Download Corticobasal Syndrome Associated With the A9D Progranulin Mutation

J Neuropathol Exp Neurol
Copyright Ó 2007 by the American Association of Neuropathologists, Inc.
Vol. 66, No. 10
October 2007
pp. 892Y900
ORIGINAL ARTICLE
Corticobasal Syndrome Associated With the A9D
Progranulin Mutation
Salvatore Spina, MD, Jill R. Murrell, PhD, Edward D. Huey, MD, Eric M. Wassermann, MD,
Pietro Pietrini, MD, PhD, Jordan Grafman, PhD, and Bernardino Ghetti, MD
Abstract
Corticobasal syndrome is characterized by cortical dysfunction
and L-dopa-unresponsive Parkinsonism, with asymmetrical onset of
clinical presentation and evidence of atrophy and/or hypometabolism at neuroimaging. Recently, the heterogeneous pathologic
substrate of corticobasal syndrome has been further expanded to
include cases with pathologic diagnosis of frontotemporal lobar
degeneration with ubiquitin/TDP-43 (TAR DNA binding protein
43)-positive inclusions associated with Progranulin (PGRN)
mutations. We report a family in which several individuals have
been affected with a dementia/movement disorder phenotype. The
proband presented at age 45 with spontaneous left arm levitation,
ideational apraxia, asymmetric parkinsonism, and dystonia. Subsequently, he developed limb-kinetic apraxia, left-side hemineglect, memory loss, and executive dysfunction. Magnetic
resonance imaging and [18F]fluorodeoxyglucose-positron emission
tomography studies revealed severe cerebral cortical atrophy and
hypometabolism, which were significantly more pronounced in the
parietal lobes (right > left). Neuropathologic examination displayed the highest degree of degeneration and ubiquitin/TDP-43
pathology in the proband`s parietal areas. Genetic analysis
revealed the presence of the c.26C>A PGRN mutation in 1 allele.
This mutation has been reported in association with hereditarydysphasic-disinhibition-dementia, Alzheimer-like dementia, progressive supranuclear palsy, and primary progressive aphasia. The
peculiar findings observed in this patient indicate that the parietal
lobe may represent the most vulnerable anatomical area in some
of the PGRN-associated frontotemporal lobar degeneration with
ubiquitin/TDP-43-positive inclusion cases.
From the Indiana Alzheimer Disease Center (SS, JRM, BG), Department of
Pathology and Laboratory Medicine, Indiana University School of
Medicine, Indianapolis, Indiana; Department of Neurological and
Behavioral Sciences (SS), University of Siena, Siena, Italy; Cognitive
Neuroscience Section (EDH, EMW, JG), National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda,
Maryland; and Laboratory of Clinical Biochemistry and Molecular
Biology (PP), University of Pisa, Pisa, Italy.
Send correspondence and reprint requests to: Bernardino Ghetti, MD,
Indiana Alzheimer Disease Center, Department of Pathology and
Laboratory Medicine, Indiana University School of Medicine, Medical
Science Building A138, 635 Barnhill Drive, Indianapolis, IN 46202;
E-mail: [email protected]
This study was supported by U.S. Public Health Service P30AG10133 (SS,
JRM, BG) and Intramural Research Programs of the National Institutes
of Health National Institute of Neurological Disorders and Stroke (EDH,
EMV, PP, JG).
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Key Words: Alien limb, Apraxia, Frontotemporal lobar degeneration, Hemineglect, Parietal lobe, Progranulin, TDP-43.
INTRODUCTION
The term Bcorticobasal syndrome^ (CBS) has been
proposed to designate a clinical phenotype characterized by
symptoms and signs of cortical dysfunction (such as
ideomotor or constructional apraxia, speech apraxia, progressive nonfluent aphasia, cortical sensory loss, alien hand
syndrome [AHS], visual or sensory hemineglect, and
myoclonus), as well as signs of extrapyramidal impairment
(such as limb rigidity or dystonia) lacking significant
response to L-dopa (1). CBS has an insidious onset followed
by a progressive course. Signs and symptoms are initially
focal or asymmetrical and correlate with neuroimaging
evidence of asymmetric atrophy and/or hypometabolism,
which are maximal in the parietofrontal cortical areas (1).
