Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic disorder characterized by symptoms such as respiratory dysfunction, seizures, orthopedic issues, and neurodevelopmental delay. Potential therapeutics for RCDP warrant the development of clinical outcome assessments to assess the efficacy of treatment and the well-being of patients. Our study aimed to develop a valid quality-of-life (QOL) caregiver-reported survey instrument, RhizoQOL, to be used as a supportive endpoint in RCDP clinical trials. Development of the RhizoQOL survey tool included three RCDP caregiver focus groups to elicit concepts to serve as potential domains in a QOL survey instrument for RCDP, pilot survey development and initial testing, cognitive interviewing of revised survey drafts to determine content validity, as well as a three-month longitudinal study for reliability and internal consistency of the survey instrument. Twenty-eight caregivers participated in the focus groups, reporting that concepts that could be appropriate domains of QOL in RCDP include psychosocial behavior, feeding symptoms, mobility symptoms, respiratory symptoms, seizures and related activity, and impact of treatment. Following pilot survey testing (n = 22) and stakeholder feedback, a revised pilot survey instrument was administered to five caregivers for cognitive interviewing. This resulted in a revised survey instrument with 31 question items, six domains, and a 1–5 Likert scale item response assessing frequency or severity of event in the question item. Longitudinal testing (n = 18) of the revised survey instrument found the average response score was 1.98 ± 0.97 for all question items, and a Cronbach’s alpha value of 0.856, suggesting strong intra-survey question reliability. Using individual question item results from reliability testing, linear regression modeling, and testing for required magnitude of significant treatment effects, eight question items were removed from the survey instrument, resulting in a total of 23 question items within 6 discrete domains. The final RhizoQOL survey instrument, consisting of 23 questions, assesses the symptoms and experiences of RCDP patients as observed by caregivers and serves as a novel clinical outcome assessment for RCDP therapeutic clinical trials to assess the impacts of RCDP and support the overall effectiveness of treatments.

ABSTRACT PPI‐1011 is a synthetic plasmalogen precursor designed to augment plasmalogen levels in patients with Rhizomelic chondrodysplasia punctata (RCDP), an ultra‐rare genetic disorder caused by a plasmalogen deficiency that results in significant physical and mental delays. We report here a Phase I, randomized, double‐blind, placebo‐controlled study that evaluated the safety, tolerability, and pharmacokinetics (PK) of single (10–100 mg/kg) and multiple (75 and 100 mg/kg/day) ascending doses of PPI‐1011 in healthy adults. All treatment‐emergent adverse events (TEAEs) were mild, monitorable, and resolved without intervention, suggesting no significant safety concerns. The most common TEAEs were gastrointestinal in both the placebo and PPI‐1011 groups, suggesting they were likely related to the oil‐based nature of the formulation. PK analysis confirmed that both single (25, 50, 75 and 100 mg/kg) and multiple‐dose (75 and 100 mg/kg, once daily) administration of PPI‐1011 significantly increased serum levels of the target plasmalogen (PlsEtn 16:0/22:6). With a once‐daily regimen, PPI‐1011 administration resulted in a sustained increase of PlsEtn 16:0/22:6 serum concentrations in healthy participants over a duration of 14 days and beyond.

Plasmalogens are vinyl-ether glycerophospholipids critical for the structure and function of neuronal membranes. Deficient plasmalogen levels are associated with neurodegenerative diseases, particularly Alzheimer’s disease (AD), which has led to the hypothesis that plasmalogen deficiency might drive disease onset and progression. However, the lack of a suitable animal model with late-onset plasmalogen deficiency has prevented testing of this hypothesis. The goal of this project was therefore to develop and characterize a mouse model capable of undergoing a plasmalogen deficiency only in adulthood, mirroring the chronic decline thought to occur in AD. We report here the creation of a novel animal model containing a tamoxifen-inducible knockout of the Gnpat gene encoding the first step in the plasmalogen biosynthetic pathway. Tamoxifen treatment in adult animals resulted in a significant reduction of plasmalogens in both the circulation and tissues as early as four weeks. By four months, changes in behavior and nerve function were observed, with strong correlations between residual brain plasmalogen levels hyperactivity, and latency. The model will be useful for further elucidating the role of plasmalogens in AD and evaluating plasmalogen therapies.

