12 Brain (2006) B. F. Boeve et al.
by guest on June 2, 2013
atrophic. The aqueduct of Sylvius was patent. Horizontal
sections of the midbrain, pons and medulla at right angles to
the neuraxis showed marked loss of pigment in the
substantia nigra and mild atrophy and discolouration of
the medial third of the cerebral peduncle. The locus ceruleus
had normal pigmentation. The cerebellar sections showed no
The neocortex had marked thinning of the cortical ribbon
with neuronal loss, gliosis and neuropil vacuolation in all
layers consistent with status spongiosis. The severe cortical
degeneration was most marked in frontal lobe, especially
the orbital frontal lobe and frontal pole, but also affecting
convexity mid- and superior frontal gyri. The insular cortex
was also severely affected. There was less marked cortical
neuronal loss and gliosis with spongiosis in the parietal
and temporal lobes. The occipital lobe, including the visual
cortex, was spared. There were many neuritic processes and
neuronal cytoplasmic inclusions with ubiquitin immuno-
staining (Fig. 10). A few neuronal intranuclear inclusions
are also present. With silver stains as well as tau and
Ab immunostains no senile plaques (SP) or neurofibrillary
tangles (NFTs) were detected and there was no evidence of
The subcortical white matter had extensive rarefaction
with fibre loss and astrocytic gliosis throughout the frontal
centrum semiovale and to a lesser extent in the temporal
white matter. There were no lipid laden macrophages.
Blood vessels had no significant arteriosclerotic changes. The
hippocampus had no NFT with silver stains as well as tau
immunohistochemistry, but the ubiquitin immunostain
showed round, crescent shaped and granular cytoplasmic
inclusions in the dentate fascia. Both anterior and posterior
hippocampal sections showed extensive neuronal loss and
gliosis in subiculum and CA1 (Fig. 11). No SP were present
in either the pyramidal layer or the molecular layer of the
dentate fascia. The entorhinal and perirhinal cortices showed
mild neuronal loss and gliosis with no SP or NFT and
preservation of neurons in layer II. The Braak NFT stage was
consistent with Stage 0.
The basal nucleus of Meynert had a normal neuronal
population and no NFT. The hypothalamus was free of SP
and NFT. No SP or NFT were present in the amygdala, but
there was mild focal gliosis in the basolateral region. There
was extensive and severe atrophy of the basal ganglia and
diffuse neuronal loss and gliosis in caudate and nucleus
accumbens. The dorsal caudate was more affected than
the ventral. The ubiquitin immunostain showed a few
dystrophic neurites and neuronal inclusions. The anterior
limb of the internal capsule was atrophic and gliotic with
marked loss of myelinated fibres. There was less neuronal
loss and gliosis in the putamen, while the globus pallidus
was least affected. There were a few axonal spheroids in the
globus pallidus and the pars reticularis of the substantia
nigra. The thalamus had marked atrophy and gliosis in the
anterior and dorsomedial regions, with minimal involve-
ment of the ventral and lateral regions. The mammillary
body was markedly atrophic and had many pyknotic
neurons and diffuse gliosis consistent with transneuronal
degeneration. The subthalamic nucleus was unremarkable.
The substantia nigra had patchy neuronal loss with
extraneuronal neuromelanin and gliosis, but no Lewy bodies
or NFT. The neuronal loss was scattered in all areas with
no clear predilection for medial or lateral cell groups. The
cerebral peduncle had atrophy with fibrillary gliosis of
the medial third (i.e. frontobulbar fibres). There was also
lesser fibre loss and gliosis in the lateral peduncle (i.e.
temporoparietobulbar fibres). The raphe nucleus, locus
coeruleus and reticular formation were well populated and
free of Lewy bodies and NFT. The lower brainstem and
brainstem fibre tracts were remarkable for myelin and
Fig. 3 Longitudinal scores on the proband on screening and global
measures of cognition as reflected by the Mini-Mental State Exam
(MMSE), Short Test of Mental Status (STMS), and Mattis Dementia
Rating Scale (DRS) (dashed horizontal lines represent cutoffs for
normal/abnormal scores). Note that the performance was in the
normal range on Evaluation 1 (DRS not performed then), and
the change over time was relatively linear over Evaluations 1–5
on the MMSE and STMS, and similarly linear on the DRS over
PGRN mutation in FTDPBrain (2006) Page 5 of 12
by guest on June 2, 2013
axonal degeneration in the longitudinal fibres in the pontine
base. The pontine nuclei neurons had cytoplasmic swelling.