The pathologic substrate of CBS is heterogeneous and
includes that of corticobasal degeneration (CBD), Alzheimer
disease, Pick disease, progressive supranuclear palsy,
dementia lacking distinctive histopathology, CreutzfeldtJakob disease, diffuse Lewy body disease, and frontotemporal lobar degeneration with ubiquitin (Ub) and TDP-43
(TAR DNA binding protein 43)-immunoreactive (ir) inclusions (FTLD-U) (1Y9).
The majority of cases of CBS are sporadic. However, a clinical phenotype closely resembling that of CBS
has been described in individuals belonging to families in
which several additional subjects were affected with
either dementia and/or movement disorder (6). In some
of these families, the genetic base of the familial disorder
has been found to be associated with the inheritance of a
pathogenic mutation in either the Microtubule Associated
Protein Tau (MAPT ) gene or in the Progranulin (PGRN)
gene, both located in chromosome 17q21 (10Y14). MAPT
mutations are associated with the clinicopathologic phenotype of frontotemporal dementia and Parkinsonism
linked to chromosome 17, a group of autosomal dominant
frontotemporal dementia (FTD) syndromes that are pathologically characterized by the deposition of hyperphosphorylated tau protein in the CNS (15). In contrast, PGRN
mutations are associated with the pathologic phenotype of
FTLD-U (16, 17). Extensive literature on MAPT mutations has shown the existence of considerable inter- and
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intrafamilial phenotypic heterogeneity (18). Similarly, the
recent reports on PGRN mutations suggest the presence of
relevant clinical and pathologic variability among different families as well as among affected individuals from
the same kindred (10, 12, 13, 19Y23).
We report a family in which several individuals have
been affected with a dementia/movement disorder phenotype. In the proband the clinical presentation was consistent
with CBS. Neuroimaging studies revealed severe atrophy
and reduced glucose metabolism in the cerebral cortex,
with predominant involvement of the right cerebral hemisphere compared with that of the left one, as well as
involvement of the parietal lobes compared with that of
frontal and temporal lobes. Neuropathologic examination
revealed abundant ubiquitin and TDP-43-ir neuronal inclusions, particularly evident in the parietal cortex, consistent
with a diagnosis of FTLD-U. Genetic analysis revealed the
c.26C>A PGRN mutation in 1 allele. The analysis of this
case highlights the possibility that parietal lobes may be a
main target of neurodegeneration in PGRN-associated
FTLD-U cases, thus, extending the knowledge of the
phenotypic variability of PGRN mutations and pathologic
heterogeneity of CBS.
MATERIALS AND METHODS
Subject
The proband was diagnosed with CBD and was
referred to the National Institute of Neurological Disorders
and Stroke (NINDS) Cognitive Neuroscience Section by an
outside neurologist. The diagnosis of CBS was ascertained
by one of us (E.M.W.), according to the proposed criteria,
and the subject was enrolled under the NINDS Corticobasal
Syndrome research protocol (1). As part of this study, the
patient underwent a neurologic and neuropsychologic evaluation as well as neuroimaging, which included magnetic
resonance imaging (MRI) and [18F]fluorodeoxyglucosepositron emission tomography ([18F]FDG-PET). A written
informed consent for the research protocol and postmortem
examination of the brain was obtained from the patient`s
durable power of attorney before enrollment. The institutional reviews boards of the NINDS and Indiana University
approved the clinical studies and neuropathologic studies,
respectively.
Neuropsychologic Testing
As part of the neuropsychologic evaluation, the
following cognitive domains were assessed: general cognition (Wechsler Adult Intelligence ScaleY3rd edition [WAISIII] and Mattis Dementia Rating Scale 2 [MDRS2]);
language (single word reading of the National Adult Reading Test); memory (Wechsler Memory ScaleY3rd edition);
visuospatial perception (Visual Object and Space Perception
[VOSP] Battery); motor control (Finger Tapping Test,
Grooved Pegboard [Lafayette Instruments, Lafayette, IN]
and Test of Limb Apraxia); and executive function (DelisKaplan Executive Function System). Mood and behavioral
symptoms were also assessed (Beck Depression Inventory,
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Corticobasal Syndrome and PGRN Mutation
2nd edition [BDI], Neuropsychiatric Inventory [NPI], and
Neurobehavioral Rating Scale [NRS]) (24Y35).
