RESEARCH ARTICLEconsensus set of criteria for AD diagnosis in a researchmild clinical symptomatology (Winblad et al., 2006). are required for the diagnosis of probable AD. Thewill have to target a population with a biologicalsignature of the disease together with the presence of
Recently, Dubois and collaborators presented a
memory (regardless of the degree of functional loss)and the presence of at least one abnormal biomarker
strength of these criteria is that they allow earlierdiagnosis of AD: hence the proposal of the termIntroduction
Future modifying treatments for Alzheimers disease(AD) will require earlier diagnosis to optimize theirpotential benefits. Furthermore, in order to show theirefficacy, upcoming trials with disease-modifying drugs
setting. The new AD diagnostic research criteria maysubstantially aid an etiological diagnosis based on abiomarker profile, and may allow this diagnosis to bemade earlier (Dubois et al., 2007). The main changeswith respect to the well-established NINDS-ADRDAcriteria are that only significant impairment in episodicCopyr(AD) patientswere included in the study. PrdAD was defined on the basis of an objective episodicmemory deficit and an AD CSF profile. Structural MRI was performed in all participants.
Results:After FWE correction, voxel-based morphometry (VBM) analysis of PrdAD patients versus CTRshowed significant clusters of decreased gray matter (GM) volume in the left hemisphere regionsincluding the parahippocampal gyrus, uncus, precuneus, and middle frontal gyrus. We did not finddifferences in brain atrophy between PrdAD and mild AD patients. Some significant associations werefound between CSF levels and episodic and semantic fluency tests in the PrdAD group. Correlations inthe PrdAD group revealed that patients with higher scores on delayed free recall had significantly greaterGM volume in the left superior temporal gyrus (t 6.64, p< 0.0001).Conclusions: PrdAD patients presented mainly medial temporal GM atrophy, which was related withsignificant episodic memory impairment. The cognitive deficit observed in PrdAD patients was alsoassociated with CSF biomarker levels. Copyright # 2011 John Wiley & Sons, Ltd.
Key words: Alzheimers disease; magnetic resonance imaging; cognition; mild cognitive impairment; cerebrospinal fluid;amyloid; neuroimage; neuropsychological tests; diagnosis
History: Received 8 October 2010; Accepted 4 January 2011; Published online 7 March 2011 in Wiley Online Library(wileyonlinelibrary.com).DOI: 10.1002/gps.2696Methods/Patients: 76 participants24 controls (CObjective: We describe the neuroimaging characteristics of prodromal AD (PrdAD) patients diagnosedusing the new research criteria in a clinical setting. In order to further characterize these patients, we alsostudy the relationship between neuropsychology, CSF biomarkers and magnetic resonance imaging(MRI) findings.
TR), 20 amnesic patients, and 32 Alzheimers diseaseApplying the new research dand neuropsychological corr
Lorena Rami1, Cristina Sole-Padulles1, Juan Fortea1, BJaume Olives1, Magda Castellv1, David Bartres-Faz3,
1Alzheimers Disease and Other Cognitive Disorders Unit, Neurol2Institut dInvestigacio Biome`dica August Pi i Sunyer (IDIBAPS)3Department de Psiquiatria i Psicobiologia Clinica, Universitat deCorrespondence to: J. Luis Molinuevo, E-mail: firstname.lastname@example.org # 2011 John Wiley & Sons, Ltd.nostic criteria: MRI findingstions of prodromal AD
iz Bosch1, Albert Llado1,2, Anna Antonell1,el Sanchez-Valle1,2 and Jose Luis Molinuevo1,2
ervice, Hospital Clnic, Barcelona, Spain
elona, Barcelona, SpainInt J Geriatr Psychiatry 2012; 27: 127134.
CSF analysis. Subjects underwent LP between 9 and12 am and 10 mL of CSF was collected. The samples
128 L. Rami et al.prodromal, with an evolution from mild cognitivesymptoms into a full-blown dementia. Since thedisease will therefore be diagnosed with minimalsymptomatology, the diagnosis should be supported bythe presence of a positive biomarker profile. Thereforeapplying these criteria will help to diagnose AD in itsprodromal stage. However, some concerns have beenraised about their applicability in a clinical setting.
