Original r atypical alzheimer Disease -...

Original research n

Neuroradiology

Radiology: Volume 000: Number 0— 2015 n radiology.rsna.org 1

White Matter Degeneration in atypical alzheimer Disease1

Francesca Caso, MDFederica Agosta, MD, PhDDaniele Mattavelli, MDRaffaella Migliaccio, MD, PhDElisa Canu, PhDGiuseppe Magnani, MDAlessandra Marcone, MDMassimiliano Copetti, PhDMonica Falautano, MDGiancarlo Comi, MDAndrea Falini, MDMassimo Filippi, MD

Purpose: To assess white matter (WM) tract damage in patients with atypical Alzheimer disease (AD), including early-on-set AD (EOAD), logopenic variant of primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA), by using diffusion-tensor magnetic resonance (MR) imaging and to identify similarities and differences across the AD spectrum.

Materials and Methods:

This study was approved by the local ethical committees on human studies, and written informed consent from all subjects was obtained prior to enrollment. WM tract damage and cortical atrophy were assessed by using dif-fusion-tensor MR imaging and voxel-based morphometry, respectively, in 28 patients with EOAD, 12 patients with lvPPA, and 13 patients with PCA relative to age- and sex-matched healthy subjects. Conjunction and interaction analyses were used to define overlapping and syndrome-specific patterns of brain damage.

Results: Patients with EOAD, lvPPA, and PCA shared a com-mon pattern of WM damage that involved the body of the corpus callosum, fornix, and main anterior-posterior pathways (P , .05). They also shared cortical atrophy of the left temporoparietal regions and precuneus (P , .05, family-wise error corrected). Patients with EOAD also had specific damage to the genu and splenium of the corpus callosum and parahippocampal tract bilaterally (P , .05). In all patients with AD, particularly in the two focal forms (lvPPA and PCA), WM damage was more se-vere and widely distributed than expected on the basis of cortical atrophy.

Conclusion: In atypical AD clinical phenotypes, the distribution of WM damage exceeds cortical atrophy and may reflect the pathologic dissemination through structural connections from atrophic to unaffected cortical regions. WM degen-eration may be an early marker of AD pathologic changes in EOAD and focal AD forms.

q RSNA, 2015

Online supplemental material is available for this article.

1 From the Neuroimaging Research Unit (F.C., F.A., D.M., E.C., M. Filippi), Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (G.M., M. Falautano, G.C., M. Filippi), Department of Clinical Neu-rosciences (A.M.), and Department of Neuroradiology and CERMAC (A.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy; INSERM, U1127, Institut du Cerveau et de la Moelle Epinière (ICM), Hôpital de la Pitié-Salpêtrière, Paris, France (R.M.); Department of Neurology, Institut de la Mémoire et de la Maladie d’Alzheimer, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France (R.M.); and Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.). Received December 1, 2014; revision requested January 22, 2015; revision received February 4; accepted February 22; final version accepted February 26. Supported in part by the Italian Ministry of Health (grant GR-2010-2303035). Address correspon-dence to M. Filippi (e-mail: [email protected]).

q RSNA, 2015

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2 radiology.rsna.org n Radiology: Volume 000: Number 0— 2015

NEURORADIOLOGY: White Matter Degeneration in Atypical Alzheimer Disease Caso et al

Alzheimer disease (AD) is not a uni-tary clinical syndrome. Patients with early-onset AD (EOAD; ,65

years of age) can present with multi-domain cognitive impairment at onset (1,2). This cognitive picture is very different from the typical profile of pa-tients with late-onset AD (65 years of age), with progressive memory deficit as the central feature (2,3). In keeping

Implication for Patient Care

n Diffusion tensor MR imaging has the potential to demonstrate early WM damage in patients with atypical forms of AD; thus, it might be a useful tool in clin-ical trials to evaluate pathologic AD progression before it becomes clinically evident.

Advances in Knowledge

n Atypical Alzheimer disease (AD) clinical phenotypes, such as early-onset AD (EOAD), logope-nic variant of primary progres-sive aphasia (lvPPA), and poste-rior cortical atrophy (PCA), shared a common pattern of white matter (WM) damage that involved the body of the corpus callosum, fornix, and main ante-rior-posterior pathways (P , .05) and cortical atrophy of the left temporoparietal regions and precuneus (P , .05).

n The cognitive profile of each group of patients with AD highly reflected the distribution of cor-tical atrophy and the patterns of WM tract damage—indeed, patients with EOAD showed severe and multidomain cognitive impairment with prominent in-volvement of the verbal memory (100% of patients) and visuospa-tial memory (96% of patients), visuospatial abilities (96% of patients), and executive functions (83% of patients); in addition to the typical language deficit pro-file, most patients with lvPPA also had verbal memory (87% of patients) and visuospatial (50% of patients) impairment, and PCA showed prominent deficits of visuospatial abilities, visuospa-tial memory, and praxis (100% of patients).

n In all patients with AD, particu-larly in the two focal forms (lvPPA and PCA), WM damage was more severe and widely dis-tributed than expected on the basis of cortical atrophy.