Neuroimaging
MRI was carried out using a Signa General Electric
1.5 Tesla scanner. High-resolution anatomical images were
acquired in the sagittal (T1-weighted) and axial (T1weighted, T2-weighted, and fluid attenuation inversion
recovery). In addition, 3-dimensional spoiled-gradient
recalled sequences were acquired in the sagittal, axial, and
coronal planes. An [18F]FDG-PET scan was performed on a
GE Advance 3D scanner (4.25 mm slice separation, 35
slices, axial field of view 15.3 cm, transverse field of view
55.0 cm) as previously described (36).
Neuropathology
The brain was cut along the midsagittal plane. The left
hemibrain was fixed in 10% buffered formalin, whereas the
right hemibrain was frozen for genetic and biochemical
studies. Sections were obtained from the following regions:
superior and middle frontal gyri, cingulate gyrus, superior
and middle temporal gyri, amygdala, superior parietal
lobule, occipital cortex, basal ganglia at the level of the
anterior commissure, thalamus at the level of the subthalamic nucleus, anterior and posterior hippocampus, cerebellar
cortex, dentate nucleus, midbrain, pons, and medulla. Tissue
was processed for classic histology and immunohistochemistry according to protocols published previously (37).
Immunohistochemistry was performed using antibodies
specific for: ubiquitin (1:100; DakoCytomation, Carpinteria,
CA), TDP43 (rabbit polyclonal antibody, 1:100; ProteinTech
Group, Chicago, IL), phosphorylated tau (AT8; Innogenetics, Antwerp, Belgium), A-amyloid (10D5, 1:100; Elan
Pharmaceuticals, South San Francisco, CA), glial fibrillary
acidic protein (1:100; DakoCytomation), prion protein (3F4,
1:800; gift from Dr. Kascsak, Institute for Basic Research in
Developmental Disabilities, Staten Island, NY), aA crystallin
(1:1000; Chemicon, Billerica, MA), phosphorylated neurofilament (SMI31, 1:1000; Covance Research Products Inc.,
Berkeley, CA) and >-synuclein (38).
Genetic Analyses
Genomic DNA was extracted from a frozen sample of
cerebellum using a standard protocol (39). The entire PGRN
coding region and flanking intronic sequences were analyzed. Polymerase chain reaction was done using 50 ng of
genomic DNA and the primers described previously (36).
The amplified products were gel-purified using the Qiaquick
Gel Extraction Kit (Qiagen, Valencia, CA) and subjected to
asymmetric amplification using the DTCS Quick Start Kit
(Beckman Coulter, Fullerton, CA). Products were analyzed
on a CEQ 8000XL DNA analysis system (Beckman
Coulter). The resulting DNA sequences were compared to
the known PGRN sequences (http://www.ncbi.nlm.nih.gov).
RESULTS
Clinical History
This right-handed man was evaluated at age 48. During
the previous 3 years he experienced progressively reduced
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Spina et al
J Neuropathol Exp Neurol Volume 66, Number 10, October 2007
control of his left arm`s movements. Initially, symptoms were
characterized by an involuntary elevation of the left arm while
the patient performed intentional movements with the contralateral limb. Subsequently, he developed increasing clumsiness and dystonic postures of the left arm. He reported
increasing difficulties in carrying out his job as a photographer because of reduced ability to plan the sequence of actions
required. He had severe difficulties dressing, including
donning a shirt backwards or forgetting to put his left arm
in. He stopped driving because of inability to plan the route,
developed deficits in managing finances and on some
occasions, he was disoriented for time. He reported falling
on several occasions due to postural imbalance.
On the physical examination he appeared alert,
appropriate, and cooperative. His speech was fluent and free
of paraphasic errors; however, impaired abstract word
retrieval and elements of superordinate substitution were
occasionally noted. Slowed saccades, saccadic breakdown of
pursuit movements, and nystagmus at the extreme lateral
gaze were noted. Strength and tone were normal except for
increased tone of the left arm. There was a bilateral tendency
to hold postures after manipulating objects or pantomiming
(left > right). Finger movement dexterity was severely
reduced on the left hand. Rapid alternating movements were
bilaterally impaired (left > right). The finger-to-nose test was
past-pointing and slow bilaterally. Deep tendon reflexes
were normal on the right and slightly hyperactive on the left.
A jaw jerk was also noted. Proprioception and graphesthesia
were reduced on the left side. He was able to walk with the
help of a cane. His gait was remarkable for widening of the
base, abnormal posturing of the trunk, lack of arm swinging
on the left and delayed step initiation in response to the
movement of the trunk (magnetic gait). Information on
the progression of the clinical phenotype is not available. The
proband died at age 51 after 6 years of disease duration.
taps with his dominant hand and 29.3 taps with his left hand.
