Download Longitudinal characterization of two siblings with frontotemporal

doi:10.1093/brain/awh356
Brain (2005), 128, 752–772
Longitudinal characterization of two siblings with
frontotemporal dementia and parkinsonism linked
to chromosome 17 associated with the S305N
tau mutation
Bradley F. Boeve,1,5 Ivo W. Tremont-Lukats,6 Andrew J. Waclawik,7 Jill R. Murrell,9 Bruce Hermann,7
Clifford R. Jack Jr,2,5 Maria M. Shiung,2 Glenn E. Smith,3,5 Anil R. Nair,1,5 Noralane Lindor,4
Vinaya Koppikar8 and Bernardino Ghetti9
Departments of 1Neurology, 2Diagnostic Radiology,
Psychiatry and Psychology and 4Medical Genetics, Mayo
Clinic College of Medicine, Rochester, Minnesota, MN,
5
Robert H. and Clarice Smith and Abigail Van Buren
Alzheimer’s Disease Research Program of the Mayo
Foundation, 6Department of Neurology, Medical University
of South Carolina, Charlston, SC, 7Department of
Neurology, University of Wisconsin, Madison, 8Monroe
Clinic, Monroe, WI and 9Indiana Alzheimer Disease Center
and Department of Pathology and Laboratory Medicine,
Indiana University School of Medicine, Indianapolis,
IN, USA
3
Correspondence to: Bradley F. Boeve, MD, Division
of Behavioral Neurology, Department of Neurology,
Mayo Clinic, 200 1st Street SW, Rochester,
MN 55905, USA
E-mail: [email protected]
Summary
The background to this study began with the reporting
of two Japanese kindreds with the S305N tau mutation.
Although the pathological findings in the autopsied cases
were well characterized, only limited ante-mortem data
were presented. In this study, longitudinal characterization was carried out in two siblings of European
ancestry found to have frontotemporal dementia and
parkinsonism linked to chromosome 17 (FTDP-17)
through comprehensive neurobehavioural examinations
and other scales at approximate 6-month intervals. Scales
included the Mini-Mental State Examination, Short Test
of Mental Status, modified motor subtest of the Unified
Parkinson’s Disease Rating Scale, detailed neuropsychological testing, and the Neuropsychiatric Inventory.
Changes in whole-brain volume and ventricular volume
were measured from serial MRI studies. All members of
the kindred underwent molecular genetic analyses to elucidate the mechanism of inheritance. The missense mutation in tau, S305N, was detected in the proband (onset
age 30), who has undergone serial evaluations for almost
4 years. Her older sister (onset age 36) was subsequently
found to have the same mutation, and has undergone serial
evaluations for 2 years. This mutation is absent in both
parents and the only other sibling, and non-paternity
was excluded by additional analyses. The siblings have
exhibited cognitive and behavioural features typical of
FTDP-17, which have proved challenging to manage
despite aggressive pharmacological and behavioural therapies. The proband’s sister has demonstrated an atypical
profile of impairment on neuropsychological testing. Both
siblings have developed striking atrophy of the anterior
part of temporal lobes and moderate atrophy of the dorsolateral and orbitofrontal cortical regions, which in both
cases is relatively symmetrical. The annualized changes in
whole-brain volume and ventricular volume, respectively,
were 35.2 ml/year (3.23% decrease per year) and +20.75
ml/year (16.93% increase per year) for the proband, and
30.75 ml/year (2.77% decrease per year) and +5.01 ml/
year (3.11% increase per year) for the proband’s sister. In
conclusion, the mutation in these siblings may have arisen
during oogenesis in the mother and probably represents
germline mosaicism. Although both patients have exhibited
the typical cognitive and behavioural features of FTDP-17,
one patient is exhibiting an atypical neuropsychological
profile. Also, despite a similar topographic pattern of progressive atrophy on MRI, the rates of change in whole-brain
volume and ventricular volume between the two patients
are quite different. These findings have implications for
future drug trial development in FTDP-17 and the sporadic
tauopathies.
# The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]
FTDP-17 associated with the S305N tau mutation
753
Keywords: frontotemporal dementia; tau; MAPT; neuropsychology; magnetic resonance imaging
Abbreviations: Ab42 = b-amyloid 1–42; CDR = Clinical Dementia Rating; COWAT = Controlled Oral Word Association Test;
CSF = cerebrospinal fluid; DRS = Mattis Dementia Rating Scale; FLAIR = fluid attenuation inversion recovery; FTD =
frontotemporal dementia; FTDP-17 = frontotemporal dementia and parkinsonism linked to chromosome 17; GDS = Global
Deterioration Scale; MAPT = gene encoding tau (microtubule associated protein tau); MLAE = Multilingual Aphasia
Examination; MMSE = Mini-Mental State Examination; NPI = Neuropsychiatric Inventory; Rey-O = Rey–Osterrieth complex
figure; ROIL = Record of Independent Living; STMS = Short Test of Mental Status; Stroop = Stroop Neurological
Screening Test; UPDRS = Unified Parkinson’s Disease Rating Scale; VV = ventricular volume; WAIS-III = Wechsler Adult
Intelligence Scale—Third Edition; WBV = whole-brain volume; WCST = Wisconsin Card Sorting Test
Received April 16, 2004. Revised August 1, 2004. Accepted October 26, 2004. Advance Access publication
December 22, 2004
Introduction
Frontotemporal dementia (FTD) is a syndrome characterized
by prominent behavioural and/or dysexecutive features
(Neary et al., 1998; McKhann et al., 2001; Miller et al.,
2003). Anterograde memory functioning and visuospatial
skills are typically preserved early in the course of the illness.
Frontal and/or temporal abnormalities are demonstrated on
structural and functional neuroimaging studies. FTD occurs in
familial and sporadic forms; frontotemporal dementia and
parkinsonism linked to chromosome 17 (FTDP-17) is one
type characterized by mutations in MAPT (gene encoding
tau), which are inherited in an autosomal dominant pattern.
Its neuropathological hallmark is an abundance of hyperphosphorylated tau protein and degeneration of neurons and glia
(Munoz et al., 2003).
Extensive research in the past 6 years has revealed well
over 30 different mutations in tau (Reed et al., 2001; Bird
et al., 2003; Ghetti et al., 2003). While the genetic, biochemical and neuropathological features of affected individuals
have been well characterized, there is remarkably little longitudinal data on the clinical, neuropsychological and radiological features. With the hope that agents potentially useful in
the treatment of FTDP-17 and the sporadic tauopathies may
some day be identified or developed, longitudinal antemortem data will be necessary for designing clinical trials.
Two Japanese kindreds with the S305N tau mutation have
been reported (Iijima et al., 1999; Kobayashi et al., 1999,
2002, 2003, 2004). Although the pathological findings in
the autopsied cases were well characterized, only limited
ante-mortem data were presented. No FTDP-17 patients
with the S305N mutation have been identified outside of
Japan to our knowledge.
In this paper, we present genetic and detailed longitudinal
clinical, neuropsychological, neuropsychiatric and radiological data on two young Caucasian female siblings with
FTDP-17 associated with the S305N tau mutation.
Methods and design
The two patients are enrolled in the Mayo Foundation Institutional
Review Board-approved Alzheimer’s Disease Research Center at
Mayo Clinic, Rochester, MN. Genetic analyses, cerebrospinal
fluid (CSF) analyses for tau and b-amyloid 1–42 (Ab42) and serial
neuropsychological assessments and MRI scans were performed
after the patients and family provided appropriate informed
consent. Both patients underwent a standardized battery of clinical,
functional, neuropsychological, neuropsychiatric and radiological
studies at approximately 6-month intervals.
Clinical evaluations
All comprehensive neurobehavioural clinical data (Members of the
Department of Neurology, 1998) were reviewed and summarized.
The modified motor subtest of the Unified 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).
Functional assessments
All data on the Clinical Dementia Rating (CDR) scale (Morris,
1993), Global Deterioration Scale (GDS) (Reisberg et al., 1988)
and Record of Independent Living (ROIL) parts A and B (Weintraub,
1986) were tabulated and analysed.
