PMC:8275828 / 13220-27626
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/8275828","sourcedb":"PMC","sourceid":"8275828","source_url":"https://www.ncbi.nlm.nih.gov/pmc/8275828","text":"Results\n\nSubject Characteristics\nCharacteristics of all 47 subjects are reported in Table 1. By design, all subjects were ≥98 years old with an average age at death of 102.2 (2.5) years old. Eighty-nine percent were Caucasian and 89% were female. Subjects who did not finish high school accounted for 51%. Seventy percent were institutionalized at the visit closest to death. Body mass index (BMI) was 22.1 (3.9) kg/m2 on average, excluding one double amputee whose BMI could not be calculated. Approximately half of the subjects had hypertension (53%) while only 3 subjects had diabetes (6%). In terms of medication and supplement uses, while no subjects took cholesterol-lowering medication, the majority of subjects used at least one form of dietary supplements (72%). Twelve subjects, ten of whom had dementia, could not provide data on history of smoking and alcohol use through recall. Among those with available data, 86% never smoked and 60% never used alcohol. Only one subject was an active smoker at death.\nTable 1 Subject characteristics.\nCharacteristic All subjects (n = 47) GDS 1-3 (n = 23) GDS 4–7 (n = 24) P-valuea\nAge in years, mean (SD) 102.2 (2.5) 102.2 (2.3) 102.2 (2.8) 0.946\nFemale, n (%) 42 (89%) 19 (83%) 23 (96%) 0.188\nRace, n (%) 0.348\n Caucasian 42 (89%) 22 (96%) 20 (83%)\n Black 5 (11%) 1 (4%) 4 (17%)\nBMI in kg/m2, mean (SD)b 22.1 (3.9) 23.1 (3.5) 21.0 (4.0) 0.067\nHypertension, n (%) 25 (53%) 12 (52%) 13 (54%) 1\nDiabetes, n (%) 3 (6%) 2 (9%) 1 (4%) 0.609\nEducation, n (%) 0.204\n \u003c High school 23 (51%) 9 (39%) 14 (64%)\n High school 12 (27%) 7 (30%) 5 (23%)\n \u003e High school 10 (22%) 7 (30%) 3 (14%)\n No data 2 0 2\nLiving, n (%) 0.212\n Community dwelling 14 (30%) 9 (39%) 5 (21%)\n Institutionalized 33 (70%) 14 (61%) 19 (79%)\nDietary supplement use, n (%) 34 (72%) 14 (61%) 20 (83%) 0.111\nMedications, n (%)\n Antidepressants 14 (30%) 4 (17%) 10 (42%) 0.111\n Antipsychotics 5 (12%) 1 (4%) 4 (17%) 0.348\n Anti-inflammatory medications 5 (12%) 4 (17%) 1 (4%) 0.188\n Antithrombotics 10 (21%) 5 (22%) 5 (21%) 1\n Antibiotics 7 (15%) 2 (9%) 5 (21%) 0.416\nSmoking, n (%) 0.570\n Never 30 (86%) 18 (86%) 12 (86%)\n Past 4 (11%) 3 (14%) 1 (7%)\n Present 1 (3%) 0 (0%) 1 (7%)\n No data 12 2 10\nAlcohol use, n (%) 0.041\n Never 21 (60%) 9 (43%) 12 (86%)\n Past 6 (17%) 5 (24%) 1 (7%)\n Present 8 (23%) 7 (33%) 1 (7%)\n No data 12 2 10\nAPOE, n (%)c\n ε2 allele carrier 8 (17%) 3 (13%) 5 (21%) 0.701\n ε4 allele carrier 8 (17%) 3 (13%) 5 (21%) 0.701\na Comparisons between subjects whose Global Deterioration Scale (GDS) = 1–3 (non-demented) and GDS = 4–7 (demented) using Student's t-test for continuous variables and Fisher's exact test for categorical variables.\nb Body mass index (BMI) cannot be calculated for a double amputee whose GDS = 5.\nc All subjects who carried an ε2 or ε4 allele were ε2/ε3 or ε3/ε4 except one subject with GDS = 4 who was an ε2/ε4. Subject characteristics between non-demented (n = 23) and demented (n = 24) subjects, as assessed by the GDS, were not statistically different, except that BMI in non-demented subjects was marginally higher than that in demented subjects [23.1 (3.5) vs. 21.0 (3.5) kg/m2, p = 0.067] (Table 1). Although higher proportion of subjects without dementia reported a history of alcohol use (p = 0.041), the data were only available for only 58% of demented participants.