Multilayer clustering: Biomarker driven segmentation of Alzheimer's disease patient population

Identification of biomarkers for the Alzheimer's disease is a challenge and a very difficult task both for medical research and data analysis. In this work we present results obtained by application of a novel clustering tool. The goal is to identify subpopulations of the Alzheimer's disease (AD) patients that are homogeneous in respect of available clinical and biological descriptors. The result presents a segmentation of the Alzheimer's disease patient population and it may be expected that within each subpopulation separately it will be easier to identify connections between clinical and biological descriptors. Through the evaluation of the obtained clusters with AD subpopulations it has been noticed that for two of them relevant biological measurements (whole brain volume and intracerebral volume) change in opposite directions. If this observation is actually true it would mean that the diagnosed severe dementia problems are results of different physiological processes. The observation may have substantial consequences for medical research and clinical trial design. The used clustering methodology may be interesting also for other medical and biological domains

APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts

10.1371/journal.pmed.1002254PLoS Medicine143e100225

Sex Differences in Cognitive Abilities among Children with the Autosomal Dominant Alzheimer Disease Presenilin 1 E280A Variant from a Colombian Cohort

Importance: We previously reported that children with the autosomal dominant Alzheimer disease (ADAD) presenilin 1 (PSEN1) E280A variant had early life plasma biomarker findings consistent with amyloid β overproduction. However, the cognitive functioning of children with this variant has not been characterized vs those without the variant. Objective: To test whether cognitive functioning of children with and without the PSEN1 E280A variant in the same ADAD cohort differed by genetic status (ie, PSEN1 variant) and sex. Design, Setting, and Participants: This cohort study was conducted among 1354 children (including 265 children with the variant) aged 6 to 16 years recruited from the Alzheimer Prevention Initiative Colombia Registry. Participants from the city of Medellín and surrounding suburban areas traveled to the University of Antioquia to undergo all procedures. Participants were administered a Spanish version of the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) to measure general cognitive functioning. Data were analyzed from July through November 2020. Main Outcomes and Measures: Univariate general linear models were used to characterize differences on WISC-IV cognitive performance by genetic status, sex, and the interaction of genetic status with sex. Urbanity, socioeconomic status, and education were entered as covariates. Results: Among 1354 children with ADAD (695 [51.3%] girls; mean [SD] age, 11.64 [2.64] years), there were 265 children with the variant (19.6%) and 1089 children without the variant (80.4%). Children with and without the variant did not differ by demographic variables or performance on WISC-IV indices. Irrespective of genetic status, boys had statistically significantly decreased mean scores on indices for working memory (90.27 [95% CI, 89.21-91.34] vs 92.99 [95% CI, 91.98-93.99]; mean difference = -2.72; P <.001), perceptual reasoning (91.56 [95% CI, 90.47-92.65] vs. 93.27 [95% CI, 91.23-94.30]; mean difference = -1.71; P =.03), and verbal comprehension (88.69 [95% CI, 87.54-89.84] vs. 90.81 [95% CI, 89.73-91.90]; mean difference = -2.12; P =.009) compared with girls. In the interaction between sex and genetic status, boys with the variant had worse mean working memory index performance (88.78 [95% CI, 86.86-90.70]) than girls with the variant (93.75 [95% CI, 91.95-95.55]; mean difference = -4.97; P =.001), as well as boys (91.77 [95% CI, 90.85-92.70]; mean difference = -2.99; P =.04) and girls (92.22 [95% CI, 91.32-93.13]; mean difference = -3.44; P =.009) without the variant. Conclusions and Relevance: This study found that boys with the PSEN1 variant had decreased working memory abilities compared with girls with the variant and boys and girls without the variant, suggesting a sex-specific genetic risk in early life cognitive performance among individuals with the PSEN1 variant. This increased risk of future cognitive difficulties among boys with the variant may have important downstream implications for learning and academic achievement and could be associated with sex differences seen in adulthood on episodic memory measures.. © 2021 American Medical Association. All rights reserved.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Excessive iron storage in captive omnivores? The case of the coati (Nasua spp.)

We collated necropsy reports for 13 coatis (Nasua spp.), revealing four cases of moderate and six cases of massive iron deposition in liver tissue. This survey corroborates an earlier report that noted a high frequency of iron deposits in coatis at necropsy. A comparison of the reported natural diet of coatis and the usually fed captive diets revealed that whereas vertebrate products (dog/cat food, prey items) represent the staple diet items for captive individuals, free-ranging coatis only rarely consume vertebrate prey; their natural diet is dominated by wild fruits and invertebrates. This discrepancy should be reflected in high levels of readily available heme iron in captive diets, with little or no heme iron in the natural diets. Therefore, it could be hypothesized that the use of vertebrate products in animals not adapted to such high levels of readily available heme iron could be a cause for dietary iron overload. Further studies on the relevance of excessive iron storage in omnivores/insectivores, and their etiopathology, are indicated

PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer's disease-causing Presenilin-1 E280A mutation carriers

Background: In contrast to sporadic Alzheimer's disease, autosomal dominant Alzheimer's disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aβ) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aβ burden to characterize the presence and age at onset of cerebellar Aβ deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world's largest extended family with ADAD. Methods: 18F florbetapir and 11C Pittsburgh compound B (PiB) PET data from two independent studies – API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aβ-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28–56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score. Results: Florbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p &lt; 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers’ estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 &amp; 0.69, p &lt; 0.001), cortical SUVR_pons (r = 0.55 &amp; 0.69, p &lt; 0.001), and negatively correlated with delayed recall memory (r = −0.21 &amp; −0.50, p &lt; 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = −0.25, p &lt; 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort). Conclusion: This PET study provides evidence of cerebellar Aβ plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder. © 2021 The Author(s)Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]