Article

Progranulin Mutations as Risk Factors for Alzheimer Disease

JAMA neurology 04/2013; 70(6):1-5. DOI: 10.1001/2013.jamaneurol.393
Source: PubMed
ABSTRACT
Importance:
Mutations in the progranulin gene are known to cause diverse clinical syndromes, all attributed to frontotemporal lobar degeneration. We describe 2 patients with progranulin gene mutations and evidence of Alzheimer disease (AD) pathology. We also conducted a literature review.

Observations:
This study focused on case reports of 2 unrelated patients with progranulin mutations at the University of California, San Francisco, Memory and Aging Center. One patient presented at age 65 years with a clinical syndrome suggestive of AD and showed evidence of amyloid aggregation on positron emission tomography. Another patient presented at age 54 years with logopenic progressive aphasia and, at autopsy, showed both frontotemporal lobar degeneration with TDP-43 inclusions and AD.

Conclusions and relevance:
In addition to autosomal-dominant frontotemporal lobar degeneration, mutations in the progranulin gene may be a risk factor for AD clinical phenotypes and neuropathology.

Full-text

Available from: Jennifer S Yokoyama, Aug 27, 2014
OBSERVATION
Progranulin Mutations as Risk Factors
for Alzheimer Disease
David C. Perry, MD; Manja Lehmann, PhD; Jennifer S. Yokoyama, PhD; Anna Karydas, BA; Jason JiYong Lee, BS;
Giovanni Coppola, MD; Lea T. Grinberg, MD, PhD; Dan Geschwind, MD, PhD; William W. Seeley, MD;
Bruce L. Miller, MD; Howard Rosen, MD; Gil Rabinovici, MD
Importance: Mutations in the progranulin gene are
known to cause diverse clinical syndromes, all attrib-
uted to frontotemporal lobar degeneration. We describe
2 patients with progranulin gene mutations and evi-
dence of Alzheimer disease (AD) pathology. We also con-
ducted a literature review.
Observations: This study focused on case reports of 2
unrelated patients with progranulin mutations at the Uni-
versity of California, San Francisco, Memory and Aging
Center. One patient presented at age 65 years with a clini-
cal syndrome suggestive of AD and showed evidence of
amyloid aggregation on positron emission tomography. An-
other patient presented at age 54 years with logopenic pro-
gressive aphasia and, at autopsy, showed both frontotem-
poral lobar degeneration with TDP-43 inclusions and AD.
Conclusions and Relevance: In addition to autosomal-
dominant frontotemporal lobar degeneration, muta-
tions in the progranulin gene may be a risk factor for AD
clinical phenotypes and neuropathology.
JAMA Neurol. 2013;70(6):774-778. Published online April
22, 2013. doi:10.1001/2013.jamaneurol.393
O
NE OF THE CHALLENGES
facing clinicians who
evaluate patients with de-
mentia is determining
what clinical syndrome
best fits with the patient’s presentation
and then predicting the most likely
underlying molecular pathology. While
clinical syndromes often help with this
prediction, there is still variability
between syndrome and pathology. The
term frontotemporal dementia (FTD)
refers to a heterogeneous group of clini-
cal syndromes featuring changes in per-
sonality, behavior, or language. Fronto-
temporal lobar degeneration (FTLD) refers
to a collection of pathologic diagnoses
that can cause these clinical syndromes.
Three major genes have been implicated
in autosomal-dominant FTD: microtu-
bule associated protein tau (MAPT), pro-
granulin (GRN), and chromosome 9 open
reading frame 72 (C9orf72). While muta-
tions in GRN have been described as
causing a variety of clinical syndromes,
including one suggesting Alzheimer dis-
ease (AD), it is thought these various pre-
sentations all result from TAR DNA-
binding protein 43 (TDP-43) pathology.
Here we present 2 patients who suggest
GRN mutations may also be risk factors
for AD pathology.
REPORT OF CASES
CASE 1
A 65-year-old right-handed man pre-
sented with 3 years of slowly progressive
cognitive changes. His first symptom was
misplacing personal items. He retired and
attempted to move his office into his home
but ultimately left everything packed in
boxes on the floor. Subsequently, he had sev-
eral minor motor vehicle accidents and ex-
hibited poor financial judgment, borrow-
ing up to $150 000 and forgetting to file his
taxes. His memory for recent events be-
came impaired, and he developed word-
finding difficulties. He angered more easily
and compulsively checked door locks. There
was no behavioral disinhibition, apathy, loss
of empathy, or change in food preferences.