The medullary pyramids were preserved. There was no
neuronal loss or gliosis in the hypoglossal nucleus. The
cerebellum was unremarkable, except for mild autolysis of
the internal granular layer.
These findings can therefore be characterized as fronto-
cytoplasmic and intranuclear neuronal inclusions, marked
striatal degeneration, wallerian degeneration of the cortico-
bulbar fibres, transneuronal degeneration of the mammillary
bodies, and hippocampal sclerosis (HS).
While the proband had a history of forgetfulness, neuro-
psychometric evidence of definite memory impairment and
visuospatial dysfunction, and parietal hypoperfusion on
SPECT (all more suggestive of underlying Alzheimer’s
disease than FTD), the bulk of her clinical, neuropsycho-
logical, neuropsychiatric, and neuroimaging findings were
more consistent with FTD than Alzheimer’s disease (Neary
et al., 1998; McKhann et al., 2001). Later in her course, the
asymmetric motor features were thought during life to repre-
sent asymmetric paraparesis due to the known association
of PSEN1 mutations and spastic paraparesis. There was no
apraxia, cortical sensory loss, myoclonus, dystonia, etc. that is
more characteristicofthecorticobasal syndrome(Boeveetal.,
2003). The most parsimonious characterization of her clinical
by asymmetric pyramidal tract findings compatible with
evolving motor neuron disease restricted clinically to the
motor neuron dysfunction during the 5 years of in-person
Remarkably little longitudinal data has been collected in a
standardized manner and published in FTD, and such
characterization will be critical in the current ‘natural
history’ state of affairs with no known drug that significantly
alters the course of the diseases that present as FTD. We
recently presented longitudinal data on two siblings with the
S305N mutation in MAPT (Boeve et al., 2005), in which
the functional and radiologic parameters appeared to reflect
the most consistent degree of change over time (i.e. slopes
were most linear when data were presented graphically). In
our proband, the neuropsychiatric burden was high in the
early and middle portions of her clinical course, particularly
when the Kluver–Bucy symptomatology was prominent, and
these features proved challenging to manage, similar to
Fig. 4 Longitudinal scores on the proband on neuropsychological measures assessing the domains of memory, language, attention/executive
functioning, and visuospatial functioning over Evaluations 1–3 (see text for specific measures and abbreviations). Scores are represented
using the norms from the Mayo Older American Normative Studies (MOANS), in which standard scores are shown with 10 reflecting
the mean for age and an SD of 3. Therefore, scores of 5–6 reflect borderline abnormal performance (at or below the dotted line)
and scores of <4 are clearly abnormal (at or below the dashed line, which is 2 SD below the mean). Note that impairment was
already apparent early in the course in the domains of memory and attention/executive functioning, while visuospatial functioning
was impaired later and language still later. After the third evaluation, the proband was too impaired to be tested further.
Page 6 of 12Brain (2006) B. F. Boeve et al.
by guest on June 2, 2013
many other patients with FTD. Several measures changed in
a relatively linear fashion over time, at least over the initial
3–4 evaluations, suggesting these measures may be worthy of
including in future drug trials in ‘hypoprogranulinopathies’.
A multi-centre protocol currently being conducted in the
United States (NIA RO1 AG23195), which is specifically
focused on measuring longitudinal change in FTD-spectrum
patients, will likely provide further insights into which
parameters will be most appropriate for assessing change in
future FTD treatment trials.