The main pathological lesions in AD are neurofi-brillary tangles and senile plaques formed by neuronalaccumulations of abnormal tau filaments and extra-cellular deposits of amyloid (AB) fibrils. Cerebrospinalfluid (CSF) studies measuring amyloid 42 (Ab142) andtau protein levels in AD patients with confirmedpathology have demonstrated that abnormal levels ofboth biomarkers constitute a specific signature of theunderlying AD-related pathology (Shaw et al., 2009).CSF studies show an acceptable sensitivity andspecificity to help in the diagnosis of AD (Blennowand Hampel, 2003; Sunderland et al., 2003; Andreasenand Blennow, 2005). In a recent study, individualsdiagnosed as having mild cognitive impairment(MCI) who had pathological concentrations of CSFtau or Ab142 had a 17.7fold increased risk ofprogressing to diagnosed AD during a 5-year period(Hansson et al., 2006). In addition, some studies havefound that biomarker levels can predict the rate ofcognitive decline across time in individuals with verymild dementia (Snider et al., 2009). Recent studies(Fagan et al., 2006, 2007) combining the use of PETamyloid ligands with the determination of CSF Ab142have accurately detected individuals who haveappreciable deposits of neocortical amyloid. Thepresence of a positive CSF profile has been proposedas a criterion for AD diagnosis, and we believe thatapplying these new AD research criteria will probablyallow clinicians to detect very mild AD with highsensitivity and specificity.
Although there were initial concerns about theapplicability of the new research criteria, Bouwmanet al. (2010) recently demonstrated that these criteriapresented good specificity in the clinical setting andallow diagnosis of the disease in the prodromal stage.This non-demented AD population is diagnosedthrough the presence of an isolated memory impair-ment and a positive CSF profile, and is a potentialtarget for upcoming treatments. It is thereforeimportant to characterize these patients clinicallyand via the use of neuroimaging techniques, and tostudy the relations between their neuropsychologicalprofile, CSF biomarker values, and neuroimagingcharacteristics. The aim of this study is to describe theneuroimaging characteristics of prodromal ADCopyright # 2011 John Wiley & Sons, Ltd.were centrifuged and stored within the first hour afterextraction in polypropylene tubes at 80 8C. Levels ofAb142, total tau (t-tau) and phosphorylated tau atthreonine-181 (p-tau) were measured by enzyme-linked immunosorbent assay kits (Innogenetics, Ghent,patients (PrdAD) who meet the new research criteriain a clinical setting. A secondary objective, in order tofurther characterize these patients, is to study therelationship between neuropsychology, CSF biomarkerlevels, and MRI findings.
Seventy-six participants24 controls, 20 amnesicpatients (14 of them considered PrdAD), and 32 ADpatientswere consecutively recruited at the AD andother cognitive disorders unit at the Hospital Clinic,Barcelona. All subjects underwent clinical and neu-ropsychological assessment and magnetic resonanceimaging (MRI). Lumbar puncture (LP) was onlyperformed in patients presenting with an isolatedmemory deficit without dementia. The study wasapproved by the local ethics committee and allparticipants gave written informed consent to partici-pate in the study.
Normal controls (CTR). Healthy elders who presentedno cognitive complaints and no evidence of cognitiveimpairment (below 1.5 standard deviation) on any ofthe neuropsychological tests administered.