Published online before print10.1148/radiol.2015142766 Content codes:

Radiology 2015; 000:1–11

Abbreviations:AD = Alzheimer diseaseCSF = cerebrospinal fluidDT = diffusion tensorEOAD = early-onset ADFA = fractional anisotropylvPPA = logopenic variant of primary progressive aphasiaPCA = posterior cortical atrophyWM = white matter

Author contributions:Guarantor of integrity of entire study, M. Filippi; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manu-script revision for important intellectual content, all authors; approval of final version of submitted manuscript, all au-thors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, F.C., F.A., D.M., R.M., E.C., G.M., M.C., M. Falautano, A.F.; clinical studies, R.M., G.M., A.M., M. Falautano; experimen-tal studies, F.C., F.A., R.M., M. Falautano, A.F.; statistical analysis, R.M., E.C., M.C., A.F.; and manuscript editing, F.C., F.A., D.M., R.M., E.C., G.M., M.C., G.C., A.F., M. Filippi

Conflicts of interest are listed at the end of this article.

with the multidomain cognitive deficits, EOAD is associated with a widespread pattern of cortical atrophy, centered around the parietal and lateral tempo-ral lobes, with a relative sparing of the medial temporal structures, which are the most severely damaged regions in typical late-onset AD (4–6).

AD can also manifest as atypical, relatively focal clinical syndromes, more frequently associated with EOAD—that is, as posterior cortical atrophy (PCA) (7,8) and logopenic variant of primary progressive aphasia (lvPPA) (9). PCA demonstrates visual and visuospatial impairment with less prominent mem-ory loss (7,8). Over time, patients with PCA can develop visual agnosia, to-pographical difficulty, optic ataxia, si-multanagnosia, ocular apraxia (Balint syndrome), alexia, acalculia, right-left confusion, agraphia (Gerstmann syndrome), and, later, more general-ized dementia. PCA is associated with main posterior temporal and occipito-parietal brain damage (6) and with an underlying AD disease process (8). Pa-tients with lvPPA present with language deficits characterized by slow rate of speech, with long word-finding pauses. Grammar and articulation are usually preserved in lvPPA, although phono-logical paraphasias could be present. Repetition and comprehension are im-paired for sentences but preserved for single words, and naming is moderately affected (9). In patients with lvPPA, cortical atrophy is usually centered around the left posterior temporopa-rietal region (6,9), and the most com-mon underlying disease process is AD (10,11).

The factors that drive AD clinico-anatomic heterogeneity are not well understood. One possible mechanism

that could explain the involvement of different brain regions in AD variants is the spread of disease via distinct brain networks, such as amyloid b, and tau aggregates may start to accumulate in some vulnerable networks and then propagate transneuronally through white matter (WM) connections, grad-ually reaching unaffected regions from affected ones (12–14). According to this hypothesis, typical AD seems to target and spread through the default mode network (12,15). What happens in atypical AD, like EOAD and focal variants, is still unclear. Investigators in recent neuroimaging studies have suggested that atypical AD forms may reflect a different pathologic dissemi-nation through specific interconnected neural networks (16,17).

Diffusion-tensor (DT) magnetic resonance (MR) imaging is used to measure the effect of tissue microstruc-ture on the random translational motion of water molecules in biologic tissues, and it is highly sensitive to WM micro-structural damage. Despite the growing number of studies that show that severe microstructural abnormalities occur



along WM tracts in late-onset AD be-sides the known loss of neurons in the gray matter, to date, a few DT MR imag-ing studies have demonstrated the WM network involvement in EOAD (4,18), lvPPA (19–21), and PCA (22–24). To our knowledge, no study has been con-ducted to compare the patterns of WM damage in EOAD, lvPPA, and PCA.

The aim of the present study was to explore the distribution of WM tract damage in EOAD, lvPPA, and PCA by using DT MR imaging and to identify similarities and differences across the AD spectrum, also in relation to the patterns of cortical atrophy. We hy-pothesized that all forms would show preferential WM damage of the struc-tural connections linking the key nodes of the default mode network, in addi-tion to the involvement of distinct syn-drome-specific pathways in each phe-notype. We also predicted that in all AD clinical phenotypes, WM damage would not mirror cortical atrophy, thus reflecting the pathologic dissemination from atrophic to unaffected cortical regions.

Materials and Methods

This study was approved by the local ethical committee on human studies, and written informed consent from all subjects was obtained prior to enroll-ment. Subjects were recruited from September 2011 to March 2014.

SubjectsPatients were recruited at the San Raf-faele Scientific Institute. We included patients with a clinical diagnosis of EOAD, lvPPA, or PCA. Clinical diag-noses were based on patients’ history, neurologic examination, and neuropsy-chological testing. The following diag-nostic criteria were applied: the crite-ria and symptom onset data prior to age 65 years for EOAD as developed by McKhann et al (25), the PCA crite-ria of McMonagle et al (26) as modi-fied by Alladi et al (27), and the lvPPA criteria of Gorno-Tempini et al (28). Clinical assessment was performed by experienced neurologists (G.M. and A.M., with 30 years of experience in

