Original Research Article

Dement Geriatr Cogn Disord 2009;28:130–135 Accepted: June 27, 2009

Published online: August 18, 2009
DOI: 10.1159/000235575

Revisiting Brain Reserve Hypothesis

in Frontotemporal Dementia:
Evidence from a Brain Perfusion Study
B. Borroni a E. Premi a C. Agosti a A. Alberici a V. Garibotto d G. Bellelli b
B. Paghera c S. Lucchini c R. Giubbini c D. Perani d A. Padovani a
a
Centre for Aging Brain and Dementia, Department of Neurology, University of Brescia, b Alzheimer Disease
Rehabilitation Unit, Cremona Hospital and Geriatric Research Group, and c Nuclear Medicine Unit, Brescia Hospital,
Brescia, and d Division of Neuroscience, Scientific Institute San Raffaele, Vita-Salute San Raffaele University,
Milan, Italy

Key Words
Frontotemporal lobar degeneration ⴢ Behavioral variant
frontotemporal dementia ⴢ Education ⴢ Occupation ⴢ
Leisure activities ⴢ Brain reserve hypothesis ⴢ SPECT
Abstract
Background: Literature data on Alzheimer’s disease suggest
that years of schooling and occupational level are associated
with a reserve mechanism. No data on patients with behav-
ioral variant frontotemporal dementia (bvFTD) are available
yet. Objective: To evaluate the impact of education, occupa-
tion, and midlife leisure activities on brain reserve in bvFTD.
Methods: Fifty-four bvFTD patients entered the study and
underwent neuropsychological and behavioral assessment,
including the FTD-modified Clinical Dementia Rating for
FTD (FTD-modified CDR), and SPECT imaging. We tested for
the linear correlation of educational and occupational level,
and midlife leisure activities with regional cerebral blood
flow (rCBF), controlling for demographic variables (age and
gender) and for cognitive performance (FTD-modified CDR)
(statistical parametric mapping). Results: A significant rela-
tionship between higher educational and occupational at-
tainments and lower rCBF in medial frontal cortex and dor-
solateral frontal cortex, bilaterally, was found (p ! 0.005).
When midlife leisure activities were considered, no correla-
tion was found. The correlation between a reserve index, ac-
counting for both educational and occupational level, and
rCBF showed the same pattern of hypoperfusion. Conclu-
sions: This study suggests that education and occupation
act as proxies for reserve capacity in bvFTD. These lifestyle
attainments may counteract the onset of this genetic-based
disease in at-risk individuals. Copyright © 2009 S. Karger AG, Basel
Introduction
The brain reserve hypothesis posits that there are in-
dividual differences in the ability to cope with brain pa-
thology, and that brain damage extent and clinical symp-
toms are not tightly linked [1].
Greater brain reserve arises through either difference
in brain anatomy, such as a greater synapse density or neu-
ron counts, or by more efficient or flexible use of brain
networks, resulting in greater ability to sustain brain dam-
age without observable deficits in brain functions [2].
Identification of factors associated with the ability to
tolerate the accumulation of brain pathology has impor-
tant implications for neurodegenerative disease preven-
tion. It has been demonstrated that high premorbid intel-
ligence, education, occupational attainment, and an ac-

