Participants
We used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). Principal Investigator Michael W. Weiner, MD, established the ADNI in 2003 as a public-private partnership. The primary aim of ADNI is to see whether serial MRI, PET, other biological imaging modalities, as well as clinical and neuropsychological tests, could be used to monitor MCI and early AD progression. In the current cross-sectional study, we included 461 patients which were diagnosed with MCI based on criteria (23, 24), with all required data, such as plasma p-Tau181 measurements and MRI processed, available at the baseline visit (adni.loni.usc.edu).. Of 461 participants with MCI, 248 (53.8%) were men and 213 (46.2%) were women with overall mean age 71.47 7.17. Mean AD Assessment Scale (ADAS)-11 and ADAS-13 scores of the participants were 8.79 4.47 and 14.06 6.78, respectively. Average FDG-PET of the angular, temporal, and posterior cingulate in our study group is ranged from 0.73 to 1.70. The mean MMSE (Mini-mental state examination) score of the study sample was 28.17 1.68. Baseline demographics with details are presented in Table 1.
Plasma p-Tau181 measurements
Plasma p-Tau181 was measured using the Single Molecule Array (Simoa) technique, by an in-house assay developed at the University of Gothenburg, Sweden, that uses a combination of two monoclonal antibodies (Tau12 and AT270) and measures N-terminal to mid-domain forms of P-tau181. The procedure is outlined in detail in (adni.loni.usc.edu).
MRI processing
Cortical reconstruction and volumetric segmentation using the FreeSurfer image analysis suite are freely available for download (http://surfer.nmr.mgh.harvard.edu/). Processing of images includes averaging of volumetric T1 weighted images and motion correction (25), using a procedure to remove non-brain tissue (26), automated Talairach transformation, intensity normalization, tessellation of the boundary between gray matter and white matter, automated topology correlation, and optimally placing the border between gray and white matter and gray matter and CSF.
The ADNI-GO clinical dataset and scans from the University of Southern California's Laboratory of Neuroimaging (LONI) data repository were used in this research (http://adni.loni.ucla.edu/). The image used in ADNI FreeSurfer is a T1 weighted image. An accelerated and non-accelerated T1 weighted images are acquired in ADNI-GO for each subject. Images are pre-processed at Mayo Clinic. Processing consisted of three main steps. The first step, autorecon-1, initiates motion correction, non-uniform intensity, Talairach transform computation, and intensity normalization skull strip. The Autoreckon-2 performs the creation of the white-matter and pial surfaces and segmentation of the gray and white matter. The autorecon-3 creates the cortical parcellation. The procedure is defined in detail at ADNI.
Cognitive measurements
The Mini-Mental State Examination (MMSE) is a 30-point questionnaire used in medicine to test for dementia and evaluate cognitive decline and thinking ability (27). Simple questions in some areas of the MMSE exam, such as repeating lists of words, language use and comprehension, and basic motor skills, are included (28). In the MMSE, scores of more than 24 indicate normal cognition, while scores of less than 9 indicate significant cognitive impairment. Additional information can be found on the oxford medical education website.
CSF Biomarkers assessments
CSF biomarkers were assessed by the electrochemiluminescence immunoassays (ECLIA) Elecsys beta-amyloid1-42 CSF, phosphorylated Tau (181p) CSF, and Total-Tau CSF on an automated Elecsys cobas e 601 instrument. These immunoassays are available only for investigational uses. Analyses were performed in 36 runs, and each sample runs one time for the CSF biomarkers mentioned above. The analyte was ranging from the lower technical limit to the upper technical limit for each biomarker. Lower and upper limits were 200 to 1700 pg/mL for ABETA, 80 to 1300 pg/mL for t-tau, and 8 to 120pg/mL for CSF p Tau, respectively. Results with higher values than the upper limit are stated as “>” and results with lower values than the lower limit are stated as “<”.
APOE genotyping
APOE ε4 genotyping was performed on collected blood samples by ADNI. Subjects with at least one allele considered positive. More details about the procedure are described: http://adni.loni.usc.edu/methods/documents/.
Statistical analysis
We used SPSS16 for data analysis. First, we implement a partial correlation model for assessing the relation between demographical variables, including age, APOE genotyping, MMSE score, FDG-PET, and sex with each other. Next, to measure the relationship between all biomarkers, we used a partial correlation adjusted for age, sex, and APOE genotype. In the last partial correlation, models adjusted for age, sex, and APOE genotype were used to assess the correlation between CSF or plasma biomarkers with brain structural changes. We added each biomarker and structural values, including thickness, cortical and subcortical volume, and surface area, separately as variables in correlation models. We used the bootstrapping method set at 0.05 for significant results for address type I error due to multiple comparisons.