\n\nNutrient Concentrations in FC and TC, and Establishing NPs\nConcentrations of nutrients averaged from the FC and TC are reported in Table 2 (vitamin K only from FC). These data have also been previously reported separately for FC and TC (27, 31, 40). Lutein was the most predominant carotenoid in all FC and TC tissues with a concentration of 79.50 (52.57) pmol/g. On the contrary, lycopene, at an average concentration of 20.41 (21.38) pmol/g, was not detected in both FC and TC in 20 subjects (43% of all subjects). Retinol, which included both free retinol, retinal, and retinyl esters before hydrolyzation during lipid extraction, had a concentration of 691.97 (305.56) pmol/g. Concentrations of α-TP and γ-TP were 66,917 (13,676) and 1,742 (1,018) pmol/g, respectively. While MK-4 was detectable in all brain tissues at 4.96 (2.32) pmol/g, PK was not detected in 17 subjects (38%). The predominant class of FA in the brain samples was SFA, which accounted for 15.36 (2.30) nmol/mg or 47.93 (1.68) mol%. Concentrations of individual FAs are shown in Supplementary Table 2. Docosahexaenoic acid (DHA, 22:6 n-3) and arachidonic acid (AA, 20:4 n-6) were the most predominant n-3 PUFA (11.90 (1.60) mol% or 90.22% of total n-3 PUFAs) and n-6 PUFA (8.54 (0.57) mol% or 66.36% of total n-6 PUFAs), respectively, in all brain tissues. Concentrations of each nutrient were not significantly different among demented and demented subjects. However, total trans-FA concentration was significantly higher among demented subjects (p = 0.020).\nTable 2 Mean (SD) of nutrient concentrations averaged from the frontal and temporal cortices (vitamin K only in the frontal cortex).\nNutrient All subjects (n = 47) GDS 1–3 (n = 23) GDS 4-7 (n = 24) P-valuea\nCarotenoids (pmol/g)\nLutein 79.50 (52.57) 76.34 (43.72) 82.52 (60.65) 0.828\nZeaxanthin 26.97 (12.73) 28.36 (14.06) 25.63 (11.44) 0.404\nCryptoxanthin (α+β) 62.06 (67.97) 57.15 (47.61) 66.76 (83.81) 0.787\nβ-Carotene 55.86 (35.56) 46.22 (24.20) 65.09 (42.27) 0.130\nLycopene 20.41 (21.38) 21.63 (21.57) 19.25 (21.59) 0.901\nRetinol (pmol/g) 691.97 (305.56) 674.11 (286.94) 709.10 (327.65) 0.688\nVitamin E (pmol/g)\nα-Tocopherol 66,917 (13,676) 68,303 (13,732) 65,588 (13,782) 0.526\nγ-Tocopherol 1,742 (1,018) 1,891 (1,049) 1,600 (989) 0.208\nVitamin K (pmol/g) b\nPhylloquinone 0.40 (0.39) 0.35 (0.42) 0.45 (0.36) 0.276\nMenaquinone-4 4.96 (2.32) 5.05 (2.82) 4.88 (1.82) 0.772\nFatty acid (nmol/mg)\nTotal SFA 15.36 (2.30) 15.04 (2.40) 15.66 (2.21) 0.333\nTotal MUFA 7.00 (2.41) 6.83 (1.93) 7.17 (2.83) 0.723\nTotal n-3 PUFA 4.20 (0.67) 4.11 (0.73) 4.29 (0.60) 0.321\nTotal n-6 PUFA 5.53 (1.26) 5.41 (1.04) 5.63 (1.45) 0.569\nTotal trans-FA 0.25 (0.09) 0.22 (0.06) 0.28 (0.10) 0.020\na Comparisons between Global Deterioration Scale (GDS) 1–3 and GDS 4–7 using Student's t-test. Log (x+1) transformation was applied prior to comparisons.\nb Brain tissue from two subjects was not available for vitamin K measures.\nSFA, saturated fatty acid; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; trans-FA, trans-fatty acid. As shown in Figure 1, significant correlations were identified among concentrations of carotenoids, and among FAs (blue represents positive and red represents negative correlations). For others that also reached statistical significance, lycopene was also positively correlated with γ-TP (r = 0.32, p = 0.027) and negatively correlated with vitamin A (r = −0.49, p \u003c 0.001), while α-TP was positively correlated with PK (r = 0.46, p = 0.002) and negatively associated with total trans-FAs (r = −0.32, p = 0.030). MK-4, but not PK, was also associated with FA concentrations including total SFA (r = 0.45, p = 0.002), n-3 PUFA (r = 0.52, p \u003c 0.001), and n-6 PUFA (r = 0.34, p = 0.023). These correlations among nutrient concentrations further warranted the investigation of nutrients as NPs.