© 2009 S. Karger AG, Basel Barbara Borroni, MD

1420–8008/09/0282–0130$26.00/0 Clinica Neurologica, Università degli Studi di Brescia
Fax +41 61 306 12 34 Pza Spedali Civili, 1
E-Mail karger@karger.ch Accessible online at: IT–25100 Brescia (Italy)
www.karger.com www.karger.com/dem Tel. +39 03 0399 5632, Fax +39 03 0399 5027, E-Mail bborroni@inwind.it
tive lifestyle provide reserve capacity against the effects of
aging and disease on brain function, decreasing the risk
of incident dementia [1, 3]. This is in line with studies
showing that up to 25% of individuals who fulfill the neu-
ropathological criteria for Alzheimer’s disease (AD) at au-
topsy remain cognitively spared during life. Accordingly,
the finding that higher education and occupational at-
tainments can somehow counterbalance AD pathology
has been widely demonstrated by neuroimaging studies.
These works have shown an inverse relationship between
the level of education and occupation and in vivo proxies
of AD pathological process, i.e. regional metabolic rate of
glucose utilization or regional blood flow (rCBF), after
adjusting for dementia severity [5–9]. Higher educational
and occupational attainment was related to greater hypo-
metabolism in the temporo-parietal lobes and precuneus,
brain areas specifically affected by the disease. More re-
cently, the brain reserve hypothesis was also supported in
pre-clinical AD, higher education and occupation level
delaying the clinical expression of dementia [9].
It has been demonstrated that educational levels are
higher in frontotemporal dementia (FTD) as compared
to AD [10]; no other previous work but Perneczky et al.
[11] have explored the brain reserve correlates in a small
sample of patients with FTD.
FTD is the second commonest cause of young-onset
dementia and no treatments affecting disease progression
are available yet [12]. Furthermore, no protective factors
which might delay disease onset are currently known.
With these caveats in mind, we tested the brain reserve
hypothesis in FTD patients by evaluating how the 3 proxy
measures of brain reserve (education, occupation, and
midlife leisure activities) might influence the clinical ex-
pression (as measured by neuropsychological and behav-
ioral assessments) of brain pathology (as reflected by
rCBF changes).
Methods
Study Sample
A total of 54 patients, fulfilling the clinical picture of behav-
ioral variant FTD (bvFTD) according to current clinical criteria
[13, 14] and undergoing brain functional imaging study, were
consecutively enrolled at the Centre for Aging Brain and Neuro-
degenerative Disorders, Department of Neurology, University of
Brescia, Italy, from January 2001 to December 2007.
All subjects underwent a somatic and neurological evaluation,
and routine laboratory examination, a brain structural imaging
study, and a brain functional single photon emission tomography
(SPECT) study.
The diagnostic assessment involved a review of full medical
history, a semi-structured neurological examination, and a com-
Education and Occupation in FTD
plete mental status evaluation by 2 independent and experienced
reviewers (B.B., C.A.). Only patients with full consensus agree-
ment by the reviewers and followed-up for at least 1 year from the
diagnosis were enrolled.
Demographic characteristics, years of education, occupation
and leisure activities were carefully recorded. Years of education
were defined as the number of completed years of formal educa-
tion, including university or apprenticeship (only when formal
education was associated). Occupational attainment was rated ac-
cording to the general project protocol, as previously published
[9], with a score ranging from 0 to 4, corresponding to the last
employment of each subject: (0) no occupation; (1) unskilled la-
borer, housewife; (2) skilled laborer, tradesman, lower-level civil
servant, employee, self-employed small business, office or sales
person; (3) mid-level civil servant or management, head of a small
business, academician or specialist in a subordinate position; (4)
senior civil servant or management, senior academic position,
self-employed with high degree of responsibility.
Leisure activities during midlife were also assessed (by A.A.),
as previously proposed by Scarmeas et al. [15]. A participation in
13 activities was carefully recorded: (1) knitting or music or other
hobby; (2) walking for pleasure or excursion; (3) visiting friends
or relatives; (4) being visited by relatives or friends; (5) physical
conditioning; (6) going to movies or restaurants or sporting
events; (7) reading magazines or newspapers or books; (8) watch-
ing television or listening to the radio; (9) doing unpaid commu-
nity volunteer work; (10) playing cards or games; (11) going to a
club or center; (12) going to classes; (13) going to church or syna-
gogue or temple. One point was given for participation to each of
the above activities and an aggregate score was assigned to each
patient for the subsequent analysis (range 0–13).
All participants were made fully aware of the research goals,
and the signature of an informed consent was required from all
subjects. The work was conducted in accordance with Brescia
Hospital clinical research regulations and in conformity with the
Declaration of Helsinki.
Exclusion Criteria
Stringent exclusion criteria were applied as follows: (a) cere-
brovascular disorders, previous stroke, hydrocephalus, and intra-
cranial mass documented by MRI; (b) a history of traumatic brain
injury or another neurological disease; (c) another neurodegen-
erative syndrome associated with dementia or belonging to the
frontotemporal lobar degeneration spectrum (e.g. semantic de-
mentia, progressive nonfluent aphasia, corticobasal degeneration
syndrome, frontotemporal dementia with motor neuron disease)
according to current clinical criteria; (d) monogenic causes of
FTD (e.g. microtubule-associated protein tau or progranulin mu-
