Background
Methods
Participants
Pre-inclusion assessment
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Pre-inclusion neuropsychological assessment: Autonomy in daily life was assessed using the Clinical Dementia Rating (CDR) scale. Anterograde verbal memory was assessed using the Free and Cued Selective Reminding Test (FCSRT) [22].
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Brain MRI: Brain MRI was performed in all participants using a Philips 3-T imager (Intera Achieva, Philips, Best, The Netherlands). A high-resolution anatomical image, using a three-dimensional (3D) T1-weighted sequence (in-plane resolution 1 × 1 mm, slice thickness 1 mm, 160 contiguous slices) and a T2-weighted sequence (reconstructed resolution 0.45 × 0.45 × 3 mm3, 43 slices) were obtained. Two independent neuroradiologists with extensive experience (FB and RG), blind to clinical information, examined all sequences at inclusion and rated them for both medial temporal lobe atrophy on the 3D T1 sequence using the Scheltens scale [23] and white matter changes on the T2-weighted images using the Fazekas and Schmidt (F&S) scale [24]. Atrophy was assessed for the two hemispheres separately. Inter-rater agreement was estimated by calculating Cohen's kappa coefficient (κ) and its 95% confidence interval (CI).
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FDG-PET scan: Scans were performed on a Biograph 6 TruePoint Hirez (Siemens Medical Solutions, Munich, Germany) hybrid PET/computed tomography (CT) scanner (3D detection mode, producing images with 1 × 1 × 1.5 mm voxels and a spatial resolution of approximately 5 mm full width at half maximum at the field of view center). Cerebral emission scans began 20 min after the injection of 1.85 MBq/kg weight of FDG on average and lasted for 10 min. Both CT and PET scans were acquired. PET data were corrected for partial volume effects. Two independent nuclear medicine physicians with extensive experience in reading FDG-PET scans (PiP and AH), blind to clinical information, examined all FDG-PET scans at inclusion. A three-point scale was used for rating FDG-PET profiles (0 = normal, 1 = temporo-parietal hypometabolism suggestive of AD, 2 = other). Inter-rater agreement was estimated by calculating κ and its 95% CI.
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CSF biomarker sampling: CSF samples were obtained by a lumbar puncture in the patient group. The samples were centrifuged for 10 min at 1,500 rpm at 4°C to remove cells, aliquoted to 0.4-mL samples in polypropylene tubes, and stored at -80°C until analysis. CSF biomarker levels of total tau (T-Tau), phospho-tau (P-Tau), Aβ42, and Aβ40 were measured using a sandwich ELISA method (Innogenetics, Gent, Belgium) according to the manufacturer's instructions. We also calculated ratios derived from single biomarkers, including the Innotest Amyloid Tau Index (IATI), combining Aβ42 and T-Tau concentrations as follows: IATI = Aβ42 / (240 + (1.18 × T-Tau)), and the Aβ42/Aβ40 ratio.
Inclusion criteria
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Scheltens score for medial temporal lobe atrophy >1 in at least one hemisphere for at least one visual rater [23].
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Temporo-parietal hypometabolism pattern on cerebral FDG-PET scan (score = 1 for at least one visual rater).
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Patients with significant white matter T2 hyperintensities (F&S score > 2 for at least one visual rater) were excluded.