Neuropsychological assessments
Testing included assessments of screening and global cognitive functioning [Mini-Mental State Examination (MMSE) (Folstein et al.,
1975), Short Test of Mental Status (STMS) (Kokmen et al., 1991;
Tang-Wai et al., 2003), Mattis Dementia Rating Scale (DRS)
(Mattis, 1988), Neurobehavioral Cognitive Status Examination,
1988], academic achievement [Wide Range Achievement Test—3:
Reading (WRAT-3) (Wilkinson, 1993)], intellectual functioning
[Kaufman Brief Intelligence Test (Kaufman and Kaufman, 1990),
Wechsler Adult Intelligence Scale—Third Edition (WAIS-III)
(Wechsler, 1997a)], attention/executive functioning [Trail Making
Test (Reitan, 1958), Stroop Neurological Screening Test (Trenerry
et al., 1989), Digit Span of the WAIS-III, Digit Symbol-Coding of
the WAIS-III, Symbol Search of the WAIS-III and Similarities
of the WAIS-III, and Wisconsin Card Sorting Test (WCST)
(Heaton, 1981)], language functioning [Boston Naming Test (Kaplan
et al., 1978), Controlled Oral Word Association Test (COWAT)
(Benton and Hamsher, 1978), Multilingual Aphasia Examination
(MLAE) Naming, Token, and Sentence Repetition (Benton and
Hamsher, 1978), and category/semantic fluency (animals, fruit, vegetables)], learning and memory [Wechsler Memory Scale—Third
Edition (WMS-III) (Wechsler, 1997b), Rey-Auditory Verbal Learning Test (Rey, 1964), and Free and Cued Selective Reminding Test
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B. F. Boeve et al.
(Free and Cued Selective Reminding Test) (Buschke, 1984; Grober
and Buschke, 1987)], and visuoconstructive and visuospatial skills
[Rey–Osterreith complex figure (Rey-O) (Osterrieth, 1944; Rey,
1941), Judgement of Line Orientation (Benton et al., 1983), Facial
Recognition Test (Benton et al., 1983) and Visual Form Discrimination (Visual Form Discrimination) (Benton et al., 1983)]. All scores
were converted to Z scores (mean of zero and standard deviation of 1)
based on comparison with appropriate norms.
Neuropsychiatric assessments
Neuropsychiatric Inventory (NPI) (Cummings et al., 1994) data were
provided by the proband’s husband (caregiver of the proband) and
mother (caregiver of the proband’s sister).
Neuroimaging examinations
MRI was performed using a GE scanner at 1.5 tesla, and images of
the brain were obtained in the sagittal (T1-weighted), axial [protondensity, T2-weighted and fluid attenuation inversion recovery
(FLAIR)] and coronal (T1-weighted) planes. Changes in wholebrain volume (WBV) and ventricular volume (VV) were measured
from serial MRI studies using the boundary shift integral method as
described by Gunter and colleagues (Gunter et al., 2003).
Genetic analyses
MAPT (the gene encoding tau) analysis was performed as previously
described (Spillantini et al., 1998). For the proband, exons 1–5, 7 and
9–13 were amplified and directly sequenced. Primers from the intronic sequences surrounding the exons were used so that the entire exon
sequence and the splice signals could be analysed. Standard amplification reactions were done with 50 ng of genomic DNA, and the
amplified products were then gel-purified. Asymmetrical amplification using the DTCS Quick Start Kit (Beckman Coulter, Fullerton,
CA, USA) was performed. The amplified products were precipitated
and resuspended in sample loading solution and loaded onto a CEQ
200XL DNA Analysis System (Beckman Coulter). The sequences
were compared with those of normal controls and to the published
MAPT sequence.
Once a pathogenic tau mutation was identified in the proband, her
family underwent genetic counselling but no additional analyses
were performed until after the proband’s sister developed symptoms.
All members of this kindred eventually underwent tau mutation
analyses using both direct sequencing and BsrDI restriction enzyme
analyses after appropriate genetic counselling. For enzyme digestion
analyses, the primers 50 -GACTGCCTCTGCCAAGTCCG-30 and 50 GGATCTGGCTGCGACCTCTG-30 were used to amplify the MAPT
exon 10. The 383 bp amplification product was then digested with
BsrDI, which recognizes the mutant allele and resulted in two bands
of sizes 252 and 131 bp.
To determine if the mother had any sign of the mutant allele and to
verify that the polymorphism (adenine at position 47) was indeed
on the normal allele, amplified exon 10 products from the proband
and the proband’s affected sister, father and mother were cloned into
pBluescript (Stratagene, La Jolla, CA, USA). Clones were analysed
by restriction enzyme digestions with BsrDI (New England Biolabs,
Beverly, MA, USA) and AciI, which was used to determine the
polymorphism (C/A) 47 bp upstream of the start of exon 10. A
few clones were sequenced as described above.
To determine if non-paternity might explain the genetic results
in this kindred, a standard paternity test was run in all five
subjects, which included nine polymorphic markers: D3S1358,
tetranucleotide repeats in the von Willebrand (vWA) gene and the
fibrinogen A a polypeptide (FGA) gene, D8S1179, D21S11,
D18S51, D5S818, D13S317, and D7S820. Markers were analysed
using the AmpFLSTR Profiler Plus PCR Amplification kit
(Applied Biosystems) on an ABI Prism 310 Genetic Analyzer
(Applied Biosystems).
Plasma and CSF tau and b-amyloid analyses
The CSF levels of tau and Ab42 in the proband were determined
using previously described methods by Athena Diagnostics.
Results
Pedigree
The pedigree is shown in Fig. 1. The maternal lineage is of
Bulgarian, English, Dutch and Swedish ancestry. The paternal
lineage is of Swedish and Norwegian ancestry.
Case reports
Case II.2
The proband is a right-handed Caucasian woman with
14 years of formal education who began exhibiting cognitive
impairment and behavioural changes at age 30. Over the
subsequent few months, she lost the ability to adequately
make decisions and execute instructions at work, resulting
in her dismissal. Her social behaviour changed such that
she altered her hair and dressing style to look similar to
her teenage daughter, her expressions of affection to her
family disappeared, and she became easily irascible and
started to withdraw socially. She drove erratically and her
driving privileges were revoked. At age 32 she became
obsessed with financial matters, was apathetic for upkeep
of the home, was intermittently aggressive towards her son,
and exhibited manic behaviour. She ate increasing amounts of
candy. By age 33 she was dependent on her husband for most
activities of daily living. She was evaluated by a psychiatrist
and commenced on risperidone, sertraline and buspirone,
I.
c=63
c=60
2
1
II.
o=36
c=39
o=30
c=36
1
c=34
2
3
Fig. 1 Pedigree. The shaded circles represent the two affected
individuals with FTD and the arrow indicates the proband. The
ages of onset (o = XX) and current ages (c = XX) are also shown.
FTDP-17 associated with the S305N tau mutation
which improved her aggressive behaviour. Valproic acid
was subsequently added, which improved her manic
symptomatology.
The past medical, family and social history of this young
woman at presentation was only notable for a sister with
cerebral palsy. Both parents were in their 50s and did not
have cognitive or behavioural symptoms. Her only other
sibling (case II.1) was not symptomatic at the time of her
presentation.
Initial neurological examination revealed a well-groomed,
adequately dressed young woman who avoided eye contact.
Her face was hypomimic, impassive throughout the encounter, looking repeatedly at her watch. She scored 29/30 on the
MMSE, missing one point on recall. She had difficulty naming the last five presidents of the USA. The remainder of her
examination was entirely normal. At the initial neuropsychological testing (Table 1), general intellectual functioning
appeared to have fallen from an estimated premorbid level
of average to low average level. Expressive language skills
were already moderately impaired but receptive skills
remained intact. Visuospatial/visuoconstructive functioning
was preserved. Immediate and delayed recall of both verbal
and non-verbal information was mildly impaired. The
patient’s perseveration during problem-solving was exceptional. Overall neurocognitive function was mildly impaired.