clinical neurology) who were blinded to MR imaging results. Recent inter-national criteria suggest that including biomarkers in the diagnostic work-up is likely to enhance the pathophysio-logical specificity of the diagnosis of AD dementia (25,28). For this rea-son, cerebrospinal fluid (CSF) samples were collected via lumbar puncture in the morning, and amyloid b 1–42, total tau values, and phosphorylated tau values were determined by using the Inno-Bia AlzBio3 kit (Fujirebio, Pomezia, Rome). AD-like CSF bio-markers were considered to be low amyloid b values and high tau values (25). In the case of unavailable CSF biomarkers, we included only patients with typical patterns of hypometabo-lism and/or perfusion at fluorodeoxy-glucose positron emission tomography (PET) or single photon emission com-puted tomography (SPECT) scanning. Exclusion criteria were a family history suggestive of an autosomal dominant disease; significant medical illnesses or substance abuse that could interfere with cognitive functioning; any other major systemic, psychiatric, or neuro-logic illnesses; and other causes of fo-cal or diffuse brain damage, including extensive cerebrovascular disorders at routine MR imaging. A total of 57 pa-tients (32 with EOAD, 12 with lvPPA, and 13 with PCA) were screened. Two patients with EOAD were excluded ow-ing to extensive cerebrovascular disor-der, and two patients with EOAD were not able to undergo a complete MR im-aging examination. CSF samples were available from 21 patients with EOAD, nine patients with lvPPA, and 10 pa-tients with PCA, and AD-like CSF bio-markers were found in all cases. The remaining seven patients with EOAD, three patients with lvPPA, and three patients with PCA showed typical pat-terns of hypometabolism and/or per-fusion on fluorodeoxyglucose PET or SPECT images. Fifty-three patients (28 with EOAD, 12 with lvPPA, and 13 with PCA) were included in the study (Table 1). For each patient variant, a group of age- and sex-matched healthy control subjects was selected (24 con-trol subjects for EOAD, 20 control

subjects for lvPPA, and 20 control sub-jects for PCA) (Table 1). Two healthy control subjects were recruited among patients’ spouses, and the others were recruited by word of mouth. Healthy control subjects underwent a multidi-mensional assessment, including neu-rologic assessment and a brief cogni-tive evaluation with mini–mental state examination. All healthy control sub-jects had mini–mental state examina-tion scores of at least 28 of 30.

Cognitive AssessmentAn extensive neuropsychological as-sessment was performed by an expe-rienced neuropsychologist who was blinded to MR imaging findings (M. Falautano., with 20 years of expe-rience in clinical neuropsychology). The cognitive protocol has been de-scribed previously (18) (Table 2). To make results comparable between different groups of patients, raw cogni-tive test scores were transformed into Z scores, and the mean Z score for each cognitive domain was calculated (Table 2). Furthermore, patients with lvPPA performed a comprehensive language and speech battery (Table E1 [online]), and patients with PCA underwent an additional evaluation aimed at investigating dorsal and ven-tral visual symptoms (22) (E.C., with 11 years of experience in clinical neu-ropsychology). For details, see Appen-dix E1 (online).

MR Imaging StudyBy using a 3.0-T MR imaging unit, three-dimensional T1-weighted fast field-echo and DT MR imaging sequences were performed in all individuals. MR im-age analysis was performed by a well-trained observer, who was blinded to the individuals’ identity (F.C., with 3 years of experience in neuroimaging). DT MR image analysis was performed by using tract-based spatial statistics implemented in the Functional MR Im-aging of the Brain, or FMRIB, software library (FMRIB Analysis Group, Oxford, England), or FSL, and cortical atrophy was assessed by using voxel-based mor-phometry in Statistical Parametric Map-ping 8 (SPM8; www.fil.ion.ucl.ac.uk/



Tabl

e 1

Dem

ogra

phic

, Clin

ical

, and

CSF

Par

amet

ers

of P

atie

nts

with

EOA

D, lv

PPA,

and

PCA

and

Age

-mat

ched

Hea

lthy

Cont

rol S

ubje

cts

Para

met

er

Heal

thy

Cont

rol S

ubje

cts

vs P

atie

nts

with

EOA

DHe

alth

y Co

ntro

l Sub

ject

s vs

Pat

ient

s w

ith lv

PPA

Heal

thy

Cont

rol S

ubje

cts

vs P

atie

nts

with

PCA

P Va

lue

for

Com

paris

ons

be

twee

n Gr

oups

†

Heal

thy

Cont

rol

Subj

ects

Patie

nts

with

EOA

DP

Valu

e*He

alth

y Co

ntro

l Su

bjec

tsPa

tient

s w

ith lv

PPA

P Va

lue*

Heal

thy

Cont

rol

Subj

ects

Patie

nts

with

PCA

P Va

lue*

No. o

f pat

ient

s24

28…

2012

…20

13…

…Ag

e at

MR

imag

ing

(y)

59.8

6 1

.9

(5

7–64

)60

.3 6

4.5

(49–

68)

.47

66.0

6 5

.3

(5

9–75

)66

.0 6

9.1

(48–

80)

.74

61.1

6 2

.7

(5

8–67

)61

.8 6

5.9

(55–

77)

.9.0

3 fo

r EOA

D vs

lvPP

A

No. o

f wom

en‡

14 (5

8)14

(50)

.55

13 (6

5)7

(58)

.71

13 (6

5)11

(85)

.22

.03

for E

OAD

vs P

CAEd

ucat

ion

(y)

15.3

6 5

.0

(5

–24)

9.2

6 4

.5 (3

–18)

,.0

114

.4 6

4.0

(8–2

2)12

.2 6

4.1

(5–1

8).1

915

.9 6

4.7

(8–2

4)9.