Post-inclusion assessment
Neuropsychological assessment
AV-45-PET scan
ApoE alleles
Statistical analysis
Neuropsychological assessment
MRI
FDG- and AV-45-PET global uptake
AV-45 regional uptake values in the cortex only
AV-45 SUVr correlation analyses
Results
Prodromal patients | Control subjects |
p value | |
---|---|---|---|
n
| 22 | 17 | NA |
Age | 72.4 ± 5.0 | 69.9 ± 4.8 | .110 |
Gender | 12 M/10 F | 7 M/10 F | .408 |
Level of education | 11.3 ± 2.7 | 12.8 ± 3.3 | .163 |
Disease duration | 3.8 ± 3.6 | NA | NA |
ApoE genotype | 2 E4/E4 | NA | NA |
9 E3/E4 | |||
5 E3/E3 | |||
3 E2/E3 | |||
Daily-life autonomy | |||
CDR scale | 0.5 ± 0.0 | 0.0 ± 0.0 | <.001* |
Anterograde verbal memory | |||
FCSRT sum of free recalls (/48) | 11.6 ± 5.9 | 32.2 ± 4.6 | <.001* |
FCSRT sum of free + cued recalls (/48) | 28.7 ± 11.9 | 46.6 ± 1.9 | <.001* |
Global cognitive state | |||
MMSE | 25.7 ± 1.4 | 28.4 ± 0.7 | <.001* |
Depression scale | |||
Beck (/39) | 3.0 ± 2.6 | 2.7 ± 2.6 | .666 |
Anxiety scale | |||
Y-A (/80) | 34.3 ± 8.9 | 3.2 ± 6.0 | .830 |
Anterograde visual memory | |||
DMS48 set 1 (/48) | 41.0 ± 6.0 | 46.5 ± 2.0 | .003* |
DMS48 set 2 (/48) | 40.0 ± 7.0 | 45.9 ± 2.2 | .014* |
Rey complex figure memory (/36) | 9.2 ± 6.6 | 19.4 ± 6.1 | .002* |
Semantic memory | |||
Information subtest (WAIS) (/28) | 13.8 ± 5.5 | 20.1 ± 6.2 | .014* |
TOP 12 faces version: global score (/96) | 74.8 ± 6.7 | 84.6 ± 6.0 | .003* |
TOP 12 faces version: naming (/12) | 5.2 ± 3.4 | 9.3 ± 2.2 | .006* |
Short-term memory | |||
WAIS-III digit span: forward | 5.6 ± 1.4 | 5.4 ± 1.0 | 1.763 |
Working memory | |||
WAIS-III digit span: backward | 4.0 ± 1.2 | 4.6 ± 0.9 | .514 |
Language | |||
DO80 (/80) | 78.1 ± 3.8 | 79.4 ± 1.2 | .549 |
Praxies | |||
Rey complex figure copy (/36) | 34.4 ± 1.9 | 34.6 ± 2.0 | 1.258 |
Speed processing | |||
Digit-symbol test (/90) | 34.1 ± 12.6 | 52.8 ± 10.2 | <.001* |
Executive functions | |||
Phonemic verbal fluency: letter (P) | 19.6 ± 8.1 | 22.6 ± 6.1 | .674 |
Semantic verbal fluency: ‘animal’ category | 21.7 ± 7.3 | 31.8 ± 7.4 | .012* |
TMT B time | 170.3 ± 85.3 | 94.1 ± 38.4 | .014* |
Interference time on the Stroop test | 108.1 ± 45.1 | 51.6 ± 31.9 | .002* |
FAB (/18) | 15.1 ± 2.5 | 17.1 ± 0.8 | .098 |
Gnosia | |||
Benton Facial Recognition (/58) | 46.0 ± 3.3 | 48.1 ± 3.5 | .476 |
Fulfillment of the inclusion criteria for prodromal AD
Inter-group comparisons of the inclusion data
Neuropsychological assessment
MRI
FDG-PET
AV-45 imaging
Whole brain profile of AV-45 binding
Regional profile of AV-45 binding
AV-45-PET values | |||
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Patients’ mean SUVr (±sd) | Control subjects’ mean SUVr (±sd) |
p value | |
Global cortex | 1.43 (±.29) | 1.15 (±.08) | .002** |
Orbito-frontal | 1.60 (±.41) | 1.23 (±.16) | .001** |
Anterior cingulate | 1.67 (±.41) | 1.30 (±.16) | .003** |
Posterior cingulate | 1.74 (±.36) | 1.36 (±.14) | .002** |
Precuneus | 1.56 (±.36) | 1.14 (±.09) | .002** |