He required 171 seconds to carry out the Grooved Pegboard
test with the right hand but was unable to execute the test
using the left hand. His performance on the test for limb
apraxia was mildly impaired, and he performed better in
response to verbal commands than to imitation. On some
occasions, an alien-limb phenomenon involving his left arm
was noted. He presented mild difficulty on the cube-counting
Family History
The proband`s father presented with behavioral changes
and dysexecutive symptoms, followed by cognitive decline,
incoordination, a tendency to fall, and leg rigidity (left >
right). He developed difficulties in controlling his left arm`s
movement but never experienced AHS. He had word-finding
difficulties that developed into mutism in his last year of life.
He was clinically diagnosed with Alzheimer disease and died
at the age of 73; no autopsy was performed. Among the
proband`s father`s siblings, 2 have been diagnosed with
dementia and 1 with Parkinson disease; 1 of them died, but
a neuropathologic assessment was not done.
Neuropsychologic Assessment
Among the different subtests of the WAIS-III, the
proband achieved an aged-scale score of 8 on Vocabulary
and 5 on Picture Arrangement. These scores are in the below
average to impaired range. The patient`s MDRS2 total score
of 116 was in the moderately impaired range. His performance on the reading test was normal. Visuospatial perception
was within normal limits. His left hand performances on
tests of motor control were severely impaired. Significantly,
his finger-tapping performances were of an average of 61.6
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FIGURE 1. Clock copying drawn by the proband displaying
left-sided hemispatial neglect (top). Proband’s drawings (copy
[middle] and recollection [bottom]) of the USA map, further
emphasizing the presence of left-sided hemineglect. Note
that when asked to indicate locations in the USA map drawn
by memory the proband gave an accurate relative spatial
localization of markers such FLA (Florida), CHAR (Charlotte,
South Carolina), W (Washington, DC), CIN (Cincinnati, Ohio),
and SF (San Francisco, California).
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J Neuropathol Exp Neurol Volume 66, Number 10, October 2007
subtest of the VOSP battery. His drawings showed left-sided
neglect (Fig. 1).
His verbal, nonverbal, and working memory functions
were all moderately impaired. When tested for executive
functioning, the proband showed difficulties in conceptual
shifting, response-inhibition, planning, and categorization.
His verbal reasoning and letter fluency were intact. He
obtained a score of 26 on the BDI, which is indicative of
moderate emotional distress. The total scores of 35 at the
NPI (apathy/indifference 8; agitation, depression, disinhibition, irritability/emotional lability 6; anxiety 3) and 41 at the
NRS (disorientation 5; memory deficits 4; disinhibition,
depressive mood, and comprehension deficit 3) are indicative of mild behavioral dysfunctions.
Brain Imaging
The MRI of the brain revealed moderate to severe
atrophy of the cerebrum with significantly more extensive
involvement of the right hemisphere compared with the left
one. Particularly striking was the severity of the narrowing
of the gyri and dilation of the sulci at the level of the right
parietal lobe and, to a lesser extent, of the right frontal lobe
(Fig. 2). In the left cerebral hemisphere, the degree of
atrophy was more severe in the parietal lobe than in the
Corticobasal Syndrome and PGRN Mutation
frontal lobe. A single punctuate focus of T2 time prolongation was observed in the left parietal lobe. The [18F]FDGPET scan showed a moderate to severe reduction of glucose
metabolism in the right frontal, temporal, and parietal
cortices with relative sparing of the left hemisphere and
subcortical nuclei (Fig. 3).