Numerous studies on blood and CSF failed to reveal findings
suggesting an infectious, autoimmune/inflammatory, toxic,
metabolic, paraneoplastic or mitochondrial process. Awake
and sleep electroencephalography was normal. An initial MRI
of the brain with and without contrast revealed regional
volume loss affecting the frontal and temporal lobes (not
shown). Tau and Ab peptide concentrations in CSF were
478 pg/ml (normally <420 pg/ml) and 521 pg/ml (normally
<1240 pg/ml), respectively.
Despite the lack of dementia in her immediate family, she
and her family underwent genetic counselling and genetic
testing. Apolipoprotein (ApoE) genotyping was negative
for the ApoE e4 allele. MAPT analysis was then performed
because of her young age and the mildly elevated CSF tau
level. Sequencing of exon 10 of MAPT revealed a G to A
substitution at the second base of codon 305, resulting in a
serine to asparagine amino acid change (S305N).
She was diagnosed with FTDP-17 due to the S305N tau
mutation, and donepezil was added to her medical regimen
and her alertness and communicability appeared to improve.
Examination 4 months later (age 34) revealed abulia and
bradyphrenia. On the STMS she scored 25/38. She recalled
none of four words on delay. She copied the Rey–Osterrieth
complex figure well. She had a mild hypokinetic dysarthria,
mild rigidity in the axial musculature and right upper
extremity with minimal rigidity elsewhere, moderately
masked facies, mildly stooped posture, moderately decreased
arm swing bilaterally, mild postural but not rest tremor, mild
diffuse bradykinesia, mildly decreased upgaze with slight
impairment of saccadic eye movements on pursuit testing,
and diffuse hyper-reflexia without pathological pyramidal
755
Table 1 Neuropsychometric performance in the proband
(case II.2)
Age (years, months)
33, 3
Global functioning/screening
Mini-Mental State Examination
29
(raw)
Short Test of Mental Status
(raw)
Academic achievement
Wide Range Achievement Test—3:
Reading
0
Intellectual functioning
Kaufman Brief Intelligence Test
Vocabulary
1.0
Matrices
1.2
Composite IQ
1.2
Attention/concentration
Trail-Making Test A (s)
0.6
Trail-Making Test B (s)
0.1
Stroop, word
1.1
Stroop, colour
0.1
Stroop, colour-word
1.0
Language functioning
COWAT
1.9
MLAE naming
2.0
MLAE token
0.8
MLAE sentence repetition
0.4
Planning, reasoning, problem-solving
Wisconsin Card Sorting Test
Categories
2.0
Perseverative responses
3.0
Failure to maintain set
0
Learning and memory
Wechsler Memory Scale—III
Auditory immediate
1.1
Visual immediate
1.6
Immediate memory
1.7
Auditory delayed
1.5
Visual delayed
2.1
Auditory recognition delayed 0.6
General memory
1.8
Working memory
0
Visuospatial functioning
Rey–Osterrieth complex figure
copy
Facial recognition test
0.2
Judgement of line orientation
2.3
Visual form discrimination
1.2
33, 7
33, 9
34, 2
25
25
23
0
2.0
2.5
2.5
1.1
1.6
2.5
1.3
2.9
3.1
3.6
3.2
2.7
2.7
3.6
0.6
2.6
0.4
2.0
0.3
Unless otherwise noted, values reflect Z scores (mean = 0, SD = 1)
based on appropriate norms.
tract signs. Glabellar and palmomental reflexes were present.
Repeat neuropsychological testing (performed 6 months following the initial assessment) (Table 1) demonstrated that
general intellectual function had fallen to the severely
impaired range. Impairment had appeared in all assessed cognitive domains. Memory function was profoundly impaired.
Receptive language deficits had joined the expressive deficits. Mild alternating attention problems had appeared. Of
the abilities assessed, only spatial judgement skills remained
756
B. F. Boeve et al.
Table 2 Responses on the Neuropsychiatric Inventory and scores on clinical and functional scales for the proband
(case II.2)
Age (yrs/mo)
33, 7
Feature
Freq
Delusions
Hallucinations
Agitation
Depression/dysphoria
Anxiety
Euphoria/elation
Apathy/indifference
Disinhibition
Irritability/lability
Aberrant motor behaviour
Night-time behaviour
Appetite/eating change
CDR
GDS
ROIL Part A
ROIL Part A
UPDRS
Medications
0
0
3
0
3
0
4
1
0
3
0
3
Sev
34, 2
Dis
0
0
0
0
2
2
0
0
1
1
0
0
2
2
1
1
0
0
2
2
0
0
2
2
1
4
30
8
25
vitamin E
buspirone
donepezil
risperidone
sertraline
Age (yrs/mo)
Freq
0
0
3
0
3
0
4
2
3
4
4
0
Sev
34, 8
Dis
Freq
0
0
0
0
1
3
0
0
2
3
0
0
3
3
1
1
2
3
2
3
2
4
0
0
2
5
35
9
16
vitamin E
buspirone
donepezil
valproic acid
memantine
quetiapine
risperidone
trazodone
ibuprofen
lorazepam
0
0
3
0
4
4
4
1
2
4
4
4
36, 3
Feature
Freq
Delusions
Hallucinations
Agitation
Depression/dysphoria
Anxiety
Euphoria/elation
Apathy/indifference
Disinhibition
Irritability/lability
Aberrant motor behaviour
Night-time behaviour
Appetite/eating change
CDR
GDS
ROIL Part A
ROIL Part B
UPDRS
Medications
0
0
3
0
0
0
4
3
0
4
0
3
Sev
0
0
1
0
0
0
2
1
0
1
0
2
3
6
58
11
9
vitamine E
buspirone
donepezil
valproic acid
memantine
quetiapine
gabapentin
mirtazepine
ibuprofen
Sev
35, 2
Dis
0
0
0
0
1
2
0
0
2
3
1
1
2
1
1
1
2
3
2
4
3
4
2
2
2
6
38
8
4
vitamin E
buspirone
donepezil
valproic acid
memantine
quetiapine
trazodone
gabapentin
ibuprofen
Freq
0
0
3
0
0
0
4
3
3
4
0
4
Sev
35, 7
Dis
0
0
0
0
1
3
0
0
0
0
0
0
1
2
1
1
2
2
2
2
0
0
2
2
2
6
40
8
3
vitamin E
buspirone
donepezil
valproic acid
memantine
quetiapine
mirtazapine
gabapentin
ibuprofen
36, 8
Dis
Freq
0
0
0
0
0
0
0
2
0
0
0
2
0
0
4
0
3
0
4
0
0
4
0
0
Sev
0
0
1
0
2
0
3
0
0
3
0
0
3
6
60
10
10
vitamin E
buspirone
donepezil
valproic acid
memantine
quetiapine
ibuprofen
Freq
0
0
4
0
3
0
4
3
0
4
3
4
Sev
Dis
0
0
0
0
2
3
0
0
2
0
0
0
3
0
1
0
0
0
1
0
2
3
3
4
3
6
56
11
14
vitamin E
buspirone
donepezil
valproic acid
memantine
quetiapine
mirtazapine
gabapentin
ibuprofen
37, 2
Dis
Freq
0
0
1
0
2
0
2
0
0
0
0
0
0
0
4
0
0
0
4
3
0
4
3
0
Sev
0
0
1
0
0
0
2
1
0
1
2
0
3
6
63
11
5
vitamin E
buspirone
donepezil
valproic acid
memantine
quetiapine
ibuprofen
CDR = Clinical Dementia Rating scale, Dis = distress, Freq = frequency, GDS = Global Deterioration Scale,
ROIL = Record of Independent Living, Sev = severity, UPDRS = Unified Parkinson’s Disease Rating Scale (modified).
Dis
0
0
0
0
0
0
0
0
0
0
0
0
FTDP-17 associated with the S305N tau mutation
within normal limits (though decline in performance was
present here also). Neurocognitive level was rated as moderately impaired. Her husband’s responses to questioning on
the NPI are shown in Table 2. MRI (Figs 2A and 3A)
showed moderate atrophy involving the amygdala, hippocampi and frontotemporal cortex.
A
B
C
Fig. 2 Continued on next page.