Fig. 5 Graphical representation of longitudinal scores (product of frequency times severity) on the proband on the 12 items of the
Neuropsychiatric Inventory, with scores on Evaluations 1–3 best seen in the top figure and scores on Evaluations 4–6 best seen in the bottom
figure. Note that apathy, disinhibition, irritability, aberrant motor behaviour, and appetite/eating change were most frequent and severe in
Evaluations 2–4, and with disease progression (Evaluations 5–6) aberrant motor behavior and appetite/eating change remained most
frequent and severe. Abbreviations: Del-F · S = delusions-frequency · severity; Hal-F · S = hallucinations-frequency · severity; Ag-F · S =
agitation-frequency · severity; Dep-F · S = depression-frequency · severity; Anx-F · S = anxiety-frequency · severity; Eu-F · S = euphoria-
frequency · severity; Apa-F · S = apathy-frequency · severity; Dis-F · S = disinhibition-frequency · severity; Ir-F · S = irritability-frequency
· severity; Ab-F · S = aberrant motor behaviour-frequency · severity; Nt-F · S = night-time disturbance-frequency · severity; App-F · S =
appetite/eating change-frequency · severity.
PGRN mutation in FTDPBrain (2006) Page 7 of 12
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The absence of amyloid pathology in this case makes the
diagnosis of Alzheimer’s disease untenable, and Pick’s disease
and other tauopathies are excluded with no tau-positive
inclusions being present. Furthermore, the findings were
highly typical of FTLD-U, which in hindsight would have
been higher on the differential diagnosis list of possibilities
had the PSEN1 genetic data not ‘clouded’ the suspicion of
the underlying disorder. This case exemplifies the critical
need to obtain autopsy in patients with unique and
perplexing ante-mortem and/or genetic findings.
The serial MRI scans demonstrated progressive increased
signal in the subcortical white matter which was topographi-
cally associated with extensive rarefaction with fibre loss and
astrocytic gliosis in the subcortical white matter, maximal in
the frontal subcortical region. The histopathologic under-
pinnings of increased signal changes in neurodegenerative
disorders are not well understood, but in this case, they may
reflect rarefaction in the subcortical white matter.
The neuronal intranuclear inclusions in the setting of
FTLD-U pathology have led some investigators to propose
that such findings suggest the presence of a familial disorder
(Mackenzie et al., 2006). Indeed recent evidence suggests
that neuronal intranuclear inclusions are associated with
mutations in PGRN (Baker et al., 2006) as well as VCP
(Forman et al., 2006). Neuronal intranuclear inclusions have
also been detected in non-familial cases of FTLD-U (Katsuse
and Dickson, 2005) indicating caution in interpreting the
significance of intranuclear inclusions in the setting of
HS is often associated with FTLD-U pathology (Josephs
et al., 2004). The aetiology of HS pathology as being of
degenerative versus vascular origin continues to be debated,
but this case supports the neurodegenerative perspective.
How specific HS plus FTLD-U pathology is associated with
PGRN mutations will also require further study.
The critical pathophysiologic issue is whether the insR352
PSEN1 is directly or indirectly pathogenic, or represents a
Fig. 6 Longitudinal coronal T1-weighted images (top row) and axial fluid attenuation inversion recovery (FLAIR) images (bottom row) of the
proband at Evaluations 1–5 (ages 57–61), demonstrating progressive right ? left frontotemporoparietal cortical and right hippocampal
atrophy with progressive increased signal changes in the subcortical/periventricular white matter.
Fig. 7 Graphical representation of longitudinal whole-brain volume
(WBV) (top) and ventricular volume (VV) (bottom) of the proband
over Evaluations 1–5, demonstrating the linear change in VV across
all evaluations and linear change in WBV across Evaluations 1–4
(motion artefact compromised the data at Evaluation 2 so no WBV
and VV could be determined).
Page 8 of 12 Brain (2006)B. F. Boeve et al.
by guest on June 2, 2013
very rare but benign polymorphism, as we pondered in our
original reports (Amtul et al., 2002; Tang-Wai et al., 2002).