\nFigure 1 Heat map of Pearson's correlation coefficients of concentrations of carotenoids, retinol, tocopherols, phylloquinone, menaquinone-4, and fatty acids averaged from frontal and temporal cortices (except vitamin K only in the frontal cortex, n = 47, *p \u003c 0.05). Log transformation has been applied to all nutrient concentrations. SFA, saturated fatty acid; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; trans-FA, trans-fatty acid. Next, PCA was used to derive NPs from brain nutrient concentrations. The first five NPs that explain the highest variance (each of which had an eigenvalue \u003e1.0) among the 47 subjects are described in Table 3. No obvious outlier was detected in a PCA plot (data not shown). NP1 which has the highest variance accounted for 26.20% of the total variance. NP1 is described as higher concentrations of SFAs, MUFAs, and n-3 and n-6 PUFAs (all loading coefficients \u003e0.40). NP2 is described by high concentrations of carotenoids (all loading coefficients ≥0.30), and NP3 is described by high concentrations of retinol, α-TP, and PK (all loading coefficients ≥0.40). The correlations of these nutrients in each NP are as depicted in Figure 1. The first five NPs accounted for 75.92% of the total variance of the original nutrient dataset.\nTable 3 Construction of nutrient patterns (NPs), NP structure and variance explained (n = 47).\nNutrient NP1 NP2 NP3 NP4 NP5\nCarotenoids\nLutein 0.02 0.45 −0.14 0.23 0.12\nZeaxanthin 0.09 0.44 −0.13 0.14 0.27\nCryptoxanthin 0.16 0.30 0.14 0.11 0.06\nβ-Carotene 0.01 0.37 0.08 0.43 0.11\nLycopene 0.02 0.32 −0.41 −0.31 0.03\nRetinol (Vitamin A) 0.06 −0.09 0.61 0.18 0.40\nVitamin E\nα-TP 0.11 0.23 0.40 −0.42 −0.04\nγ-TP 0.19 0.05 −0.16 −0.54 0.52\nVitamin K\nPK 0.07 0.23 0.41 −0.28 −0.11\nMK-4 0.26 0.19 0.12 −0.04 −0.50\nFatty acids\nTotal SFAs 0.50 −0.05 −0.05 0.07 −0.03\nTotal MUFAs 0.41 −0.13 0.02 0.04 0.08\nTotal n-3 PUFAs 0.41 0.03 −0.13 0.12 −0.23\nTotal n-6 PUFAs 0.46 −0.15 −0.06 0.01 −0.05\nTotal trans–FAs 0.22 −0.27 −0.08 0.15 0.37\nEigenvalue 3.89 3.39 1.68 1.27 1.06\n% Variance 26.2 22.76 11.28 8.53 7.15\nCumulative % variance 26.2 48.96 60.24 68.77 75.92\nSFA, saturated fatty acid; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; trans-FA, trans-fatty acid; TP, tocopherol; PK, phylloquinone; MK-4, menaquinone-4.\n\nComposite Scores on Cognitive Domains, Depression, and Activities of Daily Living\nThe time interval between the cognitive assessment at the time point closest to death and the autopsy was \u003c1 year for all subjects with an average of 156 (93) days for those whose data could be accurately calculated (81%). Subjects with GDS 1–3 had significantly higher MMSE scores than those with GDS 4–7 (p \u003c 0.001). Similarly, SIB score was higher in subjects with GDS 1–3 (p \u003c 0.001). Therefore, GDS effectively separated subjects based on their performance on global cognition as also previously reported in the original GCS cohort (n = 244) (56). Further, the composite scores for cognitive domains, depression, and activities of daily living had been calculated (Supplementary Table 3). Subjects with GDS 1–3 had significantly higher composite scores on all six cognitive domains and activities of daily living, and significantly lower scores on depression (less depression). Of note, while composite scores for other cognitive domains were available for all subjects, visuospatial function score was available for 87% of participants without dementia and 50% of participants with dementia, and attention score was available for 70% of participants without demented and 46% of participants with dementia.