Amnesic patients criteria. (i) Presence of an objectiveepisodic memory loss defined through the free andcued selective reminding test (FCSRT) (total recallsubtest) (Grober and Buschke, 1987): (ii) clinicaldementia rating scales (CDR) (Morris, 1993) of 0.5with memory box of 0.5 or 1; (iii) essentially preservedactivities of daily living, measured by the functionalactivities questionnaire (FAQ) (Pfeffer et al., 1982). Allthe amnesic patients presented a FAQ score
All patients included were in the mild stages of the
20 voxels were not considered. In order to examine
groups, two-sample t-tests were carried out and a GMmask was applied in order to eliminate any voxels that
than the other groups, all results were covariated byage. Fourteen of the twenty amnesic patients from our
ances in all episodic and semantic memory measuresthan controls (p< 0.005). Learning list and visual
Prodromal ad diagnosis: MRI and neuropsychology 129possible associations between memory performanceand GM volume in the PrdAD group, we carried outcorrelations between these variables only for this groupof patients using SPM5.
Neuropsychological and functional assessment
Participants were administered a comprehensive 1-hbattery of tests by a trained neuropsychologist. Thebattery included memory, language, praxis, visualdisease (Global Deterioration Scale 4). Two atypicalAD variants (posterior cortical atrophy) with non-significant episodic memory impairment wereexcluded from the study.
MRI acquisition and analysis
A high resolution T1-weighted three-dimensionalmagnetization prepared rapid gradient sequence wasobtained with a 3T SIEMENS MAGNETOM Trio Tim(Siemens, Erlangen, Germany) at the Centre for ImageDiagnosis of the Hospital Clinic (CDIC). Thefollowing parameters were used: 240 sagittal slices;repetition time (TR) 2300 ms; echo time (TE) 2.98 m;slice thickness 1 mm; inversion time (TI) 900; FOV(field of view) 256 mm; matrix size 256 256; flipangle 98. In order to rule out patients with a highload of ischemic damage, a T2-weighted volume (B0)or a 3D flair image sequence, when available, was usedto quantify the rate of cerebrovascular disease. TheFazekas scale was used by a neuroradiologist blind tothe clinical diagnosis and subjects with scores of 3 wereremoved (Fazekas et al., 1987). For the voxel-basedmorphometry (VBM) analysis, 3D images weremanually reoriented along the anterior and posteriorcommissure line, and a unified segmentation was thencarried out using the software SPM5 (statistical para-metric mapping). After segmentation, normalization, andmodulation, gray matter (GM) tissue segments weresmoothed with an 8-mm-full-width at half-maximumGaussian kernel. Initial results obtained at a significance of0.001 uncorrected for voxel level were saved as a mask anda false-discovery rate (FDR) and family-wise error (FWE)correction was applied using this mask in order to controlfor type I error. For the FWE correction, clusters belowBelgium). A positive CSF profile was considered whenAb142 356 or p-tau181> 54 pg/mL (Schoonenboom et al., 2004, 2005).
AD patients. NINCDS-ADRDA criteria were applied.Copyright # 2011 John Wiley & Sons, Ltd.memory from the CERAD battery and M@T scoreswere significantly lower in the AD than in the PrdADpatients (p< 0.001). Semantic verbal fluency(p
3.1 24.5 7.0 97.5 0001.6 22.5 3.3 32.6 000
130 L. Rami et al.Table 1 Clinical and neuropsychological differences among three group
CTR (n24) PrdAD
Mean SD Mean
Age (Years) 71.4 6.6 71.6Education (Years) 9.0 4.7 8.5M@T 45.0 2.9 30.4**MMSE 28.1 1.4 24.8**CERAD_L 18.2 3.8 12.6**CERAD_R 5.4 1.4 1.2**CERAD_Recognition 18.8 1.0 16.0**FCSRT- L 25.0 6.3 8.8**FCSRT - TL 40.6 6.4 18.8**FCSRT R 9.1 2.4 1.7**FCSRT -TR 13.7 2.1 4.3**CERAD_vis_mem 8.5 2.1 3.8**BNT 50.3 6.3 46.8Semantic Fluency 17.5 5.0 13.6*PDT 14.1 0.8 13.7VOSP-letters 19.6 1.5 19.3Poppelreuter 10.0 0.0 10.0CERAD_praxis 9.8 1.4 10.3TMT-A 59.9 21.0 55.5FAS 28.6 10.8 27.2Digit symbol 35.7 20.6 28.5VBM analysis
The VBM comparison of PrdAD patients versus CTRshowed clusters of decreased GM volume in bilateralmedial temporal lobe regions, and in parietal andfrontal areas (Figure 1(A), Table 2). After FWEcorrection, VBM analysis of PrdAD patients versusCTR showed significant clusters of decreased GMvolume in the left hemisphere regions including theparahippocampal gyrus, uncus, precuneus, andmiddle frontal gyrus. Compared with CTR, ADpatients showed several areas of decreased GM volumein bilateral medial temporal lobe regions and avariety of areas encompassing frontal, temporal, andparietal lobes (Figure 1(B), Table 2). When the FWEcorrection was applied, regions that remained signifi-cant were the bilateral parahippocampal gyri, the rightinferior parietal lobule and the left inferior frontalgyrus. Finally, comparison between AD and PrdADpatients did not show significant differences in GMvolume.