Since (i) other groups of investigators had reported findings
consistent with amyloid pathophysiology underlying clinical
presentations consistent with FTD (Johnson et al., 1999),
(ii) the insR352 mutation had not been found in numerous
other FTD, Alzheimer’s disease or control subjects and
(iii) the L113P mutation in PSEN1 had been linked with
a clinical phenotype resembling FTD in a larger pedigree
(Raux et al., 2000b), we thought it plausible that the insR352
mutation was pathogenic and may do so via chronic partial
inhibition of g-secretase activity (Amtul et al., 2002). We
can now argue with much greater certainty that the insR352
does not exert any pathogenic effect via any increase in
circulating amyloid nor by amyloid deposition in brain. The
results from our previous and currently-presented data
imply that mutations that cause complete loss of PSEN1
function do not cause Alzheimer’s disease—unless they also
impact the function of the normal allele (dominant-negative
mutations). Furthermore, the insR352 mutation is distinct
from known familial Alzheimer’s disease (FAD)-linked
PSEN1 mutations in that it occurs in a non-evolutionarily
conserved region of the PSEN1 protein in an area within the
large cytoplasmic loop that is devoid of most other FAD-
linked mutations that typically cluster within or near the
membrane spanning and hydrophobic domains. Until the
Fig. 9 Coronal sections of the fixed right hemisphere show
massive ventricular enlargement with diffuse atrophy of white
matter, thinning of the corpus callosum, and marked atrophy of
caudate nucleus and atrophy of the thalamus. The hippocampus
and amygdala are grossly relatively well preserved.
Fig. 8 Examples of1H MR spectra from a control (A), and the
proband (B) at baseline and ?1 year later. The follow-up spectra
are scaled to the baseline spectra taking Cr peak as reference. The
neuronal integrity marker NAA/Cr ratio is lower, and the
membrane integrity marker Cho/Cr and the glial integrity marker
mI/Cr ratio are higher in the proband than the control subject at
baseline. NAA/Cr ratio declines, mI/Cr ratio increases further
during follow-up in the proband (B). All1H MRS metabolite ratios
are fairly stable over time in the control subject (A). These findings
suggest a progressive loss of neuronal integrity, and progressively
increasing glial activity and membrane turnover during the
Fig. 10 Low magnification image of the hippocampus shows
atrophy and neuronal loss in CA1 and the subiculum consistent
with hippocampal sclerosis. Higher magnification of CA3, CA1 and
subiculum shows preservation of neurons in CA3, but almost
complete neuronal loss and fibrillary astrocytosis in CA1 and the
PGRN mutation in FTDP Brain (2006) Page 9 of 12
by guest on June 2, 2013
mutation in PGRN was identified, the question remained
whether the insR352 is involved in neurodegeneration via its
effects on g-secretase and notch processing, or through
other unknown mechanisms.
The other plausible explanation is that the insR352
mutation is a very rare but benign polymorphism and is
therefore entirely unrelated to the disease in this kindred.
This possibility would be strongly supported if a mutation
was found in a different gene associated with the FTD
syndrome and/or FTLD-U pathology. We now believe the
insR352 ‘mutation’ is non-pathogenic in our kindred.
Our findings also have implications for interpreting the
recent findings of Pick body pathology in other kindreds
with an FTD-type phenotype, particularly the case with
Pick’s disease pathology with no elevation in Ab40 and
Ab42 and no amyloid deposition (Dermaut et al., 2004),
which at least calls into question the pathogenicity of PSEN1
mutations causing a neurodegenerative disease not directly
related to abnormal amyloid deposition. The findings of the
Glu318Gly (Mattila et al., 1998; Goldman et al., 2005)
and Thr354Ile (Lee et al., 2006) ‘mutations’ in PSEN1 failing
to segregate with the disease in familial FTD suggests that
indeed not all rare alterations in PSEN1 are pathogenic.
The ‘hypoprogranulinopathies’—a new
class of neurodegenerative disease
The G to A mutation in the exon 1 splice donor site
(IVS1+1G!A) identified in our proband is predicted to
destroy the 50-splice site of exon 1 and remove the start
methionine codon, which would completely block any
PGRN protein from being generated. Subsequent analysis of
42 more FTD families by Baker et al. (2006) identified a total
of nine different mutations in PGRN, and four more
mutations were found in 13 families by Cruts et al. (2006).