On examination, he asked repetitive
questions, was suspicious of the examiner,
and made phonemic paraphasic errors in
speech. He had mild bilateral agraphesthe-
sia. He scored 17 of 30 on the Mini-Mental
State Examination.
1
Detailed neuropsycho-
Author Affi
of Neurolog
California,
Perry, Leh
m
Grinber g, S
and Rabino
Karydas); a
Psychiatry a
Institute for
Human Beh
California,
and Drs C
o
and Geschw
Author Affiliations: Depar tment
of Neurology, University of
California, San Francisco
(Drs Perry, Lehmann, Yokoyama,
Grinber g, Seeley, Miller, Rosen,
and Rabinovici, and
Ms Karydas); and Depar tments
of Psychiatry and Neurology,
Semel Institute for Neuroscience
and Human Behavior, University
of California, Los Angeles
(Mr Lee and Drs Coppola
and Geschwind).
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Page 1
logic testing revealed poor verbal and visual memory, con-
frontational naming, and executive function with relative
preservation of visuospatial skills (
Table).
Voxel-based morphometry
2
was performed on the pa-
tient’s 3-T magnetic resonance imaging scan using SPM
version 8 (http://www.fil.ion.ucl.ac.uk/spm/). Prepro-
cessing included segmentation into gray and white mat-
ter, alignment and warping with DARTEL,
3
normaliza-
tion to Montreal Neurological Institute space, modulation,
and smoothing with an 8-mm full-width at half maxi-
mum Gaussian kernel. Single-subject voxel-based mor-
phometry of combined gray and white matter segmen-
tations was compared with 30 healthy control subjects
matched for sex, age, and scanner. Age and total intra-
cranial volume were included as covariates in the regres-
sion. Results, displayed in
Figure 1A at a threshold of
P .05 (uncorrected), showed atrophy of medial and lat-
eral temporal and parietal lobes, right greater than left.
Based on his clinical presentation, neuropsychologic test-
ing, and imaging, he was diagnosed as having AD.
Positron emission tomography (PET) with the -amy-
loid (A) tracer Pittsburgh Compound B was positive for
cortical tracer binding, and PET with fluorodeoxyglu-
cose showed hypometabolism in the bilateral temporo-
parietal cortex (
Figure 2).
The patient had a family history of FTD in 3 mater-
nal relatives. His father had late-life dementia and pater-
nal grandmother had been diagnosed as having AD. Ge-
netic testing revealed that the patient carried the same
novel mutation in GRN as his affected maternal family
members, an octanucleotide insertion in the coding re-
gion (c.1263_1264insGAAGCGAG) causing frameshift
and a premature stop codon, predicted to result in non-
sense-mediated messenger RNA decay. His apolipopro-
tein E (APOE) genotype was ε3/ε4.
CASE 2
A 54-year-old woman presented for evaluation owing to
1 year of progressive language impairment involving dif-
ficulties with word finding, remembering names, and ex-
B
A
1.6 2.4 3.2 4.0
1.6 2.4 3.2 4.0
Figure 1. Voxel-based morphometry. Single-subject voxel-based
morphometry of case 1 (A) and case 2 (B), uncorrected for multiple
comparisons at P .05, displayed as T map (1 t 4) and overlaid on
Montreal Neurological Institute template brain. Images are displayed in
neurological convention.
Table. Neuropsychological Testing
Normal Values by Age
and Education for Case 1,
Mean (SD)
a
Case 1
(age 65 y)
Normal Values by Age
and Education for Case 2,
Mean (SD)
a
Case 2
(age 54 y)
General
MMSE score (max 30) 17 14
Memory
CVLT short form delayed recall (max 9) 7.8 (1.4) 0 7.9 (1.5) 0
Recognition (max 9) 8.7 (0.5) 3 8.8 (0.4) 6
Recall false positives 0.6 12 3
Benson figure delayed recall (max 17) 11.5 (2.8) 0 12.6 (2.3) 12
Visuospatial
Benson figure copy (max 17) 15.5 (1.1) 16 15.5 (1.1) 15
Language
Modified BNT (max 15) 14.3 (0.8) 11 14.5 (0.9) 2
BNT multiple choice 2 11
Repetition (max 5) 4.6 (0.6) 1 4.7 (0.7) 1
Sentence comprehension (max 5) 5 1
PPVT-R (max 16) 15.6 (0.8) 15 15.7 (0.8) 6
Executive
Digit span backward 5.8 (1.2) 3 5.4 (1.3) 2
Phonemic fluency (D word generation) 16.3 (4.5) 13 15.0 (3.9) 1
Semantic fluency (animal generation) 23.5 (5.0) 12 22.7 (4.7) 3
Abbreviations: CVLT, California Verbal Learning Test; BNT, Boston Naming Test; MMSE, Mini-Mental State Examination; PPVT-R, Peabody Picture Vocabulary
Test–Revised.
a
Age-adjusted normal values derived from University of California, San Francisco, Memory and Aging Center cohort.