757
She was commenced on vitamin E 2000 IU/day for its
putative antioxidant effects as well as ibuprofen for its
anti-inflammatory properties. Over the subsequent 4 months,
severe insomnia and wandering developed which initially
responded well to trazodone. Memantine was added 2 months
later. Insomnia, wandering and intermittent aggressive
758
B. F. Boeve et al.
D
E
F
Fig. 2 Coronal T1-weighted MRIs of case II.2 (proband) at ages 33 years 7 months (A), 34 years 2 months (B), 34 years 8 months
(C), 35 years 7 months (D), 36 years 3 months (E) and 37 years 2 months (F). Atrophy is initially most prominent in the amygdalae
(right > left), anterior temporal cortices and dorsolateral prefrontal cortices. The left lateral ventricle is slightly larger than the right. Over
time the ventricles enlarge and the atrophy progresses, with eventual profound atrophy in the amygdalae, hippocampi and frontotemporal
cortices. Note that the findings are largely symmetrical, particularly as the illness progresses, with the mesial and inferior temporal
structures more atrophic than the middle and superior temporal gyri. The orbitofrontal cortex is minimally atrophic early (A–C) and
severely atrophic late in the course (D–F).
FTDP-17 associated with the S305N tau mutation
behaviour escalated and sertraline and risperidone were
tapered off and quetiapine was added. Her ability to perform
some activities of daily living improved, as did her neuropsychiatric features, but insomnia and wandering remained
problematic.
A
B
C
Fig. 3 Continued on next page.
759
She was re-evaluated 7 months following the previous
examination. She was alert, had fair recall of recent events
in the news, repeatedly expressed her desire to leave
the examining room, was dysnomic with normal fluency,
repetition and comprehension, and had delayed responses
760
B. F. Boeve et al.
D
E
Fig. 3 Axial FLAIR MRIs of case II.2 (proband) at ages 33 years 7 months (A), 34 years 2 months (B), 34 years 8 months
(C), 36 years 3 months (D) and 37 years 2 months (E); movement artefact obscured axial images at age 35 years 7 months, so these
images are not shown. Note the progressive anteromesial temporal and frontal atrophy with associated ventricular dilatation, with the left
lateral ventricle slightly larger than the right early in the course. No significant signal changes have developed in the affected
frontotemporal structures, and only mild atrophy has evolved in the parietal cortices.
to questions. She scored 23 out of 38 on the STMS with errors
in calculations, abstraction and recall. Her copy of the
Rey–Osterrieth complex figure was again almost perfect.
Parkinsonism was similar to that noted on the prior examination, and frontal release signs were now absent. Her husband’s
responses to questioning on the NPI are shown in Table 2.
MRI (Figs 2B and 3B) showed significant progressive atrophy
involving the amygdala, hippocampi and frontotemporal
cortex. Atrophy was particularly prominent along the interhemispheric fissure and in the inferior and middle temporal
gyri. Quetiapine was titrated upwards to further manage
insomnia and intermittent agitation.
She was re-evaluated 6 months later. As insomnia, manic as
well as obsessive–compulsive features had escalated, quetiapine had been increased to 500 mg daily, valproic acid was
increased to 2000 mg daily, and gabapentin was added, yet
these neuropsychiatric features continued. Her husband was
averaging 4–5 h of sleep nightly. He was pleased to see
expressions of emotion and affection and intermittent periods
of remarkable lucidity following these pharmacological
manipulations. Her parkinsonian features had dissipated.
She scored 10 out of 30 on the MMSE. She did not answer
most questions on the STMS. She abruptly left the office
five times to use the bathroom. Language was largely fluent
with poor comprehension and repetition. There was mildly
reduced upgaze on eye movement testing, subtle rigidity in
the left upper extremity, very mild postural tremor, moderately reduced facial animation, but no other parkinsonian
signs. Frontal release signs were again absent. Responses
on the NPI are shown in Table 2. MRI (Figs 2C and 3C)
showed slightly more anterior temporal atrophy and slight
ventricular enlargement.
Her trazodone and quetiapine were increased, and she continues under the diligent care of her supportive family. Longitudinal data over the subsequent 2 years are shown in Tables 1
and 2 and Figs 2D–F and 3D and E. Thus far, over almost
FTDP-17 associated with the S305N tau mutation
4 years of longitudinal evaluations she has not developed
apraxia of speech, non-verbal oral apraxia, limb apraxia,
alien limb phenomenon, dystonia, chorea, ataxia, myoclonus,
downgaze palsy, fasciculations, pyramidal tract signs or
muscular atrophy.
Case II.1
The proband’s older sister (henceforth referred to as ‘the
sister’) began exhibiting child-like behaviour at age 36.
Although considered the most outgoing and gregarious of
the family, her behaviour was considered beyond the norm
for her. She tended to laugh and giggle at most topics of
conversation, did not seem to appreciate the levity of some
inappropriate behaviour of her 12-year-old daughter, and
tended to interact with her daughter more as a sister or
good friend rather than a mother. She rarely disciplined her
daughter. The patient was divorced from her first husband and
separated from her second husband, and her parents were the
primary caregivers for the patient and only source of discipline for her daughter. She lost her job at age 37 and spent
much of her time fishing or sunbathing. Her problem-solving
skills and judgement had declined, but neither she nor her
parents appreciated any significant problems in memory, language or visuospatial functioning. There were no symptoms
of motor dysfunction. These behaviours led to genetic counselling and genetic testing, and the same S305N tau mutation
was identified. Apolipoprotein E testing showed no e4 alleles.
Shortly thereafter the sister underwent her first evaluation at
Mayo Clinic Rochester.
Initial neurological examination at age 37 revealed an alert,
attentive young woman who provided a good history, and had
excellent recall of recent events in the news. She scored 32
out of 38 on the Kokmen STMS, taking two trials to learn
four items, missing two on calculations, two on abstraction
and one on recall. There was no significant language disturbance evident in office testing. She tended to giggle after
many of her statements. The remainder of her comprehensive
neurological examination was notable for mild generalized
hyper-reflexia, Hoffmann’s sign present bilaterally, slightly
more evident on the left than right, and no significant rigidity
except with contralateral limb movements, as tone increased
significantly on the left, mildly so on the right. There were no
other extrapyramidal signs and no gaze palsy, apraxia,
myoclonus, etc., and no findings of motor neuron disease.
Her neuropsychological test results are shown in Table 3;
these results are largely within normal limits except for
deficits in confrontation naming and recall of verbal material.
Her mother’s responses on the NPI are shown in Table 4. Her
MRI of the brain showed mild to moderate bilateral amygdala
atrophy, as well as mild hippocampal atrophy, minimal
atrophy along the falx, no significant atrophy elsewhere,
and no significant vascular changes (Figs 4A and 5A).
She was diagnosed with early FTDP-17, enrolled in the
Mayo Alzheimer’s Disease Research Center, and was closely
followed by her local psychiatrist.
She was re-evaluated 6 months later. She had become
more forgetful, and her very poor insight continued with
761
no appreciation of anything amiss. She reluctantly discontinued driving. Her personality/behavioural changes were most
problematic, particularly disinhibition and sexually inappropriate gestures and behaviours. She was also becoming
more euphoric, laughing at topics of conversation that were
not overly funny. She tended to hoard meat and feed this to
their dog rather than eat these items herself, and she greatly
increased her intake of peanut butter. She was also compulsively buying items. Her medical regimen included memantine, valproic acid, venlafaxine and high-dose vitamin E. On
examination she was alert, attentive, tended to giggle or laugh
at times during the interview and examination. She scored
30 out of 38 on the STMS, missing one point each on orientation, attention, calculations, abstractions, taking two trials to
learn one item, and missing three on recall. The remainder of
her examination was essentially unchanged from 6 months
previously. Neuropsychological testing (Table 3) showed little
change except for mild worsening of expressive language
problems. MRI of the brain (Figs 4B and 5B) showed slightly
more atrophy along the falx, anterior temporal lobes, bilateral
amygdala and bilateral hippocampi. The lateral ventricles
were slightly larger. The patient, her parents and the patient’s
daughter continued with care under the direction of local
mental health professionals. The family had been impressed
with the improvement in the proband with donepezil, and this
was instituted in this patient with marginal benefit.