5 6

3.2

(5–1

3),

.01

NS

Age

at o

nset

(y)

…56

.6 6

6.7

(48–

65)

……

62.6

6 8

.2 (4

6–77

)…

…57

.9 6

6.7

(51–

76)

….0

1 fo

r EOA

D vs

lvPP

A,

.0

5 fo

r PCA

vs

lvPP

ADi

seas

e du

ratio

n (y

from

on

set t

o M

R im

agin

g)…

3.76

2 (0

.6–8

)…

…3.

2 6

2.1

(0.6

–8)

……

3.9

6 2

.3 (1

–11)

…NS

Clin

ical

Dem

entia

Rat

ing

…1.

2 6

0.6

(0.5

–3)

……

0.7

6 0

.4 (0

–1)

……

1.1

6 0

.4 (0

.5–2

)…

.03

for E

OAD

vs lv

PPA

Clin

ical

Dem

entia

Rat

ing

Sum

of B

oxes

…5.

7 6

2.6

(2.5

–12)

……

3.9

6 2

.0 (2

–7)

……

4.9

6 2

.6 (3

–9.5

)…

.04

for E

OAD

vs lv

PPA

CSF

amyl

oid

b p

rote

in

(ng/

L) (n

orm

al v

alue

.

500

)

…31

5 6

121

(98–

571)

……

389

6 1

38

(1

95–6

27)

……

329

6 1

69

(1

50–5

82)

…NS

CSF

t-ta

u (n

g/L)

(nor

mal

va

lue,

0–5

00)

…61

9 6

515

(227

–207

2)…

…69

7 6

83

(313

–106

4)…

…51

0 6

383

(166

–147

5)…

NS

CSF

p-ta

u (n

g/L)

(nor

mal

va

lue,

0–6

1)…

99 6

64

(46–

268)

……

114

6 3

3 (6

4–15

4)…

…79

6 3

4 (3

8–14

8)…

.05

for l

vPPA

vs

PCA

Note

.—Un

less

indi

cate

d ot

herw

ise,

val

ues

are

mea

ns 6

sta

ndar

d de

viat

ions

. Num

bers

in p

aren

thes

es a

re th

e ra

nge.

NS

= n

ot s

igni

fican

t.

* P

valu

es re

fer t

o th

e M

ann-

Whi

tney

U te

st o

r the

Fis

her e

xact

test

(for

pat

ient

sex

onl

y) b

etw

een

each

pat

ient

gro

up v

s ag

e-m

atch

ed h

ealth

y co

ntro

l sub

ject

s.† P

val

ues

refe

r to

the

Man

n-W

hitn

ey U

test

or t

he F

ishe

r exa

ct te

st (f

or p

atie

nt s

ex o

nly)

bet

wee

n pa

tient

gro

ups.

‡ Num

bers

in p

aren

thes

es a

re p

erce

ntag

es.



Table 2

Neuropsychological Features of Patients with EOAD, lvPPA, and PCA

Parameter EOAD lvPPA PCA P Value*

Mini–mental state examination (cutoff = 24)

19.8 6 4.1 (85.7) 22.1 6 5.7 (54.5) 15.9 6 5.3 (92.3) .01 for PCA vs lvPPA

Digit span forward (cutoff = 3.75) 4.42 6 0.95 (23.1) 3.80 6 1.66 (40) 4.38 6 1.12 (38.5) …Rey list immediate recall (cutoff = 28.53) 22.0 6 10.08 (71.4) 27.33 6 15.53 (33.3) 23.00 6 4.18 (80) …Rey list delayed recall (cutoff = 4.69) 1.29 6 1.70 (100) 6.67 6 3.21 (33.3) 2.60 6 1.82 (80) …Prose memory (cutoff = 8) 2.24 6 2.23 (95.2) 3.38 6 2.05 (87.5) 2.28 6 2.27 (88.9) …Verbal memory domain 22.0 6 0.7 21.8 6 0.9 21.8 6 0.6 NS Spatial span (cutoff = 3.75) 2.53 6 1.18 (82.3) 3.00 6 1.33 (50) 0.86 6 1.07 (100) … Rey figure recall (cutoff = 9.47) 1.92 6 2.46 (96) 8.15 6 3.76 (50) … …Visuospatial memory domain† 22.4 6 0.8 (24.3; 20.8) 21.7 6 1.1 (23.9; 20.7) 24.9 6 1.4 (26.1; 23.4) ,.001 for PCA vs EOAD,

,.001 for PCA vs lvPPA Rey figure copy (cutoff = 28.88) 10.52 6 9.31 (95.8) 24.67 6 5.3 (77.8) 0.446 0.77 (100) … Clock-drawing test (cutoff , 8) 2.00 6 3.24 (94.4) 5.50 6 3.34 (37.5) 0.13 6 0.35 (100) …Visuospatial domain† 25.6 6 2.4 (29.3; 20.7) 22.0 6 1.7 (25.7; 0.0) 27.0 6 1.0 (28.4; 25.7) ,.001 for EOAD vs lvPPA,