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pressing herself. Her family said her speech was occa-
sionally nonsensical, describing it “like a word salad.”
Within a few months, she developed difficulty writing
and spelling, as well as decreased speech output. There
were no reported problems with recognizing words.
Memory complaints were minimal and, other than anxi-
ety, there was no change in personality or behavior. She
had some difficulty with navigation but did not get lost,
and there were no motor symptoms.
Her examination was notable for long word-finding
pauses and sparse speech, mostly consisting of single
words and short phrases. There were no articulation prob-
lems. She could follow simple commands but had diffi-
culty with complex instructions. She scored 14 of 30 on
the Mini-Mental State Examination. On neuropsycho-
logic testing, she displayed poor verbal memory (that ben-
efitted from recognition), impairment in working memory
and executive functions, and language impairment in-
cluding impairment in repetition, comprehension of syn-
tactically complex sentences, confrontational naming (that
benefitted from multiple choice), and verbal fluency
(Table).
Voxel-based morphometry was performed on her 1.5-T
magnetic resonance imaging (preprocessing and analy-
sis, as in case 1) and was compared against 16 control
subjects matched as previously described (Figure 1B).
There was asymmetric atrophy involving the left tem-
poral lobe, left medial and inferior frontal regions, and
left inferior parietal lobe.
She had a family history of dementia, including a fa-
ther who died mute at age 65 years and a paternal grand-
mother and brother who had been diagnosed as having
FTD. Her genetic testing revealed a novel GRN muta-
tion, affecting the first protein residue (g.1AT, p.M1?).
Other distinct pathogenic mutations of the same resi-
due have been reported (g.1AG, p.M1?
4
; g.2TC,
p.M1?
5,6
; and g.3GA, p.M1?
7
). Her APOE genotype was
ε3/ε4.
The patient died at age 55 years, and an autopsy was
performed 8 days post mortem. The entire brain showed
advanced autolysis, which precluded meaningful obser-
vations about cerebral atrophy and limited immunohis-
tochemical analysis. Nonetheless, immunohistochemis-
try for A (3FR antibody, antimouse, 1:250; Millipore),
hyperphosphorylated tau (PHF-1 antibody, antimouse,
1:250, courtesy of Peter Davies, PhD, Albert Einstein Col-
lege of Medicine), and TDP-43 (antirabbit, 1:2000; Pro-
teintech Group) was performed on a subset of regions
showing relative tissue integrity, including medial tem-
poral lobe, middle frontal gyrus, precentral and postcen-
tral gyri, angular gyrus, superior temporal gyrus, and lat-
eral occipital cortex. These analyses revealed moderate
to frequent neuritic amyloid plaques (
Figure 3A) in all
regions examined, and moderate to frequent tau-
positive neurofibrillary tangles in medial temporal and
neocortical regions (Figure 3B) but not the primary sen-
sorimotor cortex, consistent with National Institute on
Aging–Reagan criteria for high-likelihood AD
8
and a Braak
AD stage of V.
9
In addition, we observed superficial greater
than deep laminar TDP-43 pathology consisting of mod-
erate to frequent small round or crescentic neuronal cy-
toplasmic inclusions and neuropil threads (Figure 3C)
accompanied by scarce neuronal nuclear inclusions and
glial cytoplasmic inclusions (not pictured), consistent with
FTLD-TDP, harmonized type A,
10
the subtype seen in GRN
mutation carriers.
DISCUSSION
We present 2 patients with a clinical presentation con-
sistent with AD, one an amnestic type and the other sug-
FDG
PiB
0.4 2.0
SUVR
0.3
2.5
DVR
Figure 2. Positron emission tomography (PET) imaging of case 1. The PET
with fluorodeoxyglucose (FDG) shows bilateral temporoparietal
hypometabolism and the Pittsburgh compound B (PiB)–PET image of case 1
shows amyloid tracer binding. DVR indicates distribution volume ratio;
SUVR, standardized uptake value ratio.
B
A
C
3F4
PHF-1
TDP-43
Figure 3. Pathologic findings for case 2. In the angular gyrus, frequent
-amyloid–positive neuritic plaques (3F4 antibody, hematoxylin
counterstain) (A) and sparse to moderate neurofibrillary tangles and
neuropil threads are seen (PHF-1 antibody, hematoxylin counterstain) (B).