Over the subsequent 6 months, she experienced some
cognitive decline but still functioned reasonably well at home.
She tended to watch game shows and play solitaire on her
computer. She was enjoying sweets more, particularly
cookies, cake, ice cream and certain types of cereal. She
no longer cooked, and she continued to not discipline her
daughter. Inappropriate behaviour towards her daughter
had ceased, but her irritability towards her parents had
escalated, with one occasion requiring her father to restrain
her as she came at her mother with a knife. Quetiapine was
commenced and within 2 weeks her irritability had greatly
improved. On examination she scored 28 out of 38 on STMS,
with no other significant changes in her general neurological
examination. Neuropsychological findings were again minimally changed compared with the prior testing sessions
(Table 3). MRI showed more atrophy in the amygdala,
slightly more atrophy along the falx anteriorly, and the lateral
ventricles were slightly more dilated (Figs 4C and 5C).
Re-evaluation 6 months later revealed that most of her
cognitive and behavioural issues were relatively stable, except
for her feeding and shopping habits. She tended to eat icecream most of the day, resulting in a 20 pound increase in
weight. She enjoyed going to stores and malls with her parents
but occasionally her parents would find that she had shoplifted
items when they were not looking. She continued to refrain
from disciplining her daughter and would become very angry
when her parents attempted to discipline her. On examination
she scored 32 out of 38 on the STMS; her general examination
was again notable for subtle parkinsonism, but absence of
limb apraxia, dystonia, myoclonus, pyramidal tract signs,
muscular weakness and atrophy, and frontal release signs.
762
B. F. Boeve et al.
Table 3 Neuropsychometric performance in the sister (case II.1)
Age (years, months)
Global functioning/screening
Mini-Mental State Examination (raw)
Short Test of Mental Status (raw)
Mattis Dementia Rating Scale (raw)
Attention
Initiation and perserveration
Construction
Conceptual
Memory
Total
Academic achievement
Wide Range Achievement Test—3
Reading
Intellectual functioning
Wechsler Adult Intelligence Scale—III
Verbal IQ
Performance IQ
Full-scale IQ
Verbal comprehension
Perceptual organization
Working memory
Processing speed
Attention/executive functioning
Trail–Making Test A (s)
Trail–Making Test B (s)
Digit span of WAIS-III
Digit symbol-coding of WAIS-III
Symbol search of WAIS-III
Similarities of WAIS-III
Language functioning
Boston Naming Test, long
COWAT
Category fluency (raw)
MLAE token
Learning and memory
Wechsler Memory Scale–Revised
Verbal Memory Index
Logical memory
Immediate
Delayed
Retention (%)
Visual reproduction
Immediate
Delayed
Retention (%)
Auditory Verbal Learning Test
Trial 5
Delay
Delayed recall percent retention
Visuospatial functioning
Picture completion of WAIS-III
Block design of WAIS-III
Rey–Osterrieth complex figure copy
Visual form discrimination
37, 3
37, 9
38, 3
38, 9
29
32
28
30
27
28
27
32
37
37
6
34
25
139
34
37
6
35
22
134
31
37
6
37
21
132
35
37
6
34
22
134
0.3
0.6
0.1
0.4
0.8
0
0.5
1.3
0
0.1
0.4
1.2
0
0.7
1.3
0
0.5
0
1.5
0.19
0.9
1.7
0
0.9
0.5
1.7
1.18
1.5
1.6
0.8
1.7
0.9
0.1
0.7
0
0.3
0.3
1.0
0.3
0.1
0.6
0
0
1.3
0.6
0.1
0.3
0.3
0.3
2.0
1.6
0.7
1.3
1.3
0.3
1.3
2.8
0.1
46
0.8
3.3
0.5
33
0.2
3.1
0
38
0.9
3.3
0.4
36
1.3
0.9
0.9
1.3
1.7
0.7
1.0
52
0.7
0.8
62
0.8
1.7
33
0.9
1.5
41
0.3
0.5
79
0.4
0.8
84
0.3
0.1
91
0.9
0.9
86
2.2
3.1
33
3.4
3.9
0
3.3
3.5
29
3.8
3.8
17
1.3
0
1.0
0.3
0.3
0
1.0
0.1
0.6
0.6
1.0
0.8
2.0
0.3
1.0
1.6
Unless otherwise noted, values reflect Z scores (mean = 0, SD = 1) based on appropriate norms.
Her neuropsychological test scores remained stable in all
spared areas and unchanged in the impaired naming and
delayed recall areas (Table 3). MRI showed more atrophy
in the mesial, inferior and lateral aspect of the anterior part
of temporal lobes and anteriorly along the falx (Figs 4D and
5D). She was maintained on her pharmacological regimen
and topiramate was added in hopes of improving her eating
behaviour. She continues to reside with her parents.
FTDP-17 associated with the S305N tau mutation
763
Table 4 Responses on the Neuropsychiatric Inventory and scores on clinical and functional scales for the sister (case II.1)
Feature
Age (years/months)
37, 3
Freq
Delusions
Hallucinations
Agitation
Depression/dysphoria
Anxiety
Euphoria/elation
Apathy/indifference
Disinhibition
Irritability/lability
Aberrant motor behaviour
Night–time behaviour
Appetite/eating change
CDR
GDS
ROIL Part A
ROIL Part B
UPDRS
Medications
0
0
0
0
0
4
0
4
1
0
0
0
Sev
0
0
0
0
0
1
0
1
2
0
0
0
0.5
1
4
0
3
Vitamin E
37, 9
Dis
Freq
0
0
0
0
0
4
0
3
4
0
0
0
0
0
0
0
0
4
0
0
0
0
0
0
38, 3
Sev
0
0
0
0
0
2
0
0
0
0
0
0
1
3
6
1
2
Vitamin E
Valproic acid
Memantine
Venlafaxine
Dis
Freq
0
0
0
0
0
3
0
0
0
0
0
0
0
0
0
1
0
3
4
3
1
0
0
4
Sev
0
0
0
2
0
2
2
2
1
0
0
2
0.5
4
17
2
2
Vitamin E
Valproic acid
Memantine
Venlafaxine
Quetiapine
Donepezil
38, 9
Dis
Freq
0
0
0
3
0
1
2
2
3
0
0
2
0
0
0
3
0
3
3
2
2
0
0
4
Sev
0
0
0
1
0
1
2
3
1
0
0
2
0.5
4
20
4
2
Vitamin E
Valproic acid
Memantine
Venlafaxine
Quetiapine
Donepezil
Dis
0
0
0
2
0
0
1
2
0
0
0
1
CDR = Clinical Dementia Rating scale; Dis = distress; Freq = frequency; GDS = Global Deterioration Scale; ROIL = Record of Independent
Living; Sev = severity; UPDRS = Unified Parkinson’s Disease Rating Scale (modified).
Analysis of genetic data
All members of this kindred have undergone MAPT mutation
analyses using both direct sequencing and BsrDI restriction
enzyme digestion analyses (Fig. 6). The S305N mutation was
identified in both affected sibs and absent in the unaffected
members of the kindred. A C/A polymorphism at position
47 just before the start of exon 10 was found in both affected
sisters and their father; by cloning this polymorphism was
found to be on the normal allele in both affected sisters.
This polymorphism is listed in the National Center for
Biotechnology Information Single Nucleotide Polymorphism
Database as rs3744460 and has an average heterozygosity of
0.467 (analysed in several Japanese samples). In addition,
nine polymorphic markers (D3S1358, tetranucleotide repeats
in the von Willebrand gene and the fibrinogen A a polypeptide gene, D8S1179, D21S11, D18S51, D5S818, D13S317,
and D7S820) used in a standard paternity test were run in
all five samples (Table 5). Results of these tests ruled against
non-paternity. Over 250 clones were analysed from the
mother and over 80 from the father and none were found
to have the mutation, suggesting germline mosaicism.
diagnosis was obvious when she began exhibiting behaviours
similar to the proband. As shown in Tables 1 and 3, the sister
was diagnosed at a much earlier stage of the illness, as
reflected by the lower scores on the CDR, GDS and ROIL.