tations); (e) significant medical problems (e.g. poorly controlled
diabetes or hypertension; cancer within the past 5 years; clini-
cally significant hepatic, renal, cardiac, or pulmonary disorders);
(f) major depressive disorder, bipolar disorder, schizophrenia,
substance abuse disorder, or mental retardation according to cri-
teria of the Diagnostic and Statistical Manual of Mental Disorders
4th edition [DSM-IV reference].
Cognitive, Behavioral and Functional Assessment at
Enrolment
At first evaluation, global cognitive function assessment was
made according to a standardized battery, including the Mini-
Dement Geriatr Cogn Disord 2009;28:130–135 131
Mental State Examination [16]. The neuropsychological assess- Table 1. Demographic and clinical characteristics of the included
ment was made with tests tapping the different cognitive do- patients according to gender
mains. The Instrumental Activities of Daily Living [17] and Basic
Activities of Daily Living [18] were assessed as well. Behavioral Variable bvFTD bvFTD bvFTD
and psychiatric disturbances were evaluated by the Neuropsychi- overall female male
atry Inventory [19] and the Frontal Behavioral Inventory [20]. To
assess dementia severity, the newly introduced FTD-modified Patients (%) 54 (100) 32 (59.3) 22 (40.7)
Clinical Dementia Rating (FTD-modified CDR) was computed, Age, years 65.487.4 65.388.1 66.086.6
as it includes executive dysfunction and behavioral disturbance Age at onset, years 63.587.6 63.288.7 64.086.0
evaluation [21]. FTD-modified CDR score was calculated by sum- FTD-modified CDR 4.784.0 4.884.1 4.783.9
ming the individual box scores [21]. MMSE 22.285.1 22.484.3 21.886.2
BADL lost 0.4181.0 0.2880.8 0.6081.1
Image Acquisition, Pre-Processing and Analysis IADL lost 1.482.0 1.782.2 1.181.6
Patients with bvFTD were administered an intravenous injec- FBI 16.3811.9 15.6811.7 17.3812.5
tion of 1110 MBq 99mTc-ethylcysteinate dimer (ECD) (Neurolite, NPI 16.4812.7 16.6811.3 16.3813.8
Bristol-Myers Squibb Pharma, Boston, Mass., USA) in a rest con-
dition, and were imaged using a dual-head rotating gamma cam- MMSE = Mini-Mental State Examination; BADL = Basic Ac-
era (VG MILLENIUM GE) fitted with a low-energy, high-reso- tivities of Daily Living; IADL = Instrumental Activities of Daily
lution collimator, 30 min after intravenous injection of 99mTc- Living; FBI = Frontal Behavioral Inventory; NPI = Neuropsychi-
ECD, as previously described [22]. atric Inventory.
Statistical parametric mapping (SPM2, Welcome Department
of Cognitive Neurology, University College, London), and Matlab
6.1 (Mathworks Inc., Sherborn, Mass., USA) were used for image
pre-processing [23]. Images were spatially normalized to a refer-
ence stereotactic template (Montreal Neurological Institute, Can- The overall group showed a mild disease severity, as
ada), and smoothed by a Gaussian kernel of 8 ! 8 ! 8 mm full- measured by the FTD-modified CDR [4.7 8 3.9 (range
width at half maximum. SPECT data analysis was performed in
blind to clinical data. 0.5–19)].
We conducted a regression analysis to evaluate the role
Statistical Analysis of education, occupation and leisure activities on brain
We calculated 3 multiple linear regression analyses across all reserve. Education and occupation scores were signifi-
subjects group, considering years of education, level of occupation, cantly related; the higher the education levels, the higher
or leisure activities as independent variables, and rCBF as the de-
pendent variable. In the analysis design, we also included 3 covari- the occupational attainment (Spearman’s ␳ = 0.493, p =
ates of no interest: dementia severity as measured by FTD-modi- 0.001).
fied CDR and demographic variables, i.e. age and gender. This sta- As shown in table 2, the correlation analysis showed a
tistical design allowed us to test for a correlation between education, significant relationship between higher education and
occupation, or leisure activities and rCBF, after excluding the ef- lower rCBF in the medial frontal cortex and in the dor-
fect of all covariates of no interest on brain perfusion variance.
Findings meeting a threshold of p ! 0.005, uncorrected, were con- solateral frontal cortex, bilaterally (see fig. 1a).
sidered significant. The extension threshold was set at 50 voxels. A significant relationship was also present between
In order to evaluate the combined effect of more than 1 reserve higher occupation attainment and lower rCBF in the me-
proxies on rCBF, we created indicator variables [reserve indexes dial frontal cortex and in the left dorsolateral frontal cor-
(RI)], as the pairwise sum of the two-rank transformation of all tex (table 2, fig. 1b). As the evaluation of occupation on
significant variables, in order to give equal weight to each contri-
bution (SPSS 16.0 software package for Windows, SPSS Inc., Chi- brain reserve might be affected by a floor effect, we re-run
cago, Ill., USA). the analyses using the dichotomous variable for occupa-
tion (subgrouping FTD patients according to the median
value). This approach allowed us to bypass the problem of
Results the linearity and minimize the effect of the skewed distri-
bution of occupation scores. Using dichotomous occupa-
Demographic and clinical characteristics of the in- tion as an independent variable (and adjusting for age, gen-
cluded bvFTD patients who underwent SPECT scan (n = der, and FTD-modified CDR), the results obtained were
54) are shown in table 1. comparable to those with the 5-point occupation scale.
The mean educational level in bvFTD patients was 6.4 When midlife leisure activities were considered in the
8 2.8 (range 4–19), the mean occupational level was 1.46 linear regression analysis, no correlation was found.
8 0.77 (range 1–4), and the mean leisure activity score We tested also the effect of a higher RI, accounting for
was 5.4 8 2.3 (range 1–10). both education and occupational level. We did not con-