\n\nRelationship Between Brain Nutrient Concentrations and Cognition\nScores of the first five NPs were not statistically different between demented and non-demented subjects (data not shown). However, among non-demented subjects, subjects who had mild cognitive impairment (GDS 3, n = 11) had significantly lower NP2 score than that of cognitively intact subjects (GDS 1–2, n = 12, p = 0.002), but not for other NPs. The difference remained statistically significant after an adjustment for sex, education, hypertension, diabetes, and presence of APOE ε4 allele (p = 0.004).\nA heat map was constructed to provide Pearson's partial correlation coefficients between NP scores or nutrient concentrations and scores on cognitive domains, depression, and activities of daily living in all subjects (Figure 2A, p-values provided in Supplementary Table 4A). Pearson's partial correlations were adjusted for sex, education, diabetes, hypertension, and presence of APOE ε4 allele. No consistent relationship between NPs and cognitive domain scores that reached statistical significance was observed.\nFigure 2 Heat map of Pearson's correlation coefficients between nutrient pattern (NP) scores or nutrient concentrations and scores on cognitive domains, depression, and activities of daily livings in (A) all subjects (n = 47) and (B) non-demented subjects (Global Deterioration Scale = 1–3, n = 23). Correlations are adjusted for sex, education, diabetes, hypertension, and APOE ε4 allele (#p \u003c 0.10, *p \u003c 0.05). SFA, saturated fatty acid; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; trans-FA, trans-fatty acid. A subset analysis among non-demented subjects (GDS 1–3) was performed and Pearson's coefficients are illustrated in a heat map (Figure 2B, p-values provided in Supplementary Table 4B). In the models adjusted for covariates among the five NPs representing the highest variances, NP2 was consistently associated with higher scores on global cognition (r = 0.38, p = 0.070), memory (r = 0.38, p = 0.073), language (r = 0.42, p = 0.046), and lower depression score (r = −0.40, p = 0.090) (Figure 3). After additional adjustment for antidepressant use, the correlation with lower depression score remained borderline significant (r = −0.35, p = 0.100). Since NP2 is mainly described by carotenoids, significant correlations were also consistently observed between lutein, zeaxanthin, β-carotene and scores on global cognition, memory, language, and depression. Other notable associations included NP3 and NP5 and higher depression. Additional adjustment for antithrombotic use was performed for PK and MK-4 and their correlations with different cognitive domain composite scores remained statistically non-significant (p \u003e 0.05) for all six cognitive domains and activities of daily living, while the correlation between MK-4, but not PK, and depression remained statistically significant (Supplementary Table 4B).\nFigure 3 The relationship between nutrient pattern 2 (NP2) score and composite scores of (A) global cognition, (B) memory, (C) language, and (D) depression among non-demented subjects (Global Deterioration Scale = 1–3, n = 23). Pearson's correlation coefficients are adjusted for sex, education, diabetes, hypertension, and APOE ε4 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