Scores on the UPDRS have indicated parkinsonism in both
siblings. Parkinsonism was far greater in the proband while
she was receiving risperidone, and scores decreased upon its
discontinuation. Neither sibling has developed features
strongly suggestive of evolving corticobasal syndrome or
progressive supranuclear palsy (Boeve et al., 2003), nor
have features of motor neuron disease evolved.
Analysis of neuropsychological data
In both siblings, mental status test scores were within normal
limits early in their course, and visuospatial/visuoconstructive
skills were spared until late in the course. The proband performed poorly on the WCST early in her course, yet performance on several tests of attention/executive functioning has
been minimally impaired or normal in the sister. Retention of
(memory for) verbal information functioning and particularly
confrontation naming were impaired in both siblings.
Analysis of clinical data
Analysis of neuropsychiatric inventory data
The diagnosis of FTDP-17 in the proband was elusive until the
neuropsychological and radiological studies suggested
changes referable to the frontotemporal lobes. Her sister’s
In the proband (Table 2), the NPI Total (sum of frequency 3
severity) ranged from 24 to 56 over this interval (30–45–56–
32–52–24–34–25). This is in spite of an increasing burden of
764
B. F. Boeve et al.
A
B
C
D
Fig. 4 Coronal T1-weighted MRIs of case II.1 (sister) at ages 37 years 3 months (A), 37 years 9 months (B), 38 years 3 months (C) and
38 years 9 months (D). Atrophy is initially present in the amygdalae. Over time the mesial and inferior anterior temporal structures and
mesial dorsolateral prefrontal and orbitofrontal cortex atrophy further, and the lateral ventricles enlarge (particularly the temporal horns).
FTDP-17 associated with the S305N tau mutation
765
A
B
C
D
Fig. 5 Axial FLAIR MRIs of case II.1 (sister) at ages 37 years 3 months (A), 37 years 9 months (B), 38 years 3 months (C) and 38 years
9 months (D). The distribution of atrophy and lack of signal changes are quite similar to the proband’s FLAIR MRI studies (Fig. 3).
766
B. F. Boeve et al.
A
400
300
200
100
383
252
131
1
2
3
4
5
6
Fig. 6 BsrDI restriction enzyme digestion of amplified MAPT
exon 10 products from family members. Amplified products were
run on a 2% agarose gel. Lane 1 contains 100 bp ladder DNA
marker (Seegene, Seoul, Korea). The two affected sisters (lanes 2
and 4) have bands at 252 and 131 bp signifying the presence of the
S305N allele.
B
Table 5 Alleles of polymorphic markers analysed in
family members
Locus
Father
Mother
D31358
vWA
FGA
D8S1179
D21S11
D18S51
D5S818
D13S317
D7S820
16
15, 19
23
8, 13
31.2, 32.2
16, 17
11
11, 12
8, 12
17,
17
22,
12,
30,
12,
11
12,
10
18
Proband* Sibling 1* Sibling 2
16,
17,
25
22,
13
12,
32.2 30,
16
12,
11
13
11,
10,
17
19
23
13
31.2
16
13
12
16, 18
17, 19
22, 23
8, 12
31.2, 32.2
12, 16
11
12
8, 10
16, 18
17, 19
23, 25
13
30, 31.2
16, 17
11
11, 13
8, 10
*Individuals with frontotemporal dementia.
psychotropic medications intended to address the behavioural
disturbances. Apathy/indifference was present from the
outset, and this has remained the most pervasive feature.
Emotional lability is also present, with euphoria being present
at one point, anxiety varying throughout her course, in spite of
continued apathy. Sleep/wake problems were problematic
early in her course, and some degree of aberrant motor
behaviour and agitation has been present throughout. Hyperphagia was present at the initial NPI assessment. Disinhibition
was perceived to be mild and minimally distressing. The
emotional distress perceived by the proband’s husband
over this interval (10–20–21–12–10–4–5–0) was maximal
early in the course, and decreased over the most recent
212 years. The drop in emotional distress despite continued
neuropsychiatric symptomatology suggests that the husband
has adapted, developed tolerance and become a savvy caregiver. These may all be the same process.
In the proband’s sister (Table 4), the mother’s ratings on the
NPI Total ranged from 8 to 31 over this interval (10–8–31–
28), and the emotional distress varied in a similar fashion
(11–3–13–6). The sister has exhibited euphoria, disinhibition
Fig. 7 Graphs depicting longitudinal whole-brain volume (WBV)
in ml (A) and ventricular volume (VV) in ml (B) over time for the
proband and sister. Note that the plots are quite linear and the
initial WBV values are similar for the two cases, but the initial
VV values and slopes are quite different.
and irritability from the outset, with depression, apathy and
hyperphagia developing as the illness progressed.
At no time during their periods of assessment were
delusions or hallucinations present in either sibling.
Analysis of radiological data
Both siblings have developed striking atrophy of the anterior
part of temporal lobes and moderate atrophy of the dorsolateral frontal, and orbitofrontal cortices, which in both cases is
relatively symmetrical (Figs 2–5). As shown in Fig. 7, the
plots of WBV (A) and VV (B) are quite linear, and the initial
WBV values are similar. Yet the initial VV values and the
slopes for WBV and VV are different. The annualized changes
in WBV and VV, respectively, were –35.2 ml/year (3.23%
FTDP-17 associated with the S305N tau mutation
decrease per year) and +20.75 ml/year (16.93% increase
per year) for the proband, and 30.75 ml/year (2.77%
decrease per year) and +5.01 ml/year (3.11% increase per
year) for the sister.
Discussion
Clinical and neuropsychiatric issues
We present two young Caucasian siblings of European
descent with many clinical, neuropsychological and radiological features typical of FTDP-17 (onset ages 30 and 36
years). While cognition is clearly impaired in both siblings,
the most prominent aspect of their illness has been the neuropsychiatric features which heralded the onset and have proven
challenging to manage despite aggressive pharmacological
manipulations. Mild parkinsonism is also present in the
proband, but this is probably due partly to risperidone as
the parkinsonism has improved upon its discontinuation;
subtle parkinsonism also exists in her sister. No features of
the corticobasal syndrome (Boeve et al., 2003) or motor
neuron disease have developed in these siblings and, interestingly, frontal release signs faded as the illness progressed
in both cases.
While the initial features in the proband were typical of
FTDP-17, a familial disorder was not suggested by her family
history at the time of her presentation. This case exemplifies
that a genetic disorder may be at play even without a compatible family history.
The CSF findings in the proband are also notable, as the
results indicated that patients with a tauopathy can have a
CSF tau and Ab profile consistent with Alzheimer’s disease
(Galasko et al., 1998). There are conflicting data on CSF
tau and Ab levels in FTD, some investigators finding elevations in tau compared with controls (Arai et al., 1997; Green
et al., 1999; Molina et al., 1999; Fabre et al., 2001;
Vanmechelen et al., 2001; Riemenschneider et al., 2002;
Rosso et al., 2003) and others not (Mecocci et al.,
1998; Sjögren et al., 2000a, b, 2001). CSF tau has been consistently elevated in Alzheimer’s disease, often exceeding
levels in FTD (Arai et al., 1997; Green et al., 1999; Molina
et al., 1999; Sjögren et al., 2000a, b; Vanmechelen et al.,
2001; Riemenschneider et al., 2002). CSF Ab levels have
tended to be lower in Alzheimer’s disease compared with
FTD (Sjögren et al., 2000a; Vanmechelen et al., 2001;
Riemenschneider et al., 2002). Even among patients with
FTD associated with tau mutations, total tau and phosphorylated tau T181 levels were normal or only mildly increased
(Rosso et al., 2003). These discrepancies in CSF tau levels in
FTD compared with controls and Alzheimer’s disease may
reflect methodological (e.g. technique for quantifying tau) or
sampling (e.g. percentages of FTD patients with tauopathies)
differences.