132 Dement Geriatr Cogn Disord 2009;28:130–135 Borroni et al.

 Table 2. Results of the linear regression analysis between regional brain perfusion and education, occupation,
or RI in bvFTD, indicating the areas where higher reserve proxies correlate with lower brain perfusion

Region x y z T p Cluster size

Education
Medial frontal cortex 4 48 54 4.57 <0.001 913
20 26 –10 3.08 0.002 347
R dorsolateral frontal cortex 32 44 22 3.35 0.001 1,050
L dorsolateral frontal cortex –30 72 0 3.88 <0.001 647
Occupation
Medial frontal cortex 4 48 56 4.22 <0.001 391
–6 6 –12 3.61 <0.001 1,448
Anterior cingulate cortex –11 37 8 3.04 0.002 397
L dorsolateral frontal cortex –30 –4 24 3.79 <0.001 390
RI
Medial frontal cortex 6 48 56 5.08 <0.001 1,224
2 76 –4 4.79 <0.001 1,666
R dorsolateral frontal cortex 18 –4 30 3.52 <0.001 2,110
L dorsolateral frontal cortex –28 66 26 4.15 <0.001 574
R medial temporal cortex 46 0 –30 3.34 <0.001 1,187

Talairach coordinates of significant voxels, at threshold p < 0.005, are shown.