All of the mutations effectively knock out one copy of
the gene, and therefore its ability to direct production of
progranulin. This contrasts with other neurodegenerative
diseases such as Alzheimer’s disease, Parkinson’s disease and
FTD caused by mutations of MAPT, which are characterized
by the accumulation of disease-specific proteins within
surviving brain cells. Thus, a 50% reduction in PGRN (i.e.
hypoprogranulin production) appears sufficient to cause a
Progranulin plays an important but previously unrecog-
nized role in neuronal survival. Replacing progranulin is one
obvious therapeutic approach, which might be possible
through gene therapy or agents that promote progranulin
This study is supported by NIA grants AG11378, AG08031,
and AG16574. R.R. is a post-doctoral fellow of the Fund for
Scientific Research (FWO). We thank the staff of the Robert
H. and Clarice Smith and Abigail Van Buren Alzheimer’s
Disease Research Program of the Mayo Foundation for
assisting with the collection of data and care of the patient
and family. We are particularly grateful to the proband and
her family for participating in this research.
Amtul Z, Lewis P, Piper S, Crook R, Baker M, Findlay K, et al. A presenilin
1 mutation associated with familial frontotemporal dementia inhibits
gamma-secretase cleavage of APP and Notch. Neurobiol Dis 2002;
et al. Mutations in progranulin cause tau-negative frontotemporal
dementia linked to chromosome 17. Nature 2006; 442: 916–9.
Benton A, Hamsher Kd. Multilingual Aphasia Examination (Manual). Iowa
City, Iowa: University of Iowa; 1978.
Boeve B, Lang A, Litvan I. Corticobasal degeneration and its relationship to
progressive supranuclear palsy and frontotemporal dementia. Ann Neurol
2003; 54: S15–9.
Boeve B, Tremont-Lukats I, Waclawik A, Murrell J, Hermann B, Jack CRJ,
et al. Longitudinal characterization of two siblings with frontotemporal
Fig. 11 Low magnification of temporal cortex (A) shows mild neuronal loss and minimal vacuolation, but ubiquitin immunostaining of an
adjacent section (B) shows many ubiquitin-immunoreactive structures. At higher magnification [inset in B], some of the ubiquitin
immunoreactivity is associated with intranuclear inclusions. Higher magnification of lamina II of the temporal cortex immunostained for
ubiquitin (C) shows curvilinear and irregularly shaped neuritic processes, while neuronal cytoplasmic inclusions [insets in C] show crescent
shaped and round cytoplasmic inclusions.
Page 10 of 12 Brain (2006)B. F. Boeve et al.
by guest on June 2, 2013
dementia and parkinsonism linked to chromosome 17 associated with the
S305N tau mutation. Brain 2005; 128: 752–72.
Borchelt D, Thinakaran G, Eckman CB, , Lee MK, Davenport F, Ratovitsky T,
et al. Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta
1-42/1-40 ratio in vitro and in vivo. Neuron 1996; 17: 1005–13.
variant of Alzheimer’s disease with spastic paraparesis and unusual
plaques due to deletion of exon 9 of presenilin 1. Nat Med 1998; 4: 452–5.
mutations in progranulin cause ubiquitin positive frontotemporal
dementia linked to chromosome 17q21. Nature 2006; 442: 920–4.
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA,
Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of
psychopathology in dementia. Neurology 1994; 44: 2308–14.
Dermaut B, Kumar-Singh S, De Jonghe C. Cerebral amyloid angiopathy is a
pathogenic lesion in Alzheimer’s disease due to a novel presenilin
1 mutation. Brain 2001; 124: 2383–92.
Dermaut B, Kumar-Singh S, Engelborghs S, Theuns J, Rademakers R,
Searens J, et al. A novel presenilin 1 mutation associated with Pick’s disease
but not B-amyloid plaques. Ann Neurol 2004; 55: 617–26.
Fahn S, Elton R, for the Members of the UPDRS Development Committee.
Unified Parkinson’s disease rating scale. In: Fahn S, Marsden C, Calne D,
Goldstein M, editors. Recent developments in Parkinson’s disease. Vol. 11.
Florham Park, NJ: MacMillan; 1987. p. 153–63.