C, Dorsolateral frontal cortex shows frequent TAR DNA-binding protein 43
(TDP-43)–immunoreactive crescentic or compact neuronal cytoplasmic
inclusions with surrounding wispy neuropil threads, consistent with
frontotemporal lobar degeneration–TDP, type A. Scale bars indicated 500 µM
(A), 100 µM (B), and 50 µM (C).
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gestive of logopenic progressive aphasia, a syndrome typi-
cally caused by AD pathology.
11
One patient had a positive
amyloid PET scan demonstrating fibrillary amyloid pa-
thology suggestive of AD and the other had autopsy
confirmation of AD pathology. Notably, both patients
harbored a GRN mutation, which predicts underlying
FTLD-TDP pathology rather than AD.
Mutations in GRN have been associated with several
clinical syndromes, including behavioral-variant FTD
(bvFTD), nonfluent primary progressive aphasia, and cor-
ticobasal syndrome.
4
Prior studies have also noted that 9%
to 17% of GRN mutation carriers may present with an AD
phenotype.
4,12
While pathologic validation is lacking in most
cases, one such patient had both AD and FTLD-TDP at
autopsy
13
and another showed an AD-like cerebrospinal
fluid biomarker profile with an AD-like syndrome (low
A42 and elevated total tau).
14
Other studies have indi-
cated that polymorphisms in GRN modify the risk for de-
veloping AD.
15-17
As prior clinicopathological series of GRN
have shown only rare evidence of copathology with AD,
12,13
if there is a risk for AD conferred by alterations in GRN,
the association is less direct than with FTLD.
Prior data on the influence of APOE status on clinical
phenotype in GRN carriers has been mixed, with one study
showing early memory problems in ε4 allele carriers,
12
and
2 other studies showing no clear modulatory effect on clini-
cal symptoms.
5,18
Both patients in this report were hetero-
zygous for the APOE ε4 allele. It is possible that AD pa-
thology found in these patients was strictly due to APOE
ε4 status, as the prevalence of amyloid deposition (as
detected by Pittsburgh Compound B–PET imaging) is
approximately 10% in 45-year-old to 59-year-old cog-
nitively normal ε4 carriers, and 37% in 60-year-old to 69-
year-old carriers.
19
On the other hand, the early age at symp-
tom onset and the AD-like clinical syndrome and atrophy
pattern, as well as the advanced neurofibrillary pathology
(Braak stage V), seen in case 2 argue that AD contributed
to and perhaps was the main cause of dementia.
Mutations in GRN are thought to lead to neurodegen-
eration via haploinsufficiency, although the direct molecu-
lar link to TDP-43 translocation and aggregation remains
unclear. Recent theories have focused on the anti-inflam-
matory properties of the progranulin protein.
20
Mutations
in GRN result in haploinsufficiency of functional pro-
granulin, which might then result in a proinflammatory
state. Patients with GRN mutations have been shown to
have elevated levels of the proinflammatory cytokine in-
terleukin 6.
21
Functional progranulin promotes an in-
crease in the anti-inflammatory cytokine interleukin 10
in macrophages,
22
which would be decreased in haplo-
insufficiency. Progranulin interacts with tumor necro-
sis factor (TNF) receptors, thereby antagonizing TNF-
activity.
23
Therefore, in a state of progranulin defi-
ciency, relative TNF- activity is increased.
This proinflammatory state might predispose not only
to the development of FTLD, but to other forms of neu-
rodegeneration. Alzheimer disease has also been linked to
increased expression of inflammatory cytokines,
24
and mi-
croglial activation has been observed in AD post mor-
tem
25
and in vivo.
26
Whether this activity is detrimental
or protective and primary or secondary has been de-
bated, but there is evidence suggesting that high levels of
proinflammatory cytokines might decrease phagocytosis
of A by microglia.
27
An increase in TNF- is associated
with cognitive decline in AD.
28
In mouse models of AD,
TNF- is implicated in enhanced amyloid production,
29
tau hyperphosphorylation, and cell death,
30
and counter-
ing TNF- improves both symptoms and pathology.
31,32
-Amyloid aggregation in mouse hippocampus and cor-
tex has also been induced by inflammation.
33
In AD, abnormal TDP-43 staining is seen in up to 34%
of cases.
34
In most cases of comorbid AD/TDP, TDP in-
clusions are restricted to the medial temporal lobe, but
a minority of cases shows a more widespread deposition
pattern consistent with FTLD-TDP type A, the same pat-
tern associated with GRN cases.