R = Right hemisphere; L = left hemisphere.

sider leisure activities in computing RI, because they did
not significantly correlate with rCBF.
We found a significant association between higher RI
and lower regional brain perfusion in the same brain re-
gions identified by education and occupation separately
(table 2, fig. 1c).
To test whether reserve variables are affected by brain
pathology, we subgrouped patients according to the FTD-
modified CDR scores (median values, low vs. high FTD-
modified CDR). The association between education, oc-
cupation, and RI and lower regional brain perfusion was
greater in patients with lower FTD-modified CDR scores
compared to higher scores, presumably a floor effect: as
the neuropathological process progresses, the effect of
proxies decreases (data not shown).
Discussion
In the present study, we found an inverse association
between educational and occupational attainments and
the rCBF in medial and dorsolateral frontal cortex in
FTD patients; a higher RI, accounting for both education
and occupation levels, was associated to a broader pattern
of rCBF found in those brain regions, characterized by
the disease pathology.
When the midlife leisure activities were considered,
they were not found to affect rCBF.
These results suggest that in FTD, environmental fac-
tors may have an influence on mechanisms by which pa-
thology is translated into clinical symptoms, and that ed-
ucation and occupation may help to delay the onset of
dementia symptoms, by allowing to use compensatory
networks that enable to cope better with brain damage.
Overall present data are consistent with the brain re-
serve hypothesis, which implies that people with more
years of schooling and higher occupational attainment
have greater reserve capacity, and that greater pathologi-
cal changes are needed for dementia to be manifest [1, 2].
The protective effect may reflect processing mechanisms
learned as a byproduct of educational and occupational
experiences or may serve as proxies of innate differences
to use brain networks [1].
The brain reserve hypothesis has been largely explored
in AD, providing a wide body of evidence and demon-
strating that cognitive reserve takes part in the same brain
regions where AD pathology is most often found [3–8].
Recently, a brain [18F]-fluorodeoxyglucose positron emis-
sion tomography study performed on a large sample of
242 patients with AD, 72 with mild cognitive impairment,
and 144 healthy controls, further confirmed that educa-
tion and occupation may be proxies for brain functional