CTR, controls; PrdAD, prodromal AD patients; AD, Alzheimers disease; M@T
Neuropsychological Battery of the Consortium to Establish a Registry for Alzheim
total learning; R, recall; TR, total recall; vis_mem, visual memory; BNT, Boston
perception battery; TMT-A, trail making test A; FAS, phonetic verbal fluency.
All post-hoc contrasts between CTR and AD were significant (p< 0.005) excep
*Significant post-hoc contrast (p< 0.05) between CTR and PrdAD.
**Significant post-hoc contrast (p< 0.005) between CTR and PrdAD.Significant post-hoc contrast (p< 0.05) between PrdAD and AD.Significant post-hoc contrast (p< 0.005) between PrdAD and AD.
Copyright # 2011 John Wiley & Sons, Ltd.3.8 7.8 3.9 47.1 0001.1 0.5 0.9 97.0 0003.0 14.9 2.4 19.3 0004.5 6.3 4.0 94.6 0008.0 13.8 8.8 70.0 0001.6 0.7 1.9 105.1 0002.9 2.8 3.4 76.8 0001.9 1.8 2.2 56.8 0004.9 41.9 8.7 5.9 0041.6 10.0 3.4 24.2 0000.7 12.0 1.7 19.1 0001.4 17.3 3.1 7.5 0010 9.6 0.6 6.1 0041.0 9.2 1.9 3.1 n.s
27.4 110.9 47.3 14.3 0007.8 21.0 9.6 4.4 016
10.6 19.6 10.9 6.8 002ntrols, PrdAD and AD)
14) AD (n 32) F p
SD Mean SD
5.3 75.5 5.5 3.8 0.0285.0 8.3 2.9 0.1 n.s
Association between neuropsychological variablesand CSF levels in PrdAD
Some significant correlations were found between CSFlevels and neuropsychological tests. Lower Ab142levels significantly correlated with poorer semanticverbal fluency (r 0.54; p< 0.005). Higher t-tau levelscorrelated with poorer performance on retention listfrom the CERAD battery (r0.487; p< 0.005) andhigher p-tau correlated with poorer performance onthe three memory tests: M@T (r0.521; p< 001),retention list from the CERAD (r0.527;p< 0.001) andtotal free recall from the FCRST (r 0.518; p< 0.005).
Association between neuropsychological variablesand VBM in PrdAD
Correlations between delayed recall measures of theFCSRT and GM volumes in the PrdAD group revealedthat patients with higher scores on delayed free recall
, memory alteration test; MMSE, mini mental state examination; CERAD,
ers Disease; FCSRT, free and cued selective reminding test; L, learning; TL,
naming test; PDT, perceptual digital test; VOSP, visual object and space
t in VOSP-letters, CERAD-Praxis, Poppelreuter and FAS (p< 0.05).
Int J Geriatr Psychiatry 2012; 27: 127134.
had significantly greater GM volume in the leftsuperior temporal gyrus (t 6.64, p< 0.0001). Like-wise, patients with bett...