,.001 for PCA vs lvPPA Phonemic fluency (cutoff = 17) 16.54 6 9.50 (53.8) 13.27 6 7.90 (45.4) 17.69 6 10.69 (38.5) … Semantic fluency (cutoff = 25) 19.50 6 9.77 (65.4) 19.64 6 10.92 (54.5) 16.316 8.02 (76.9) …Fluency domain† 21.8 6 0.9 (23.4; 0.5) 21.6 6 1.0 (23.0; 1.0) 21.6 6 0.9 (22.6; 0.3) NS Raven Colored Progressive Matrices

(cutoff = 18)13.466 7.29 (60.9) 21.75 6 8.70 (33.3) 3.67 6 4.59 (100) …

Attentive matrices (cutoff = 31) 27.46 6 11.93 (69.2) 31.20 6 9.35 (60) 8.29 6 7.80 (100) … Digit span backward (cutoff = 3.29) 2.67 6 0.82 (83.3) 2.00 6 0 (100) 2.33 6 0.58 (66.7) … Trail Making Test (B-A) (cutoff = 186) 282.75 6 266.62 (37.5) 156.0 6 60.37 (0) … …Executive domain† 22.9 6 1.3 (25.4; 20.4) 21.5 6 1.3 (23.7; 0.6) 23.7 6 1.4 (25.5; 21.3) .02 for EOAD vs lvPPA,

.001 for PCA vs lvPPA Right ideomotor apraxia (cutoff = 13) 12.60 6 5.12 (60) 14.88 6 6.13 (25) 4.50 6 3.08 (100) … Left ideomotor apraxia (cutoff = 13) 12.60 6 5.14 (60) 13.63 6 5.93 (37.5) 3.83 6 3.76 (100) …Praxic domain† 217.3 6 12.1 (236.6; 0.3) 213.46 14.2 (242.5; 0.3) 237.4 6 7.7 (247.3; 229.4) .01 for PCA vs EOAD,

.003 for PCA vs lvPPA

Note.—Unless indicated otherwise, values are means 6 standard deviations, with the percentage of patients with abnormal test scores compared with the normative data of reference in parentheses. NS = not significant.

* Mini–mental state examination and Z scores were compared between groups by using the analysis of variance model, followed by pairwise comparisons with Bonferroni correction.† Numbers in parentheses are ranges.

spm/software/spm8) (18). For details, see Appendix E1 (online).

Statistical AnalysisStatistical analysis was conducted by M.C., with 6 years of experience in biostatistics.

WM damage.—DT MR imaging vox-elwise statistical analysis was performed to compare mean diffusivity, fractional anisotropy (FA), axial diffusivity, and radial diffusivity between groups by us-ing a permutation-based inference tool for nonparametric statistical threshold-ing (“randomise,” part of FSL) (29). The number of permutations was set at 5000 (29). Analyses were adjusted for

individual age. The resulting statistical maps were thresholded at a P value less than .05, family-wise error corrected for multiple comparisons at the cluster level by using the threshold-free cluster enhancement option (30).

Two WM atlases within FSL (http://fsl.fmrib.ox.ac.uk/fsl/data/atlas-descriptions.html), the Johns Hopkins University WM tractogra-phy atlas (http://fsl.fmrib.ox.ac.uk/fsl/data/atlas-descriptions.html), and the ICBM DTI WM labels atlas (http://www.loni.usc.edu/ICBM/Downloads/Downloads_DTI-81.shtml) were used to guide the identification of WM tracts of interest: the body, genu, and splenium

of the corpus callosum; fornix; cingu-lum; parahippocampal tract; external capsule; anterior inferior fronto-occip-ital fasciculus and uncinate fasciculus; posterior part of the inferior fronto-oc-cipital fasciculus and inferior longitudi-nal fasciculus; superior longitudinal fas-ciculus; and medial parietal WM. WM tracts of interest were overlaid onto the mean FA image of each individual and masked with the WM skeleton. For each subject, mean FA and mean diffusivity values were derived for each WM tract bilaterally. By using SAS re-lease 9.1 software (SAS Institute, Cary, NC), normal distribution assumption was checked by means of Q-Q plot and



Shapiro-Wilk and Kolmogorov-Smirnov tests. FA and mean diffusivity values were compared between groups by us-ing analysis of covariance models, fol-lowed by pairwise comparisons (SAS release 9.1; SAS Institute). A conjunc-tion analysis was performed to identify the overlapping components of the WM damage among AD syndromes, and interaction analyses were conducted to define the patterns of WM damage specific to each AD variant (SAS re-lease 9.1; SAS Institute). To account for the two different DT MR imaging sequences, we used a linear mixed-ef-fects model with random intercepts for sequence covariates. All analyses were adjusted for age. The analyses were repeated by also adjusting for years of education.