Education and Occupation in FTD Dement Geriatr Cogn Disord 2009;28:130–135 133

Fig. 1. Brain hypoperfusion and correlation with proxies for re-
serve in bvFTD. a The statistical parametric map of the voxels
showing a correlation between rCBF and education, and the 3D
Amira visualization of significant clusters superimposed on a
standard MRI template (Amira, Mercury Computer System;
Chelmsford, Mass., USA). b The statistical parametric map of the
voxels showing a correlation between brain perfusion and occu-
pation, and the 3D Amira visualization of significant clusters su-
reserve, reducing the severity and delaying the clinical ex-
pression of AD pathology, and that functional reserve is
already at play in the predementia phase of AD [9].
Educational level was found to play a different role in
FTD and AD, with the role of educational level being sig-
nificantly higher in FTD as compared to AD [10]. Addi-
tionally, in this functional neuroimaging study we dem-
onstrated that in FTD patients, a similar protective factor
134 Dement Geriatr Cogn Disord 2009;28:130–135
Color version available online
R
perimposed on a standard MRI template. c The statistical para-
metric map of the voxels showing a correlation between brain
perfusion and RI, and the 3D Amira visualization of significant
clusters superimposed on a standard MRI template. In bvFTD,
higher reserve proxies (a–c, education and/or occupation) corre-
late with lower rCBF in medial frontal cortex and dorsolateral
frontal cortex, bilaterally (see text for details). Threshold set at
p ! 0.005. R indicates right side in the figure.
is exerted by the 2 proxies of reserve as measured by RI,
acting on the brain substrates specifically involved in the
disease. In bvFTD patients, higher occupational attain-
ment primarily affects the mesial frontal cortex and the
anterior cingulate cortex, whilst the protective effect of
education accounts for a recruitment of the dorsolateral
frontal cortex, bilaterally. This latter finding is in agree-
ment with the observation by Perneczky et al. [11] that
Borroni et al.
found a negative association between years of schooling
and bilateral inferior frontal cortex in 29 FTD patients;
further studies are needed to single out whether these dif-
ferences are specific.
Some limitations should be acknowledged. Our vari-
ables fail to capture all dimensions of mental stimulation;
however, a larger sample group and a more detailed eval-
uation of physical and leisure activities should be further
analyzed to confirm our negative results. Indeed, we con-
sidered leisure activities during midlife, but without con-
sidering the time and the degree of exposure, whilst oc-
cupation and education are more easily measured. Final-
ly, the differences in brain reserve in FTD individuals
could also result from genetic background or from health-
ier lifestyle associated with higher education.
No protective factors are known in FTD. We claimed
that bvFTD patients with a greater brain reserve, as re-
flected in amount of educational and occupational at-
tainment, can withstand a greater amount of brain dam-
age without delaying the dementia onset. Thus, it might
be argued that in FTD, which has been largely considered
a genetic-based disease, environmental modifiable fac-
tors might play a crucial role in affecting disease course,
and this could represent a target for interventions in pub-
lic health politics.
Acknowledgements
The authors wish to thank patients and their families for par-
ticipating in the study. This work was supported by a grant of the
Centro Universitario Disturbi del Comportamento e Malattie
Neurodegenerative, Ente Universitario Lombardia Orientale.