Neuropathology
The fresh brain weight was 980 g (left hemibrain, 520 g;
right hemibrain, 460 g). In the dorsolateral portion of the left
cerebral hemisphere, severe atrophy was evident in the
superior and middle frontal gyri, superior parietal lobule,
supramarginal gyrus, and angular gyrus. In the mesial
surface of the brain, atrophy was particularly evident in the
superior frontal gyrus and precuneus. In contrast, there was
only mild atrophy of the temporal and occipital lobes and
minimal atrophy of the hippocampus and parahippocampal
gyrus. The corpus callosum was severely reduced in thickness, particularly in its posterior portion. The bulk of the
centrum semiovale was also reduced. The lateral ventricle
was extensively enlarged. The thickness of the cortical
ribbon was ~1 mm in the parietal lobe (Brodmann`s area
[BA] 3) and ~2 mm in the frontal lobe (BA 4) (approximately 50% reduction), as well as ~3 mm in the temporal
FIGURE 2. Coronal spoiled-gradient recalled (A) and axial T1-weighted (B) magnetic resonance (MR) images of the proband’s
brain, in radiologic orientation, displaying severe atrophy of the right frontoparietal regions with a significant anteroposteriorpositive gradient of involvement. In the left cerebral hemisphere, moderate atrophy of the parietal lobe is also seen. Note the
significant asymmetric enlargement of the lateral ventricles (right > left) and the relative sparing of the temporal lobes. Sagittal
T1-weighted MR images (C) from the right (first 2 panels from the left) and left (first 2 panels from the right) cerebral
hemispheres, taken at the same distance from the midsagittal plane, display the asymmetric predominant involvement of the
right hemisphere in the disease process. In the mesial portion of both cerebral hemispheres, the significant involvement of
superior frontal gyrus and precuneus is shown.
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J Neuropathol Exp Neurol Volume 66, Number 10, October 2007
Spina et al
FIGURE 3. The proband’s glucose cerebral metabolism was assessed by [18F]fluorodeoxyglucose-positron emission tomography. Significant glucose hypometabolism is noted in the right frontoparietal cortical areas and, to a lesser extent, in the
dorsolateral left parietal cortex.
lobe (BA 41) (average) (40). The head of the caudate
nucleus was moderately flattened and the body was reduced
in bulk, as was that of putamen, amygdala, and thalamus.
The cerebellum was mildly atrophic. Substantia nigra and
locus coeruleus were moderately depigmented.
The histologic findings in the cerebral cortex and
subcortical nuclei are displayed in the Table. Immunohistochemical findings are shown in Figure 4. A mild loss of
axons and myelin and moderate astrocytosis were observed
in the subcortical white matter. In the brainstem, substantia
nigra and locus coeruleus displayed moderate neuronal loss.
Ub-ir and TDP-43-ir neuronal cytoplasmic inclusions and
dystrophic neurites were abundant in the second cortical
layer of the parietal and, to a lesser extent, frontal cortices.
They were also found in a significantly lower number in the
superior/middle temporal and parahippocampal cortices as
well as in the dentate gyrus, caudate nucleus, putamen,
amygdala, and thalamus (Fig. 4AYD). Ub-ir and TDP-43-ir
neuronal intranuclear inclusions were overall infrequent and
mostly confined to the frontal, temporal, parietal, and
cingulate cortices, dentate gyrus, and striatum (Fig. 4AYC,
E). In the subcortical white matter, TDP-43-ir thread-like
TABLE. Histologic Findings and TDP-43 Pathology in the Proband`s Cerebral Cortex and Subcortical Nuclei
Superior/middle frontal gyri
Superior/middle temporal gyri
Superior parietal lobe
Occipital cortex
Cingulate gyrus
Hippocampus CA 1-4
Dentate gyrus
Entorhinal cortex
Amygdala
Caudate nucleus
Putamen
Globus pallidus
Substantia innominata
Thalamus
Subthalamic nucleus
Hypothalamus
Neuronal Loss
Gliosis
NII
NCI
DN
+++
++
+++
++
++
++
++
+++
+++
++
++
++
++
++
+
+
++
+
+
+
++
+
+
+++
+++
+
+
+
++
++
+
+
+
+
+
+
+
+
+
-
++
+
+++
+
+
+
+
+
+
+
+
+
+
-
++
+
+++
+
+
+
+
+
++
++
+
+
+
-
NII, TDP-43-immunoreactive (ir) neuronal intranuclear inclusions; NCI, TDP-43-ir neuronal cytoplasmic inclusions; DN, TDP-43-ir dystrophic neurites; -, absent; +, mild; ++,
moderate; +++, severe.