Cortical atrophy.—In SPM8, linear contrasts were performed to identify patterns of cortical atrophy in patients with each syndrome versus age-matched healthy control subjects. A conjunction analysis was conducted to identify re-gions of common atrophy across the AD variants. To investigate regions of atrophy specific to each AD syndrome compared with the others, the relevant linear contrast (eg, less in patients with PCA than in healthy control subjects) was inclusively masked with the appro-priate contrast between that syndrome and the other two (eg, less in patients with PCA than in patients with EOAD and lvPPA), as described previously (6). All analyses were adjusted for total intracranial volume and age, and results were tested at a P value less than .05, family-wise error corrected for mul-tiple comparisons. The analyses were repeated by also adjusting for years of education.

Results

Cognitive FindingsPatients with EOAD showed severe and multidomain cognitive impairment with prominent involvement of the verbal and visuospatial memory, visuospatial abilities, and executive functions (Table 2). In addition to the typical language deficit profile (Table E1 [online]), most

patients with lvPPA also presented with verbal memory and visuospatial impair-ment. PCA showed prominent deficits of visuospatial abilities, visuospatial memory, and praxis. Patients with lvP-PA were the least cognitively impaired group, compared with the others (Table 2). Patients with PCA performed worse than those with lvPPA and EOAD in praxis and visuospatial memory do-mains and performed lower than those with lvPPA in visuospatial and executive tasks (Table 2). Patients with EOAD scored lower on visuospatial and execu-tive tests relative to patients with lvPPA (Table 2).

Table E1 (online) shows the language test scores obtained in pa-tients with lvPPA and highlights def-icits in sentence repetition, naming, and syntactic comprehension, whereas object knowledge and single-word com-prehension were relatively spared. Al-most all patients with PCA showed ven-tral symptoms, such as visual agnosia (92%), prosopagnosia (69%), or alexia (85%). Among ventral symptoms, si-multagnosia was detected in 15% of patients. A minority of patients with PCA also showed dorsal signs, such as optic ataxia (38%), oculomotor apraxia (31%), and neglect (23%). Simultagno-sia (often resulting from both ventral and dorsal stream impairment) was de-tected in 15% of patients. Gerstmann syndrome signs were common in the PCA group, including left-right disori-entation (31% of patients), dysgraphia (77%), calculation difficulties (54%), and finger agnosia (85%).

WM DamagePatients with each syndrome versus matched healthy control subjects.—Patients with EOAD compared with control subjects showed a distributed and symmetric pattern of FA decrease and mean diffusivity, axial diffusivity, and radial diffusivity increases in the corpus callosum and most association WM tracts, including the fornix, cingu-lum, parahippocampal tract, superior longitudinal fasciculus, inferior longitu-dinal fasciculus, inferior fronto-occip-ital fasciculus, and uncinate fasciculus (P , .05, family-wise error corrected;

Figs 1, 2; Figs E1, E2 [online]). Patients with EOAD relative to healthy control subjects showed DT MR imaging alter-ations in the brainstem, involving the cerebral peduncles and middle and in-ferior cerebellar peduncles bilaterally (P , .05, family-wise error corrected; Figs E1, E2 [online]).

Compared with control subjects, patients with lvPPA showed a left-lateralized FA decrease in the corpus callosum, cingulum, fornix, parahippo-campal tract, and dorsal frontoparietal pathways, including the superior longi-tudinal fasciculus (P , .05, family-wise error corrected; Figs 1, 2; Figs E1, E2 [online]). In the right hemisphere, pa-tients with lvPPA showed only a small area of FA decrease in the frontal WM (P , .05, family-wise error corrected; Fig 1). The pattern of increased mean diffusivity, axial diffusivity, and radial diffusivity was more distributed and extended to the left external and inter-nal capsules and the same regions of the right hemisphere (P , .05, family-wise error corrected; Fig 2; Figs E1, E2 [online]).

Compared with control subjects, patients with PCA showed a distrib-uted and symmetrical pattern of FA de-crease, as well as axial diffusivity and radial diffusivity increases in the corpus callosum, parahippocampal tracts, and posterior part of the cingulum, superior longitudinal fasciculus, inferior longitu-dinal fasciculus, and inferior fronto-occipital fasciculus (P , .05, family-wise error corrected; Fig 1; Figs E1, E2 [online]). The pattern of increased mean diffusivity extended to the frontal regions, although a decreasing gradient from posterior to anterior was present (P , .05, family-wise error corrected; Fig 2).

Overlapping and specific patterns of WM damage across the AD variants.—Figures 1 and 2 show the overlapping patterns of FA decrease and mean dif-fusivity increase among AD variants in the left corpus callosum, frontopari-etal, and parietotemporal connections. Tables E2 and E3 (online) show the mean FA and mean diffusivity values of the main WM tracts in patients and control subjects. The conjunction



Figure 1

Figure 1: Axial (left six columns) and sagittal (right column) MR images of FA results in patients with AD variants relative to matched healthy control subjects. Patients with A, EOAD, B, lvPPA, and C, PCA have decreased FA compared with that in age-matched healthy control subjects. D, The overlapping pattern of decreased FA among the AD variants is shown. Voxelwise group differences are shown in red. Results are overlaid on the axial and sagittal sections of the Montreal Neurologic Institute standard brain in neurologic convention (the left side appears on the left) and displayed at a P value less than .05, family-wise error corrected for multiple comparisons. The WM skeleton is green. L = left, R = right.

analysis demonstrated that patients with EOAD, lvPPA, and PCA shared DT MR imaging abnormalities of the body of the corpus callosum, fornix, right cingulum, left superior longitudinal fas-ciculus, and external capsule bilaterally (P , .05). In addition to this common pattern, the interaction analysis showed that patients with EOAD experienced additional damage to the genu and splenium of the corpus callosum and parahippocampal tract bilaterally (P , .05; Tables E2 and E3 [online]). There were no additional regions of damage specific to patients with lvPPA or PCA relative to the other two groups. All the results described herein did not change when years of education were added as covariates in the statistical design.