References
1 Stern Y: Cognitive reserve and Alzheimer
disease. Alzheimer Dis Assoc Disord 2006;
20:112–117.
2 Roe CM, Xiong C, Miller JP, Morris JC: Edu-
cation and Alzheimer disease without de-
mentia: support for the cognitive reserve hy-
pothesis. Neurology 2007;68:223–228.
3 Fratiglioni L, Wang HX: Brain reserve hy-
pothesis in dementia. J Alzheimers Dis 2007;
12:11–22.
4 Price JL, Morris JC: Tangles and plaques in
nondemented aging and pre-clinical Alz-
heimer’s disease. Ann Neurol 1999; 45: 358–
368.
5 Alexander GE, Furey ML, Grady CL, Pietrini
P, Brady DR, Mentis MJ, Schapiro MB: As-
sociation of premorbid intellectual function
with cerebral metabolism in Alzheimer’s
disease: implications for the cognitive re-
serve hypothesis. Am J Psychiatry 1997;154:
165–172.
6 Scarmeas N, Zarahn E, Anderson KE, Hilton
J, Flynn J, Van Heertum RL, Sackeim HA,
Stern Y: Association of life activities with ce-
rebral blood flow in Alzheimer disease: im-
plications for the cognitive reserve hypoth-
esis. Arch Neurol 2003;60:359–365.
7 Perneczky R, Drzezga A, Diehl-Schmid J,
Schmid G, Wohlschlager A, Kars S, Grimmer
T, Wagenpfeil S, Monsch A, Kurtz A: School-
ing mediates brain reserve in Alzheimer’s
disease: findings of fluoro-deoxy-glucose-
positron emission tomography. J Neurol
Neurosurg Psychiatry 2006;77:1060–1063.
8 Kemppainen NM, Aalto S, Karrasch M,
Nagren K, Savisto N, Oikonen V, Viitanen
M, Parkkola R, Rinnie JO: Cognitive reserve
hypothesis: Pittsburgh Compound B and
fluorodeoxyglucose positron emission to-
mography in relation to education in mild
Alzheimer’s disease. Ann Neurol 2008; 63:
112–118.
9 Garibotto V, Borroni B, Kalbe E, Herholz K,
Salmon E Holtoff V, Sorbi S, Cappa SF, Pado-
vani A, Fazio F, Perani D: Education and oc-
cupation as proxies for reserve in aMCI con-
verters and AD: FDG-PET evidence. Neu-
rology 2008; 71:1342–139.
10 Borroni B, Alberici A, Agosti C, Premi E, Pa-
dovani A: Education plays a different role in
frontotemporal dementia and Alzheimer’s
disease. Int J Geriatr Psychiatry 2008; 23:
796–800.
11 Perneczky R, Diehl-Schmid J, Drzezga A,
Kurz A: Brain reserve capacity in frontotem-
poral dementia: a voxel-based 18F-FDG PET
study. Eur J Nucl Med Mol Imaging 2007;34:
1082–1087.
12 Vossel KA, Miller BL: New approaches to the
treatment of frontotemporal lobar degenera-
tion. Curr Opin Neurol 2008;21:708–716.
13 Neary D, Snowden JS, Gustafson L, Passant
U, Stuss D, Black S, Freedman M, Kertesz A,
Robert PH, Albert M, Boone K, Miller BL,
Cummings J, Benson DF: Frontotemporal
lobar degeneration: a consensus on clinical
diagnostic criteria. Neurology 1998; 51:
1546–1554.
14 McKhann GM, Albert MS, Grossman M,
Miller B, Dickson D, Trojanowski JQ, Work
Group on Frontotemporal Dementia and
Pick’s Disease: Clinical and pathological di-
agnosis of frontotemporal dementia: report
of the Work Group on Frontotemporal De-
mentia and Pick’s Disease. Arch Neurol
2001;58:1803–1809.
15 Scarmeas N, Levy G, Tang MX, Manly J,
Stern Y: Influence of leisure activity on the
incidence of Alzheimer’s disease. Neurology
2001;57:2236–2242.
16 Folstein MF, Folstein SE, McHugh PR: ‘Mini-
Mental State’: a practical method for grading
the cognitive state of patients for the clini-
cian. J Psychiatr Res 1975;12:189–198.
17 Lawton MP, Broody EM: Assessment of old-
er people: self-maintaining and instrumen-
tal activities of daily living. Gerontologist
1969;9:179–186.
18 Sheikh K, Smith DS, Meade TW, Goldenberg
E, Brennan PJ, Kinsella G: Repeatability and
validity of a modified activities of daily liv-
ing (ADL) index in studies of chronic dis-
ability. Int Rehabil Med 1979;1:51–58.
19 Cummings JL, Mega M, Gray K, Rosenberg-
Thompson S, Carusi DA, Gornbein J: The
Neuropsychiatric Inventory: comprehensive
assessment of psychopathology in dementia.
Neurology 1994;44:2308–2314.
20 Kertesz A, Nadkarni N, Davidson W, Thom-
as AW: The Frontal Behavioral Inventory in
the differential diagnosis of frontotemporal
dementia. J Int Neuropsychol Soc 2000; 6:
460–468.
21 Knopman DS, Kramer JH, Boeve BF, Caselli
RJ, Graff-Radford NR, Mendez MF, Miller
BL, Marcaldo N: Development of methodol-
ogy for conducting clinical trials in fronto-
temporal lobar degeneration. Brain 2008;
131(Pt 11):2957–2968.
22 Borroni B, Grassi M, Agosti C, Paghera B,
Alberici A, Di Luca M, Perani D, Padovani A:
Latent profile analysis in frontotemporal lo-
bar degeneration and related disorders: clin-
ical presentation and SPECT functional cor-
relates. BMC Neurol 2007;7:9.
23 Friston KJ, Holmes AP, Worsley KJ, Poline
JB, Frith CD, Frackowiack RSJ: Analysis of
fMRI time-series revisited. Neuroimage
1995;2:45–53.

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