Forman M, Mackenzie I, Cairns N, Swanson E, Boyer P, Drachman D, et al.
Novel ubiquitin neuropathology in frontotemporal dementia with valosin-
containing protein gene mutations. J Neuropathol Exp Neurol 2006;
Presenilin 1 Glu318Gly polymorphism: interpret with caution. Arch
Neurol 2005; 62: 1624–7.
Gunter J, Shiung M, Manduca A, Jack CJ. Methodological considerations for
measuring rates of brain atrophy. J Magn Reson Imaging 2003; 18:
Halliday G, Song Y, Lepar G, Brooks W, Kwok J, Kersaitis C, et al. Pick bodies
in a family with presenilin-1 Alzheimer’s disease. Ann Neurol 2005;
He Z, Bateman A. Progranulin (granulin–epithelin precursor, PC-cell derived
growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol
Med 2003; 81: 600–12.
Heaton R. Wisconsin Card Sorting Test Manual. Odessa, FL: Psychological
Assessment Resources, Inc; 1981.
Hutton M, Busfield F, Wragg M, Crook R, Perez-Tur J, Clark RF, et al.
Complete analysis of the presenilin 1 gene in early onset Alzheimer’s
disease. Neuroreport 1996; 7: 801–5.
Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, et al.
Association of missense and 50-splice-site mutations in tau with the
inherited dementia FTDP-17. Nature 1998; 393: 702–5.
Ivnik R, Malec J, Smith G, Tangalos E, Petersen R, Kokmen E, et al. Mayo’s
Older American Normative Studies: WAIS-R, WMS-R, and AVLT norms
for ages 56–97. Clin Neuropsychol 1992; 6 (Suppl): 1–104.
Ivnik R, Malec J, Smith G, Tangalos E, Petersen R. Neuropsychological tests’
norms above age 55: COWAT, BNT, MAE Token, WRAT-R reading,
AMNART, STROOP, TMT and JLO. Clin Neuropsychol 1996; 10:
IvnikRJ, Smith GE, LucasJA, TangalosEG, KokmenE, Petersen RC. Free and
cued selective reminding test: MOANS norms. J Clin Exp Neuropsychol
1997; 19: 676–91.
Johnson JK, Head E, Kim R, Starr A, Cotman CW. Clinical and pathological
evidence for a frontal variant of Alzheimer disease. Arch Neurol 1999;
Josephs K, Holton J, Rossor M, Godbolt A, Ozawa T, Strand K, et al.
Frontotemporal lobar degeneration and ubiquitin immunohistochemistry.
Neuropathol Appl Neurobiol 2004; 30: 369–73.
et al. 1H MR spectroscopy in common dementias. Neurology 2004;
Kaplan E, Goodglass H, Weintraub S. Boston Naming Test (Second Edition).
Philadelphia: Lea & Febiger; 1983.
Katsuse O, Dickson D. Ubiquitin immunohistochemistry of frontotemporal
lobar degeneration differentiates cases with and without motor neuron
disease. Alz Dis Assoc Disord 2005; 19 (Suppl 1): 37–43.
Kokmen E, Smith G, Petersen R, Tangalos E, Ivnik R. The short test of mental
status: correlations with standardized psychometric testing. Arch Neurol
1991; 48: 725–8.
Lee P, Medina L, Ringman J. The Thr354Ile substitution in PSEN-1:
disease–causing mutation or polymorphism? Neurology 2006; 66:
Lilly R, Cummings JL, Benson DF, Frankel M. The human Kluver–Bucy
syndrome. Neurology 1983; 33: 1141–5.
Lucas JA, Ivnik RJ, Smith GE, Bohac DL, Tangalos EG, Graff-Radford NR,
et al. Mayo’s older Americans normative studies: category fluency norms.
J Clin Exp Neuropsychol 1998a; 20: 194–200.
Lucas JA, Ivnik RJ, Smith GE, Bohac DL, Tangalos EG, Kokmen E, et al.
Normative data for the Mattis Dementia Rating Scale. J Clin Exp
Neuropsychol 1998b; 20: 536–47.
