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ANA_22448_sm_SuppFigsandTabs.doc4600KSUPPORTING FIGURE (1). Plasma VILIP-1 levels by CDR Category in CNC and AD. Mean (±SE) plasma VILIP-1 levels were significantly elevated in CDR 1 (118 ± 7.6 pg/ml, n=14) compared to PIB-negative CNC (86 ± 2.6 pg/ml, n=72) (p<0.0001) and CDR 0.5 (94 ± 3.6 pg/ml, n=48) (p=0.0038). Mean plasma VILIP-1 levels were higher in CDR 0.5 compared to PIB-negative CNC (p=0.054). The CDR 2 group included only 2 individuals (not shown). One-Way ANOVA with Bonferroni's correction was performed for all group comparisons. SUPPORTING FIGURE (2). Correlations between CSF VILIP-1 and CSF tau, p-tau181, Aβ42, and amyloid load by PET-PIB. CSF VILIP-1 levels correlated with (A) CSF tau (r=0.71, p<0.0001) and (B) p-tau181 (r=0.73, p<0.0001) (n=296) (C) but not Aβ42 (r=0.004, p=0.94) (n=295) levels in the combined (AD and CNC) cohort. CSF VILIP-1 remained significantly correlated with CSF tau in AD (r=0.64) and CNC (r=0.71) (p<0.0001). Similarly, CSF VILIP-1 correlated with CSF p-tau181 in AD (r=0.65) and CNC (r=0.73) (p<0.0001). (D) CSF VILIP-1 levels (r=0.25, p=0.0017) correlated with PET-PIB MCBP in the combined cohort (n=156). CSF VILIP-1 remained correlated with MCBP in CNC (r=0.24, p=0.0053), but not in AD (r=-0.06, p=0.76) when examined separately. (E) CSF VILIP-1 levels (r=0.40, p=0.017) correlated with MCBP in CNC who have evidence of preclinical AD (MCBP>0.18) (n=36). MCBP, mean cortical binding potential. SUPPORTING FIGURE (3). Baseline CSF VILIP-1 and Aβ42 Levels in Converters and Non-converters. (CDR 0, n=164). Individuals who converted from CDR 0 to CDR 0.5 or greater (converters) with a clinical diagnosis of AD are presented as red dots (n=16) while converters with a clinical diagnosis of non-AD dementia or whose cause of cognitive impairment was clinically uncertain are presented as green squares (n=10). Individuals who remained at CDR 0 on follow-up (non-converters) are presented as black dots (n=138). Cut-off values for Aβ42 (500 pg/ml) and VILIP-1 (375 pg/ml) were chosen based on values which provided the highest rates of agreement between CSF biomarker levels and clinical diagnoses (Supplementary Table 1A). The majority of converters whose cause of cognitive impairment was thought to be AD (red dots) fall in the right lower quadrant (corresponding to individuals with CSF VILIP-1 ≥ 375 pg/ml and CSF Aβ42 ≥ 500 pg/ml). SUPPORTING FIGURE (4). VILIP-1 Immunoreactivity in Normal and AD Brain. (A) VILIP-1 immunoreactivity (purple) is detected in the neuronal perikarya, cytoplasmic processes (thick arrows), and neuropil, but not in glial cells (thin arrows) in a normal brain. (B) VILIP-1 immunoreactivity is seen in dystrophic neurites (light blue arrow) surrounding an amyloid plaque (light blue arrowhead) of a study participant with AD pathology. The nuclear stain (Nuclear Fast Red) was used to demonstrate cell nuclei in A and B. (C) (VILIP-1) - reactive dystrophic neurites (purple indicated by the small arrows) are seen surrounding amyloid plaques (red indicated by the large arrow) of a study participant with AD pathology. The 10D5 anti-Aβ antibody and Alkaline Phosphatase Red stain were used to demonstrate Aβ immunoreactivity. (D) Intracellular tau aggregates (red indicated by the large arrow) are seen in the cytoplasm of a (VILIP-1) - reactive neuron (dark purple indicated by the small arrows) of a study participant with AD pathology. (E) VILIP-1 immunoreactivity is detected in a neuron (arrowhead) but not in a nearby GFAP-positive astrocyte (red indicated by arrow) in a normal brain. (F) VILIP-1 immunoreactivity is detected in two neurons (arrowheads) but not in nearby (1BA-1) - immunoreactive microglial cells (red indicated by arrows) in a normal brain. SUPPORTING TABLE (1). (A) Rates of Agreement Between CSF Biomarkers and Clinical Diagnoses. These analyses included cognitively normal controls (CNC) (n=211), individuals with a clinical diagnosis of Alzheimer's disease (AD) (n=98), and individuals with a clinical diagnosis of non-AD dementias (n=19). (B) Rates of Agreement Between CSF Biomarkers and PIB-status. Study participants who underwent PET-PIB (n=156) were categorized by PIB status as PIB-positive (MCBP>0.18) (n=54) or PIB-negative (n=102) irrespective of clinical diagnoses. For each biomarker or ratio, the proposed cut-off value represents the value which provided the maximum rate of agreement with the clinical diagnoses (A and B). SUPPORTING TABLE (2). (A) Demographic, Clinical, and Genotype Characteristics of Individuals with MRI and CSF Measures by Clinical Diagnosis. Individuals with AD who underwent MRI were CDR 0.5 (n=35), CDR 1 (n=6), or CDR 2 (n=2). (B) CSF Biomarker and MRI Measures by Clinical Diagnosis. Differences between CNC and AD were significant for all CSF biomarker and MRI measures with the exception of the pericalcarine volumes (used as a control region). nWBV, normalized whole brain volume;*p<0.05. SUPPORTING TABLE (3). Adjusted Correlations Between CSF Biomarker and MRI Measures in AD. Partial correlations (adjusting for age, gender, and scanner type) of CSF biomarkers and ratios with whole brain and regional atrophy in AD (n=43). The p values are reported in parentheses;*p<0.05. SUPPORTING TABLE (4). Adjusted Correlations Between CSF Biomarker and MRI Measures in AD by CDR category. Partial correlations (adjusting for age, gender, and scanner type) of CSF biomarkers and ratios with whole brain and regional volumes in the (A) CDR 0.5 (n=35) and (B) CDR ≥ 1 (n=8) cohorts. CSF VILIP-1, tau, and tau/Aβ42, but none of the other CSF markers or ratios, negatively correlated with nWBV in the CDR 0.5 cohort. In the cohort studied herein, VILIP-1 was the only CSF marker to demonstrate significant negative correlations with hippocampal and entorhinal volumes. The correlations of tau with hippocampal and entorhinal volumes in the CDR 0.5 cohort approached statistical significance. In the CDR ≥ 1 cohort, CSF VILIP-1, but none of the other CSF markers or ratios, demonstrated strong negative correlations with nWBV, hippocampal, and entorhinal volumes. The p values are reported in parentheses;*p<0.05. SUPPORTING TABLE (5). (A) Adjusted Correlations Between CSF Biomarker and MRI Measures in all CDR Categories (CDR 0-2). Partial correlations (adjusting for age, gender, and scanner type) of CSF biomarkers with whole brain and regional volumes in all CDR categories 0-2 (n=192) are shown. (B) Adjusted Correlations Between CSF Biomarker Measures and MRI Measures in CNC (CDR 0). Partial correlations (adjusting for age, gender, and scanner type) of CSF biomarkers with whole brain and regional volumes in cognitively normal controls (n=149) are shown. The p values are reported in parentheses,*p<0.05.
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