35
The molecular links be-
tween TDP-43 and AD pathologies are not known. One
study found elevated TDP-43 levels in an AD mouse model
that correlated with A oligomers; decreasing A42 lev-
els normalized TDP-43 in these mice.
36
Whether this re-
lationship could be bidirectional and TDP-43 levels may
contribute to A deposition as well is a topic for further
investigation.
The present cases add support to the association be-
tween GRN and AD. As pathology from more cases be-
comes available, the strength and frequency of this as-
sociation will be clarified.
Accepted for Publication: August 17, 2012.
Published Online: April 22, 2013. doi:10.1001/2013
.jamaneurol.393
Correspondence: David C. Perry, MD, University of Cali-
fornia, San Francisco (UCSF) Memory and Aging Cen-
ter, MC: 1207, 675 Nelson Rising Lane, Suite 190, San
Francisco, CA 94158 (dperry@memory.ucsf.edu).
Author Contributions: Study concept and design: Perry,
Lehmann, Seeley, Miller, Rosen, and Rabinovici. Acqui-
sition of data: Perry, Karydas, Lee, Coppola, Grinberg, See-
ley, Rosen, and Rabinovici. Analysis and interpretation of
data: Perry, Lehmann, Yokoyama, Lee, Coppola, Grin-
berg, Geschwind, Seeley, Rosen, and Rabinovici. Draft-
ing of the manuscript: Perry, Lehmann, and Rabinovici.
Critical revision of the manuscript for important intellec-
tual content: Lehmann, Yokoyama, Karydas, Lee, Cop-
pola, Grinberg, Geschwind, Seeley, Miller, Rosen, and
Rabinovici. Statistical analysis: Lehmann and Coppola.
Obtained funding: Seeley, Rosen, and Rabinovici. Admin-
istrative, technical, and material support: Lehmann, Yo-
koyama, Lee, Grinberg, Seeley, and Rosen. Study super-
vision: Geschwind, Seeley, Miller, Rosen, and Rabinovici.
Conflict of Interest Disclosures: Dr Perry’s work is funded
by grant T32 AG23481 from the National Institutes of
Health’s National Institute on Aging. Dr Lehmann’s work
is funded by Alzheimer’s Research UK. Dr Yokoyama’s
work is funded by a diversity supplement through grant
P50 AG03006 from the National Institutes of Health’s
National Institute on Aging (principal investigator, Dr
Miller). Dr Coppola’s work is funded by R01 AG026938
and RC1 AG035610 from the National Institutes of
Health’s National Institute on Aging. Dr Grinberg’s work
is supported by the John Douglas French Alzheimer’s
Foundation and grants P50 AG023501-06 and
1R01AG040311-01 from the National Institutes of Health.
Dr Rosen’s work is supported by R01AG032306 and
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R01AG030688 from the National Institutes of Health’s
National Institute on Aging. Dr. Geschwind has re-
ceived institutional support from Alzheimer’s Disease Re-
search Center of California (ARCC) grants 03-7527 and
R01 AG026938. Dr Seeley’s work is funded by grant P50
AG1657303 from the National Institutes of Health, the
John Douglas French Alzheimer’s Disease Foundation,
the Consortium for Frontotemporal Dementia Re-
search, the James S. McDonnell Foundation, and the Larry
Hillblom Foundation. Dr Seeley has received support for
travel by the Alzheimer’s Association; has received pay-
ment for lectures by the Alzheimer’s Association, the
American Academy of Neurology, and Novartis Korea;
and has served on advisory boards for Bristol Myers-
Squibb. Dr Miller serves as board member on the John
Douglas French Alzheimer’s Foundation and Larry L. Hill-
blom Foundation; and he serves as a consultant for TauRx
Ltd, Allon Therapeutics, the Tau Consortium, the Con-
sortium for Frontotemporal Research, and the Siemens
Molecular Imaging Biomarker Research Alzheimer’s Ad-
visory Group. Dr Miller has received institutional sup-
port from Novartis, and his work is funded by grants
P50AG023501, P01AG019724, and P50 AG1657303 from
the National Institutes of Health, and the state of Cali-
fornia. Dr Rabinovici’s work is funded by grant K23-
AG031861 from the National Institutes of Health’s Na-
tional Institute on Aging.
Funding/Support: Funding support for this study came
from the Consortium for Frontotemporal Research, the
John Douglas French Alzheimer’s Foundation, the Larry
Hillblom Foundation, and the James S. McDonnell Foun-
dation, as well as grants P50AG023501, P01AG019724,
P50AG1657303, NIA K23-AG031861, R01AG040311,
R01 AG026938, RC1 AG035620, T32AG23481, and
R01AG032306 from the National Institutes of Health.
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