The three affected relatives in the report of Iijima and
colleagues had ages of onset ranging from 29 to 38 years,
with personality changes evident early in the illness followed
by cognitive decline, and parkinsonism was described as
767
minimal in one case and absent in the others (Iijima et al.,
1999). Neuroimaging studies indicated left greater than right
frontotemporal atrophy. There is no mention of symptoms or
signs of motor neuron disease in this report, nor discussion of
any of the typical clinical findings of the CBS despite the
pathological findings in the proband being most consistent
with corticobasal degeneration (CBD). We have specifically
sought to identify signs typical of CBS and all have been
absent thus far, which is not surprising as clinicopathological
heterogeneity is known to exist in corticobasal degeneration
(Boeve et al., 1999). In the only other reported kindred with
the S305N tau mutation, the proband and his brother exhibited cognitive and behavioural changes typical of FTDP-17
(Kobayashi et al., 1999, 2002, 2003, 2004). The proband
began exhibiting aggressive tendencies and personality
changes at age 34, followed by disinhibited and stereotyped
behaviours. Computed tomography of the head showed frontal lobe atrophy. He subsequently developed abulia, echolalia
and limb rigidity that was levodopa-unresponsive. Terminally he displayed quadriplegia in flexion with rigidity, spasticity, and frontal release signs present prior to his death at
age 46. Neuropathological examination revealed greater temporal than frontal lobe atrophy, profound nigral degeneration,
and numerous Pick bodies and Pick cells compatible with the
diagnosis of Pick’s disease (Kobayashi et al., 1999). This
patient’s younger brother subsequently exhibited similar
behavioural and cognitive changes beginning at age 39,
and had MRI evidence of asymmetrical temporal–occipital
cortical and hippocampal atrophy, with minimal frontal lobe
atrophy (Kobayashi et al., 2002). Neuropathologically, taupositive Pick-like inclusions were identified (Kobayashi et al.,
2003, 2004). Thus our cases appear clinically similar to the
few described with this mutation, but the radiological features are slightly different, with only slight asymmetrical
temporal > frontal atrophy in our two patients but asymmetrical temporal > frontal atrophy in the Japanese cases (Iijima
et al., 1999; Kobayashi et al., 1999, 2002, 2003, 2004).
Neuropsychological issues
Based on previous studies, the expected neuropsychological
features in the frontal variant or behavioural/dysexecutive
subtype of FTD would include impaired performance on
tests sensitive to frontal lobe functions (e.g. Trail-Making
Test, Stroop, COWAT, WCST) and minimal or no impairment on tests assessing anterograde memory functioning (e.g.
Wechsler Memory Scale—Third Edition, Wechsler Memory
Scale—Logical Memory, Wechsler Memory Scale—Visual
Reproductions, Free and Cued Selective Reminding Test) and
visuospatial functioning (e.g. clock drawing, Rey–Osterrieth
complex figure, Judgement of Line Orientation, Visual Form
Discrimination) (Miller et al., 1991; Pachana et al., 1996;
Neary et al., 1998; Hodges, 2001; Rascovsky et al., 2002).
Performance on screening (e.g. MMSE, STMS) and global
(e.g. DRS) tests of cognitive functioning are often normal or
near normal early in the course (Gregory et al., 1997, 1999;
768
B. F. Boeve et al.
Rahman et al., 1999). At the initial assessments, our cases
indeed performed quite well on screening and global tests of
cognition as well as on most tests of visuospatial functioning
(Tables 1 and 3). In fact over the 2 years of assessments on the
sister, she has scored in the normal range on the MMSE and
STMS, and her total score on the DRS has achieved marginal
impairment on only one round of testing (at least when compared with normative data on individuals many years older
than she). The proband was unable to achieve all six categories on the WCST and had numerous perseverative errors,
typical of FTD (the WCST is not part of our research protocol
and therefore the sister has not been assessed on this measure).
The sister has scored in the impaired range on the Digit Span,
Digit Symbol-coding, and Similarities subtests of the WAISIII, as well as attention subtest of the DRS, while performance
on other tests of attention/executive functioning has been
minimally impaired or normal. While the neuropsychiatric
features have dominated the sister’s clinical course, with
only mild forgetfulness occurring in everyday activities,
her performance on some tests of anterograde memory functioning has been poor. Although reports of severe memory
impairment in FTD do exist (Caine et al., 2001), performance
on delayed recall measures is typically minimally affected
early in the course of FTD (Gregory et al., 1997, 1999;
Rahman et al., 1999; Pasquier et al., 2001). Although considerable data have been accumulated on memory measures in
FTD, no score on any memory measure has been accepted as
necessary to warrant or negate the diagnosis of FTD. Poor
performance on memory measures can also reflect poor attention, or impaired semantic processing on verbal memory
measures. The proband and particularly the sister therefore
exemplify how some patients with FTD associated with a
presumed pathogenic mutation in tau can perform poorly
on episodic memory measures. We suspect the hippocampal
atrophy now present in both siblings is the radiological correlate for their memory impairment, which is consistent with
another reported FTD patient (Pickering-Brown et al., 2004).
We cannot exclude some degree of medication effect contributing to impairment on some measures in both siblings.
Receptive aphasia and agnosia have not been prominent
problems in either sibling’s clinical course, yet both have
performed poorly on confrontation naming tests (e.g.
MLAE naming, Boston Naming Test) even at their initial
assessments. Since integrity of the anterior inferolateral
temporal region in the dominant hemisphere is necessary
for intact confrontation naming, and this region is typically
affected early in the course in frontal variant FTD as well as
temporal variant FTD (Edwards-Lee et al., 1997; Hodges and
Miller, 2001b), poor performance in confrontation naming in
the setting of more normal performance on other measures
(particularly memory) may suggest underlying FTD rather
than AD (Boone et al., 1999; Hodges et al., 1999; Miller
and Gearhart, 1999; Hodges and Miller, 2001b; Boccardi
et al., 2003).
Progressive language dysfunction, which certainly occurs
to some degree in most FTD patients, can lead to what may
appear to be a rapid rate of progression based on clinical and
neuropsychological assessments. Since performance on most
clinical and neuropsychological measures is dependent on
relatively preserved language functioning, an aphasic disturbance can lead to poor performance on measures assessing
non-language domains. The proband’s progressive aphasia
probably contributed to her notable decline on clinical and
neuropsychological measures.
Radiological issues
As noted above, our patients’ MRI findings are similar to
those of the few other S305N tau mutation cases, with
temporal greater than frontal lobe atrophy, although atrophy
was largely symmetrical in our cases and markedly asymmetrical in the other cases (Iijima et al., 1999; Kobayashi et al.,
1999, 2002, 2003, 2004).
The MR findings in our siblings are also quite typical of
FTD (Miller and Gearhart, 1999; Hodges, 2001; Boccardi
et al., 2002, 2003; Rosen et al., 2002). Most reports note
asymmetrical atrophy in FTD patients, although one report
specifically investigated symmetrical frontotemporal atrophy
in sporadic FTD cases (Boccardi et al., 2002). Compared with
FTD patients with asymmetrical brain atrophy, those with
symmetrical atrophy had an earlier age of onset, more severe
global and medial temporal atrophy, and a greater frequency
of ApoE e4 alleles, yet this report involves 10 FTD patients of
whom three possessed an ApoE e4 allele (Boccardi et al.,
2002). Our siblings indeed had an early age of onset, but
neither had ApoE e4 alleles. A much larger number of
FTD cases with symmetrical and asymmetrical atrophy,
with and without ApoE e4 alleles, will be necessary to determine if any association exists between brain atrophy in FTD
and the presence or absence of the ApoE e4 allele.
The longitudinal volumetric MRI findings in our two
patients permit some interesting observations. The slightly
greater WBV in the sister compared with the proband is consistent with the clinical and neuropsychological data reflecting less impairment in the sister at the time of her first scan.
Yet the VV is much greater in the sister than the proband,
which is not readily explainable. The rate of decline in WBV
and the rate of increase in VV are far greater in the proband
than in the sister, which is also consistent with the rather
minimal clinical and neuropsychological changes over time
in the sister compared with the more dramatic changes in the
proband. Yet why these rates are so different is not clear. Both
patients presumably have the same disease, both have many of
the same clinical and neuropsychiatric features, and both have
been treated with almost identical treatment regimens.