Cortical AtrophyVoxel-based morphometry results of patient groups relative to healthy con-trol subjects are shown in Figure E3 (online) (P , .05, family-wise error corrected). The severity and regional distribution of cortical atrophy in each AD variant were consistent with those reported previously (4–6,18). Briefly, patients with EOAD showed a wide-spread pattern of gray matter atrophy, involving mainly the medial and lateral parietal, temporal, and occipital lobes, extending bilaterally to the frontal re-gions. Patients with lvPPA showed a focal, left-lateralized atrophy of the temporoparietal junction and hippo-campus. In PCA, cortical atrophy was localized in the bilateral occipital lobes;

temporal regions, including the hippo-campus; and medial and lateral parietal cortices, with smaller regions of atro-phy in the frontal cortex bilaterally.

Overlapping and specific patterns of gray matter atrophy in AD variants were in line with our previous report (6) (Fig 3). Patients with EOAD, lvP-PA, and PCA shared left-sided areas of cortical atrophy, including the pre-cuneus, inferior parietal regions, and lateral temporal cortex (P , .05, fam-ily-wise error corrected). Cortical at-rophy specific to EOAD included the right hippocampus, parahippocampal cortex, and precuneus (P , .05, fam-ily-wise error corrected). The lvPPA-specific cortical atrophy occurred in the left middle temporal gyrus (P ,



.05, family-wise error corrected). Cor-tical atrophy specific to PCA included the inferior and middle occipital gyri, fusiform and lingual gyri bilaterally, left calcarine cortex, and small regions in the right lateral temporal and parie-tal cortices (P , .05, family-wise error corrected). All the results described herein did not change when years of education were added as covariates in the statistical design.

Discussion

EOAD, lvPPA, and PCA offer an ideal framework for exploring AD pathologic changes in terms of altered brain cor-tical and WM networks. In this study, we used DT MR imaging to compare

the patterns of WM tract damage in these patients. We also explored the distribution of cortical atrophy by us-ing voxel-based morphometry. We found that all patients shared a com-mon pattern of WM damage involv-ing the corpus callosum and the main anterior-posterior pathways. When we looked at the commonly altered cortical regions, we found that the three groups shared a pattern of atrophy, including the left temporoparietal regions and precuneus, in agreement with previous studies (6,31). More importantly, we demonstrated that the microstructural WM damage is more severe and more widely distributed than expected on the basis of cortical atrophy in all clinical phenotypes studied.

The cognitive profile of each group of patients highly reflects the distribution of cortical atrophy and the patterns of WM tract damage. In EOAD, brain damage was severe and diffuse, in keeping with the multido-main cognitive dysfunction. Compared with lvPPA and PCA and consistent with the anterior brain damage, pa-tients with EOAD were more impaired in executive tasks consistently with their anterior brain damage and had greater memory deficits in agreement with their more severe involvement of the medial temporal and parietal cor-tices, splenium of the corpus callosum, and parahippocampal tracts. Patients with PCA, who are characterized by poor performance in visuospatial tests,

Figure 2

Figure 2: Axial (left six columns) and sagittal (right column) MR images of mean diffusivity results in patients with AD variants relative to matched healthy control subjects. Increased mean diffusivity is shown in patients with A, EOAD, B, lvPPA, and C, PCA compared with age-matched healthy control subjects. D, The overlapping pattern of increased mean diffusivity among the AD variants is shown. Voxelwise group differences are shown in blue. Results are overlaid on the sagittal and axial sections of the Montreal Neurologic Institute standard brain in neurologic convention (the left side appears on the left) and displayed at a P value less than .05, family-wise error corrected for multiple com-parisons. The WM skeleton is green. L = left, R = right.



Figure 3

Figure 3: MR images of A, common and B, syndrome-specific patterns of cortical atrophy across the AD variants. A, Voxel-based morphom-etry results show the common pattern of cortical atrophy in patients with EOAD, lvPPA, and PCA, displayed in yellow to red. B, Voxel-based morphometry results show regions of specific cortical atrophy in each AD group: The EOAD-specific pattern is displayed in red, the lvPPA-spe-cific pattern is displayed in blue, and the PCA-specific pattern is displayed in green. Results are overlaid on the coronal (left two columns), axial (middle two columns), and sagittal (right two columns) sections of the Montreal Neurologic Institute standard brain in neurologic convention (the right side appears on the right) and displayed at a P value less than .05, family-wise error corrected for multiple comparisons. GM = gray matter, L = left, R = right.

showed a severe and diffuse pattern of cortical atrophy, but this was more centered around bilateral occipitopari-etal regions. We also found that fibers connecting the occipital cortices with temporal and frontal regions, particu-larly on the right side, were those with more severe DT MR imaging abnormal-ities in patients with PCA. Patients with lvPPA showed highly asymmetric brain damage on the left side of the brain to posterior temporal and parietal regions and superior longitudinal fasciculus and inferior fronto-occipital fasciculus and uncinate involvement, in agreement with their typical language deficits.