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Corticobasal Syndrome and PGRN Mutation
FIGURE 4. TDP-43 immunohistochemistry in frontal (A), temporal (B), and parietal (C) cortical sections from the proband’s
brain. In the frontal cortex, a large number of TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCI) (arrowhead)
and dystrophic neurites (arrow) are seen in layer II. Neuronal intranuclear inclusions (NII) (star) are also occasionally noted (A). In
contrast, only a very limited amount of TDP-43-ir inclusions is seen in the temporal cortex. Scattered NII are mainly confined in
the upper sector of layer III (B). Abundant TDP-43-ir deposits are observed in layer II of the parietal cortex (C). In addition, note
the severe extent of gliosis and microvacuolar changes in the frontal (A) and parietal (C) cortices. A TDP-43-ir NCI (arrowhead)
seen in the dentate gyrus (D). (E) Parietal cortex section showing TDP-43-ir NII, cat’s eye-like, (left) and NCI (right). Subcortical
white matter displaying thread-like deposition (F) and coiled body-like deposition (G). Scale bars = (AYC) 20 Km; (D) 10 Km;
(EYG)5 Km.
deposits were frequently noted (Fig. 4F). In addition, TDP43-ir coiled body-like deposits were occasionally noted in
close proximity to oligodendroglial cells (Fig. 4G). A few
tau-ir neurons and neurites were seen in the frontal cortex,
transentorhinal cortex, and locus coeruleus. No >-synuclein,
prion protein, or AA-protein-ir deposits were found. No >Bcrystallin-ir or hyperphosphorylated neurofilament-ir ballooned neurons were observed.
Genetics
A cytosine to adenine transversion at position 26 in
exon 1 of PGRN (c.26C>A) was found in 1 allele. This
Ó 2007 American Association of Neuropathologists, Inc.
change is predicted to cause an Ala to Asp substitution at
residue 9 (Ala9Asp) in the signal peptide of progranulin.
DISCUSSION
We have identified a family in which a dementing and/
or a movement disorder was diagnosed in several individuals
from different generations. In the proband, who presented
with CBS, the neuropathologic examination displayed findings consistent with FTLD-U. Genetic analysis revealed the
c.26C>A PGRN mutation in 1 allele. This mutation occurs
in the signal peptide of progranulin and is predicted to alter
targeting and translocation of progranulin across the
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membranes of the endoplasmic reticulum. This change is
associated with reduced levels of the mutant mRNA for
reasons that are not yet completely understood (12).
The proband presented with spontaneous left arm
levitation, ideational apraxia, asymmetric parkinsonism,
and dystonic postures of the hands. This presentation is
consistent with the diagnosis of CBS, according to the
proposed criteria (1). Later in the disease course, features of
limb-kinetic apraxia, gait apraxia, dressing apraxia, temporospatial disorientation, memory loss, and executive dysfunction became relevant. In addition, language and behavior
became mildly impaired.
Spontaneous arm levitation, in the absence of grasp
reflex, groping behavior, and intermanual conflict is referred
to as the posterior variant of AHS (41, 42). The posterior
variant of AHS has been associated with ischemic lesions
involving the parietal lobe and/or the posterior thalamus of
the nondominant hemisphere (42). Ideational apraxia, a
high-order disorder of goal-directed sequencing of actions,
is a well-known consequence of extended pathology of the
left parietal lobe, variably associated with further involvement of frontal, temporal, occipital, or subcortical brain
regions (43Y47).
The proband`s clinical presentation was thus indicative
of a predominant and early involvement of the parietal lobes
in the disease process (48). This topographic diagnosis was
supported by evidence of left-side inattention and visuoconstructional impairment. Features of ideomotor apraxia, such
as the presence of temporal and/or spatial errors in the
execution of movements as well as improper spatial
orientation and use of body parts as objects, were not
observed (49). Consistently, there was no significant difference between the proband`s performance of transitive
actions and intransitive actions; performances on imitation
were poorer than that on response to verbal commands (50,
51). The later development of limb-kinetic apraxia, apraxia
of gait, dysexecutive symptoms, and language deterioration
are suggestive of a delayed involvement of the frontal lobes
in the disease process (52Y54).
Indeed, a correlation between the clinical symptoms
and pathology as demonstrated by neuroimaging was
achieved in vivo through the demonstration of severe
atrophy and reduced glucose metabolism of the parietal
lobes (right > left) and, to a lesser extent, of the superior and
middle frontal gyri (right > left). These findings were
consistent with the higher degree of atrophy and the
abundance of Ub-ir/TDP-43-ir deposition observed in the
parietal areas at the neuropathologic examination. Parkinsonism and dystonic postures may be explained by the
concomitant pathology of the striatum and substantia nigra.