Mackenzie I, Baker M, West G, Woulfe J, Oadi N, Gass J, et al. A family with
tau-negative frontotemporal dementia and neuronal intranuclear inclu-
sions linked to chromosome 17. Brain 2006; 129: 853–67.
Mattila K, Forsell C, Pirttila T, Rinne J, Lehtimaki T, Roytta M, et al. The
Glu318Gly mutation of the presenilin-1 gene does not necessarily cause
Alzheimer’s disease. Ann Neurol 1998; 44: 965–7.
Mattis S. Dementia Rating Scale: professional manual. Odessa: Psychological
Assessment Resources; 1988.
McKhann GM, Albert MS, Grossman M, Miller B, Dickson D,
Trojanowski JQ, et al. Clinical and pathological diagnosis of frontotem-
poral dementia: report of the Work Group on Frontotemporal Dementia
and Pick’s Disease. Arch Neurol 2001; 58: 1803–9.
Members of the Department of Neurology, Mayo Clinic, Clinical
Examinations in Neurology. St Louis: Mosby-Year Book, Inc; 1998.
Morris JC. The Clinical Dementia Rating (CDR): current version and scoring
rules. Neurology 1993; 43: 2412–4.
Neary D, Snowden J, Gustafson L, Passant U, Stuss D, Black S, et al.
Frontotemporal lobar degeneration: a consensus on clinical diagnostic
criteria. Neurology 1998; 51: 1546–54.
Ong C, Bateman A. Progranulin (granulin-epithelin precursor, PC-cell
derived growth factor, acrogranin) in proliferation and tumorigenesis.
Histol Histopathol 2003; 18: 1275–88.
Osterrieth P. Le test de copie d’une figure complexe. Arch Psychol 1944;
Raux G, Gantier R, Martin C, Pothin Y, Brice A, Frebourg T, et al. A
novel presenilin 1 missense mutation (L153V) segregating with early-
onset autosomal dominant Alzheimer’s disease. Hum Mutat 2000a;
et al. Dementia with prominent frontotemporal features associated with
L113P presenilin 1 mutation. Neurology 2000b; 55: 1577–9.
Reisberg B, Ferris S, deLeon M, Crook T. Global deterioration scale (GDS).
Psychopharmacol Bull 1988; 24: 661–2.
Reitan R. Validity of the Trail-Making Test as an indication of organic brain
damage. Percept Mot Skills 1958; 8: 271–6.
Rey A. L’examen psychologique dan les cas d’encephalopathie traumatique.
Arch Psychol 1941; 28: 286–340.
Rey A. L’Examen Clinique en Psychologie. Paris, France: Presses
Universitaires de France; 1964.
Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, et al. Screening
for PS1 mutations in a referral-based series of AD cases. Neurology 2001;
Tang-Wai D, Boeve B, Lewis P, Hutton M, Golde T, Baker M, et al. Familial
frontotemporal dementia associated with a novel presenilin-1 mutation.
Dement Geriatr Cogn Disord 2002; 14: 13–21.
PGRN mutation in FTDP Brain (2006) Page 11 of 12
by guest on June 2, 2013
Tang-Wai DF, Knopman DS, Geda YE, Edland SD, Smith GE, Ivnik RJ, et al. Download full-text
Comparison of the short test of mental status and the mini-mental state
examination in mild cognitive impairment. Arch Neurol 2003; 60:
Tedde A, Forleo P, Nacmias B, Piccini C, Bracco L, Piacentini S, et al. A
presenilin-1 mutation (Leu392Pro) in a familial AD kindred with
psychiatric symptoms at onset. Neurology 2000; 55: 1590–1.
Wechsler D. Wechsler Adult Intelligence Scale—Revised (Manual). San
Antonio: The Psychological Corporation; 1981.
Wechsler D. Wechsler Memory Scale—Revised (Manual). New York:
Psychological Corporation; 1987.
Weintraub S. The record of independent living: an informant-completed
measure of activities of daily living and behavior in elderly patients with
cognitive impairment. Am J Alzheimer Care Rel Disord 1986; 7: 35–9.
Page 12 of 12Brain (2006)B. F. Boeve et al.
by guest on June 2, 2013