Whether drug intervention earlier in the illness in the sister
afforded her a slower rate of progression or whether some
other environmental or biological factors are at play cannot be
determined at this time. However, variability in the phenotypes, ages of onset and durations of disease is well known
among relatives with the same genetic mutation in familial
neurodegenerative disorders. This issue has implications for
FTDP-17 associated with the S305N tau mutation
treatment trials (see below). Furthermore, variable penetrance
or non-penetrance could affect the phenotypic expression;
non-penetrance has been reported in tau mutations (Murrell
et al., 1999; Pickering-Brown et al., 2002; van Herpen et al.,
2003).
We and others have been refining techniques to quantify
rates of regional or whole-brain atrophy using MRI in patients
with mild cognitive impairment and Alzheimer’s disease
(Jack et al., 1998, 2000, 2003; Fox et al., 1999, 2000;
Gunter et al., 2003), and more recently in patients with
FTD (Chan et al., 2001a, b). The automated methods, such
as the boundary shift integral method used in our patients and
the gradient-matching method, allow excellent precision and
high throughput (Gunter et al., 2003), and such methods look
promising as surrogate markers of disease progression for
naturalistic (such as the findings reported herein) and
therapeutic trials. The fact that the relationship is linear in
most patients bodes well for developing and interpreting
therapeutic drug trials.
Genetic issues
Since its initial description, several investigators have determined that the exonic S305N mutation is unique in that it does
not result in the impairment of the tau–microtubule binding
but in the overproduction of four-repeat isoforms through
increased splicing-in of exon 10 and destabilization of the
RNA stem–loop structure, an abnormality characteristic
of intronic mutations in the MAPT gene (Grover et al.,
1999; Hasegawa et al., 1999; Varani et al., 1999). Another
mutation in exon 10 (N279K) acts in a similar fashion
(D’Souza et al., 1999; Hasegawa et al., 1999). More recently,
a S305S tau mutation associated with progressive supranuclear palsy clinical and pathological features has been reported
(Stanford et al., 2000). Although this mutation does not result
in an amino acid change, splicing of exon 10 is significantly
increased (Stanford et al., 2000). Thus, the S305N mutation in
our cases is very likely pathogenic.
The polymorphism on the normal MAPT allele (position
47, adenine for cytosine) in the affected sibs and their father
suggests that he is the biological father. The additional analyses (Table 5) confirm that he is indeed the biological father,
thus arguing against non-paternity in this family. Incomplete
penetrance cannot explain the findings in this kindred as
neither parent has the S305N mutation. Since the likelihood
of an identical spontaneous mutation occurring in two siblings
is extremely low, we suspect germline mosaicism is the most
likely explanation for the findings in this kindred. Somatic
mosaicism was recently reported in a subject with earlyonset Alzheimer’s disease (Beck et al., 2004). The subject
showed signs of disease in the mid 50s and had a daughter who
showed signs at age 27. The daughter was found to have
a mutation in the Presenilin 1 gene (P436Q). After further
testing, it was shown that the mother did have the mutation in
a few of her somatic cells. Gonadal mosaicism was reported in
one unaffected mother who had two daughters with repeat
769
expansions of the CAG trinucleotide repeat in the Huntington
disease gene (Laccone and Christian, 2000). Germline
mosaicism has never been reported in the parents of an individual with a MAPT mutation to our knowledge.
Implications for future drug trials
The longitudinal findings in these siblings are particularly
relevant for future experimental drug trials in FTD and the
tauopathies. Much of the research on FTD has centred on
features that discriminate FTD from other dementias (Gregory
and Hodges, 1996; Mendez et al., 1996, 1998; Pachana et al.,
1996; Gregory et al., 1997; Lindau et al., 2000; Mummery
et al., 2000; Perry and Hodges, 2000; Hodges and Miller,
2001a; Lough et al., 2001; Boxer et al., 2003; Nyatsanza
et al., 2003). While this work is certainly important for
improving the diagnosis of FTD, there is little published
data on the longitudinal course of FTD (Gregory, 1999;
Chan et al., 2001a), nor is there much data that help guide
the future treatment of patients with FTD. To date there have
been few reports on the symptomatic management of neuropsychiatric manifestations of FTD (Swartz et al., 1997), and
since no agent has yet been identified that significantly
impacts tau protein pathophysiology, no treatment trial for
FTDP-17 or the sporadic tauopathies has begun. Developing
treatment trials will be challenging for several reasons. The
disorders that can manifest as the syndrome of FTD include
Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal lobar degeneration with and
without motor neuron disease-like inclusions, neurofilament
inclusion body disease, and rarely Creutzfeldt–Jakob disease
and Alzheimer’s disease (Hodges and Miller, 2001a;
McKhann et al., 2001; Rossor, 2001; Boeve et al., 2003;
Josephs et al., 2003). Hence, treatments active against tau
pathophysiology may be effective for one or more of the
tauopathies, but may not be effective for frontotemporal
lobar degeneration with or without MND since most cases
do not have tau-positive pathology. Furthermore, even among
the tauopathies drug development will be challenging to
assess, as there are cognitive, neuropsychiatric and motor
manifestations that must be monitored, and relatives with
the same mutation may exhibit quite different features.
When considering how efficacy will be determined in any
treatment trial, one would want to make measurements of various parameters over time and determine if the intervention will
delay the rate of progression or halt progression altogether
(Fig. 8). The parameters to be assessed could include clinical
(e.g. MMSE, UPDRS), functional (e.g. GDS, ROIL), neuropsychological (e.g. DRS, TMT), neuropsychiatric (e.g. NPI
scales) and radiological (e.g. WBV, VV, hippocampal volume)
measures. One would need to assess a sufficient number of
patients with FTD with a standardized battery of tests over
time to determine which parameters change in the most consistent and linear fashion. In our two cases, the parameters that
appeared to trend in the most consistent manner were the
ROIL, WBV and VV. Using the theoretical construct shown
770
B. F. Boeve et al.
normal
d
c
measure
b
a
abnormal
time
Fig. 8 Graph depicting theoretical constructs for considering a
treatment trial, where the values of any measure ( y axis) are
plotted against time (x axis). The arrow represents the onset of
treatment, line ‘a’ represents the course in the untreated setting,
line ‘b’ represents the course if the treatment decreases the rate of
progression, line ‘c’ represents the course if the treatment halts
progression altogether, and line ‘d’ represents the course if
treatment results in improvement (e.g. neuropsychological
measure, NPI measure).
in Fig. 8, patients with FTD features could act as their own
controls, with the hope that therapy would alter the rate of
change (as in line b or c in Fig. 8). Because members of a
kindred with the same mutation can exhibit different features
and rates of change (as demonstrated by our two siblings), and
the same is true of sporadic FTD and some tauopathies, one
important question is whether to design clinical trials with
placebo and active drug arms and compare rates of change
by groups (placebo versus active drug), or use crossover
methodology with patients using placebo for one period of
assessment and active drug for another period of assessment,
and then comparing rates of change within each patient. Clearly
more patients will need to be assessed in a standardized
longitudinal manner to optimally develop treatment trial
methodologies appropriate for patients with FTDP-17 and
the sporadic tauopathies. We are hopeful that data such as
we report herein may aid investigators to develop methodology;
many of the cognitive, neuropsychological, neuropsychiatric,
motor and radiological findings discussed in this report are
being assessed in longitudinal FTD study funded by the
National Institute on Aging (RO1 AG23195).
Acknowledgements
This study was supported by grants P50 AG 16574 (Mayo
Alzheimer’s Disease Research Center) P30 AG10133
(Indiana Alzheimer Disease Center) and R01 NS 37431
(J. M.). We thank the staff of the Robert H. and Clarice
Smith and Abigail Van Buren Alzheimer’s Disease Research
Program of the Mayo Foundation, Indiana Alzheimer’s Disease Research Center, University of Wisconsin Departments
of Neurology and Genetics, and Monroe Clinic for assisting
with the collection of data and care of the patients and
families. We also thank Dr David Knopman for his critical
review of this paper. We are particularly grateful to the
patients and their families for participating in this research.
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