The most important finding of the present study is that WM damage was more severe and more widely distrib-uted than expected on the basis of cor-tical atrophy and the cognitive profiles, particularly in the atypical AD forms in which cortical atrophy remains

localized and the clinical symptoms rel-atively focal. Together with the few pre-vious studies in which WM damage was assessed in separate series of EOAD (4,18), PCA (22–24), and lvPPA (19–21), our findings indicate that DT MR imaging may be able to demonstrate subtle abnormalities along WM path-ways that link atrophic regions with still unaffected gray matter regions. More importantly, we found that DT MR im-aging has the potential to allow assess-ment of the extensive disorganization of brain networks in focal AD, even before overt cognitive deficits become apparent.

To date, the causes of WM degen-eration in AD are still unknown. In mild cognitive impairment and healthy subjects, WM damage can be detected even before the development of cortical atrophy and overt dementia (32,33). Converging data support the notion

that WM damage has a central role in how the disease strikes and progresses. A series of recent studies has provided evidence for prion-like mechanisms of pathologic transmission of amyloid b and tau aggregates in AD from neuron to neuron along WM connections (14). We recently proposed (34) that microg-lia activation in the presence of amyloid b in excess produces neurotoxic and ol-igodendrotoxic oligomers that, through WM tract damage, spread disease to neighboring and connected areas.

Within this framework, the WM damage we observed in patients with EOAD, lvPPA, and PCA may be inter-preted as a result of the disease spread-ing through structural connections. The discrepancy we found between cortical atrophy and WM damage, together with the anatomic distribution of our find-ings, may suggest that the disease has targeted specific peripheral networks



(memory, visual, language) at onset and then converged to medial and dorsal frontoparietal regions—that is, the key hubs of the default mode network. The spread would occur through the corpus callosum and the main long-range WM fibers between the posterior and ante-rior brain regions, as suggested by our DT MR imaging findings. This model is also consistent with recent resting-state functional MR imaging findings (17). However, in the absence of longitudinal data to show otherwise, another inter-pretation might be that the primary le-sion of AD is in the WM and that the cortical atrophy results from secondary amyloid and tau involvement of the var-ious cortical areas, as hypothesized pre-viously (35).

The main caveat of this study is its cross-sectional nature. Another limita-tion is the relatively small number of patients included, which, however, is in line with previous studies (6,20) and reflects the rarity of atypical AD forms. In addition, language and high visual functioning tests were performed only in patients with lvPPA and PCA, respec-tively. Future studies that include larger patient populations will need to be con-ducted to investigate the relationship between brain damage and specific cog-nitive deficits.

In conclusion, our study indicates that WM degeneration may be an early marker of AD pathologic changes in EOAD and atypical AD forms, preced-ing gray matter atrophy. Our findings also suggest that the clinical heteroge-neity of AD may be related to the fact that the disease process starts from different medial temporal or lateral neocortical hubs and then eventually progresses along the same WM net-work to converge to a similar pattern of involvement, matching the brain areas that are included in the default mode network. Longitudinal studies of patients with EOAD, lvPPA, and PCA in the early and/or prodromic stages of disease, by using more sophisticated statistical models such as generalized linear mixed models, are now warrant-ed to confirm our model and elucidate the direction of the disease spreading in AD.

Disclosures of Conflicts of Interest: F.C. dis-closed no relevant relationships. F.A. Activities related to the present article: disclosed no rel-evant relationships. Activities not related to the present article: author received payment from Excemed and Biogen Idec. Other relationships: disclosed no relevant relationships. D.M. dis-closed no relevant relationships. R.M. disclosed no relevant relationships. E.C. disclosed no relevant relationships. G.M. disclosed no rele-vant relationships. A.M. disclosed no relevant relationships. M.C. disclosed no relevant rela-tionships. M. Falautano disclosed no relevant relationships. G.C. disclosed no relevant rela-tionships. G.C. Activities related to the present article: disclosed no relevant relationships. Ac-tivities not related to the present article: author received payment from Novartis, Teva, Sanofi, Genzyme, Merck, Biogen, Bayer, Excemed, Serono Symposia International Foundation, Almirall, Chugai, and Receptos. Other relation-ships: disclosed no relevant relationships. A.F. disclosed no relevant relationships. M. Filippi Activities related to the present article: dis-closed no relevant relationships. Activities not related to the present article: author received payment from Bayer Schering Pharma, Biogen Idec, Merck Serono, and Teva Pharmaceutical Industries for consulting and/or speaking; in-stitution received grants from Bayer Schering Pharma, Biogen Idec, Merck Serono, and Teva Pharmaceutical Industries. Other relationships: disclosed no relevant relationships.

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