To date, the c.26C>A (p.A9D) PGRN mutation has
been reported in affected individuals from a large FTLD-U
kindred of European ancestry (HDDD2), as well as in 3
independently ascertained individuals with FTD/FTLD-U
(12, 20). The neuropathologic phenotype in the affected
individuals from the HDDD2 family presented interesting
similarities with that of our case. Remarkably, severe
neuronal loss and abundant Ub-ir neuronal intranuclear
inclusions, neuronal cytoplasmic inclusions, and dystrophic
898
neurites were present in the parietal cortex. However, in the
HDDD2 cases, the extent of pathology in the parietal lobe
was consistently lower than that in the frontal and temporal
areas and the clinical phenotype was that of hereditary
dysphasic disinhibition dementia (HDDD) or Alzheimer-like
dementia (20). Gass et al (12) and Josephs et al (19) reported
2 subjects in which the c.26C>A PGRN mutation was
associated with FTLD-U, the presence of neuronal intranuclear inclusions and absence of pathologic hallmarks of
motor neuron disease. One of the subjects` clinical presentation was that of FTD and the other was that of progressive
supranuclear palsy (19). No neuropathologic information is
available on an additional subject, whose clinical presentation was that of primary progressive aphasia and who was
alive at the time of the report (12).
Before this study, a clinical presentation consistent
with CBS was reported in association with 3 additional
PGRN mutations: IVS7+1G>A (p.Val200GlyfsX18), IVS81G>C (p.Val279GlyfxX5), and c.813_816delCACT
(p.Thr272SerfsX10) (10, 12, 13). The IVS7+1G>A
(p.Val200GlyfsX18) mutation was identified in affected
individuals from a Canadian family of Chinese origin. The
clinical phenotype of the family`s proband, suggestive of
right parieto-occipital dysfunction, was associated with right
greater than left hemispheric cortical atrophy and hypometabolism, which were more prominent in the posterior
regions (13). Similar clinical and neuroimaging findings
have been described in 1 affected individual from an Italian
family, who was diagnosed with CBS associated with the
c.813_816delCACT (p.Thr272SerfsX10) PGRN mutation
(10). Features of limb apraxia and/or AHS have been
observed in the advanced stage of the disease course in
additional subjects with FTLD-U carrying a PGRN mutation, whose initial clinical presentation differed from that of
CBS (19, 21, 36). In addition, a study of a large series of
FTLD-U cases has shown a marked degree of parietal lobe
degeneration in 50% of cases associated with a PGRN
mutation [PGRN(+)] and in 17% of cases without a PGRN
mutation [PGRN(-)]. A trend for a higher severity of parietal
lobe degeneration in PGRN(+) cases compared with the
PGRN(-) was also observed (19).
Consistent evidence of the existence of a highly
variable and largely overlapping spectrum of clinical
presentations associated with PGRN mutations has been
collected from the description of numerous cases. In this
sense, PGRN(+) FTLD-U presents interesting similarities
with MAPT-associated frontotemporal dementia and Parkinsonism linked to chromosome 17 and with the larger
category of FTD syndromes (5, 18). This observation stands
in contrast with the pathogenic mechanism of the PGRN
mutations, which are all thought to lead to neurodegeneration through nonsense mediated decay of the mutant mRNA
and haploinsufficiency (16, 17). The proband`s neurologic,
neuropsychologic, and neuroimaging presentation shows that
PGRN mutations may lead to a neurodegenerative process
predominantly involving the parietal lobes in the early
disease stage. Remarkably, a higher extent of atrophy and
ubiquitin/TDP-43 pathology in the parietal cortex, compared
with that of other cortical areas, was found in the proband
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J Neuropathol Exp Neurol Volume 66, Number 10, October 2007
also at the neuropathologic examination. These findings
demonstrate that the parietal lobes may constitute the most
vulnerable anatomical areas in some cases of PGRN(+)
FTLD-U, therefore, raising questions on the accuracy of the
term FTLD to describe these syndromes. The detailed
clinical, pathologic, and molecular characterization of cases
with peculiar clinical presentations may provide important
insights on the neurobiologic base of this heterogeneity.
ACKNOWLEDGMENTS
The authors thank Linda Bailey, Brenda Dupree,
Francine Epperson, Brad Glazier, and Rose Richardson for
technical assistance and Dr. Masaki Takao for critical
reading of the manuscript and insightful comments.
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