PPI-1011 is a synthetic plasmalogen precursor in development as a treatment for multiple plasmalogen-deficiency disorders. Previous work has demonstrated the ability of PPI-1011 to augment plasmalogens and its effects in vitro and in vivo, however, the precise uptake and distribution across tissues in vivo has not been investigated. The purpose of this study was to evaluate the pharmacokinetics, mass balance, and excretion of [14C]PPI-1011 following a single oral administration at 100 mg/kg in Sprague-Dawley rats. Further tissue distribution was examined using quantitative whole-body autoradiography after both single and repeat daily doses at 100 mg/kg/day. Non-compartmental analysis showed that following a single dose, PPI-1011 exhibited peak levels between 6 and 12 h but also a long half-life with mean t1/2 of 40 h. Mass balance showed that over 50% of the compound-associated radioactivity was absorbed by the body, while approximately 40% was excreted in the feces, 2.5% in the urine, and 10% in expired air within the first 24 h. Quantitative whole-body autoradiography following a single dose showed uptake to nearly all tissues, with the greatest initial uptake in the intestines, liver, and adipose tissue, which decreased time-dependently throughout 168 h post-dose. Following 15 consecutive daily doses, uptake was significantly higher across the entire body at 24 h compared to single dose and remained high out to 96 h where 75% of the initially-absorbed compound-associated radioactivity was still present. The adipose tissue remained particularly high, suggesting a possible reserve of either plasmalogens or alkyl diacylglycerols that the body can pull from for plasmalogen biosynthesis. Uptake to the brain was also definitively confirmed, proving PPI-1011's ability to cross the blood-brain barrier. In conclusion, our results suggest that oral administration of PPI-1011 results in high uptake across the body, and that repeated dosing over time represents a viable therapeutic strategy for treating plasmalogen deficiencies.

Background Rhizomelic chondrodysplasia punctata (RCDP) is an inherited ultra-rare disease which results in severely impaired physical and mental development. Mutations in one of five genes involved in plasmalogen biosynthesis have been reported to drive disease pathology. Estimates of disease incidence have been extremely challenging due to the rarity of the disorder, preventing an understanding of the unmet medical need. To address this, we have prepared a disease incidence and prevalence model based on genetic epidemiology approaches to estimate the total number of RCDP patients affected, and their demographic characteristics. Results Extraction of allelic frequencies for known and predicted pathogenic variants in PEX7, GNPAT, AGPS, FAR1, PEX5 (limited to the PTS2 domain encoding region) genes, from large-scale human genetic diversity datasets (TopMed and gnomAD) revealed the mutational landscape contributing to the RCDP patient population in the US and Europe. We computed genetic prevalence to derive birth incidence for RCDP and modeled the impact to life expectancy to obtain high confidence estimates of disease prevalence. Our population genetics-based model indicates PEX7 variants are expected to contribute to the majority of RCDP cases in both the US and Europe; closely aligning with clinical reports. Furthermore, this model provides estimates for RCDP subtypes due to mutations in other genes, including exceedingly rare subtypes. Conclusion In total, the estimated number of RCDP patients in the US and the five largest European countries (UK, Germany, France, Italy and Spain) is between 516 and 847 patients, all under the age of 35 years old. This model provides a quantitative framework for better understanding the unmet medical need in RCDP, to help guide disease awareness and diagnosis efforts for this specific patient group.

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Wedad Fallatah and Tara Smith are co-first authors on ‘Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata’, published in DMM. Wedad is a PhD student in the lab of Dr Nancy Braverman at the Research Institute of the McGill University Health Center and McGill University, Montreal, QC, Canada, investigating mouse models to characterize and establish preclinical therapeutic interventions for rhizomelic chondrodysplasia punctate (RCDP). Tara is Vice President of Therapeutics in the lab of Dr Shawn Ritchie at Med-Life Discoveries LP, Saskatoon, SK, Canada. Her research focuses on evaluating plasmalogen precursors as potential therapeutic agents for the treatment of peroxisomal disorders such as RCDP, as well as neurodegenerative diseases of aging including Alzheimer's disease, Parkinson's disease and multiple sclerosis.

Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic disorder caused by mutations in peroxisomal genes essential for plasmalogen biosynthesis. Plasmalogens are a class of membrane glycerophospholipids containing a vinyl-ether-linked fatty alcohol at the sn-1 position that affect functions including vesicular transport, membrane protein function and free radical scavenging. A logical rationale for the treatment of RCDP is therefore the therapeutic augmentation of plasmalogens. The objective of this work was to provide a preliminary characterization of a novel vinyl-ether synthetic plasmalogen, PPI-1040, in support of its potential utility as an oral therapeutic option for RCDP. First, wild-type mice were treated with 13C6-labeled PPI-1040, which showed that the sn-1 vinyl-ether and the sn-3 phosphoethanolamine groups remained intact during digestion and absorption. Next, a 4-week treatment of adult plasmalogen-deficient Pex7hypo/null mice with PPI-1040 showed normalization of plasmalogen levels in plasma, and variable increases in plasmalogen levels in erythrocytes and peripheral tissues (liver, small intestine, skeletal muscle and heart). Augmentation was not observed in brain, lung and kidney. Functionally, PPI-1040 treatment normalized the hyperactive behavior observed in the Pex7hypo/null mice as determined by open field test, with a significant inverse correlation between activity and plasma plasmalogen levels. Parallel treatment with an equal amount of ether plasmalogen precursor, PPI-1011, did not effectively augment plasmalogen levels or reduce hyperactivity. Our findings show, for the first time, that a synthetic vinyl-ether plasmalogen is orally bioavailable and can improve plasmalogen levels in an RCDP mouse model. Further exploration of its clinical utility is warranted. This article has an associated First Person interview with the joint first authors of the paper.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. It is typically associated with motor symptoms originating from the degeneration of nigrostriatal dopamine (DA) neurons. Early stages of PD have been associated with an alteration in DA production in intestinal DAergic neurons along with inflammation. Interestingly, decreased serum concentrations of ethanolamine plasmalogens (PlsEtn) have been reported in PD patients. Ethanolamine plasmalogens play a role in vesicular fusion and release during neurotransmission, and store neuroprotective polyunsaturated fatty acids, such as docosahexaenoic acid (DHA) and are strong anti-oxidants, highlighting areas of potential therapeutic interest. Docosahexaenoic acid is known to play important roles in both the central nervous and peripheral systems, in addition to acting as a precursor of several molecules that regulate the resolution of inflammation. The present study investigated the neuroprotective and anti-inflammatory properties of the DHA-containing PlsEtn precursor, PPI-1011, in the intestine of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Treatment with PPI-1011 prevented the MPTP-induced decrease in PlsEtn levels. In addition it prevented the loss of tyrosine hydroxylase (TH) expression and reduced the infiltration of macrophages in the myenteric plexus of MPTP-treated mice. The protective effects of PPI-1011 were observed regardless of whether it was administered pre- or post- MPTP treatment. These results suggest that PPI-1011 has neuroprotective and anti-inflammatory properties in the gut and indicate its potential utility as a treatment for both early and more advanced stages of PD.

Cleft palate is a common congenital abnormality that results from defective secondary palate (SP) formation. The Sine oculis-related homeobox 2 (Six2) gene has been linked to abnormalities of craniofacial and kidney development. Our current study examined, for the first time, the specific role of Six2 in embryonic mouse SP development. Six2 mRNA and protein expression were identified in the palatal shelves from embryonic days (E) 12.5 to E15.5, with peak levels during early stages of palatal shelf outgrowth. Immunohistochemical staining (IHC) showed that Six2 protein is abundant throughout the mesenchyme in the oral half of each palatal shelf, whereas there is a pronounced decline in Six2 expression by mesenchyme cells in the nasal half of the palatal shelf by stages E14.5-15.5. An opposite pattern was observed in the surface epithelium of the palatal shelf. Six2 expression was prominent at all stages in the epithelial cell layer located on the nasal side of each palatal shelf but absent from the epithelium located on the oral side of the palatal shelf. Six2 is a putative downstream target of transcription factor Hoxa2 and we previously demonstrated that Hoxa2 plays an intrinsic role in embryonic palate formation. We therefore investigated whether Six2 expression was altered in the developing SP of Hoxa2 null mice. Reverse transcriptase PCR andWestern blot analyses revealed that Six2 mRNA and protein levels were upregulated in Hoxa2(-/-)palatal shelves at stages E12.5-14.5. Moreover, the domain of Six2 protein expression in the palatal mesenchyme of Hoxa2(-/-)embryos was expanded to include the entire nasal half of the palatal shelf in addition to the oral half. The palatal shelves of Hoxa2(-/-)embryos displayed a higher density of proliferating, Ki-67 positive palatal mesenchyme cells, as well as a higher density of Six2/Ki-67 double-positive cells. Furthermore, Hoxa2-/-palatal mesenchyme cells in culture displayed both increased proliferation and elevated Cyclin D1 expression relative to wild-type cultures. Conversely, siRNA-mediated Six2 knockdown restored proliferation and Cyclin D1 expression in Hoxa2(-/-)palatal mesenchyme cultures to near wild-type levels. Our findings demonstrate that Six2 functions downstream of Hoxa2 as a positive regulator of mesenchymal cell proliferation during SP development.

This paper argues that the judiciary’s use of the Rational Basis Test splinters Constitutional sovereignty and thereby undermines the Constitution’s supremacy. It replaces the rule of the Constitution with the rule of a conceivable Constitution and subjects the governed to an array of reasonable readings thereof. While others have raised sharp criticisms of the Rational Basis Test in recent years, they have failed to appreciate its fundamental failing. Most critics contend that the test’s increasingly permissive character could be corrected, if only it were employed within sensible proportions. My claim, by contrast, is that the test is misguided in principle. A re-fortified Rational Basis Test is not the needed remedy. By examining the conventional critique’s complaints of jurists’ fanciful imagining of lawmakers’ possible motives, I show that motives (whether imaginary or actual) are a red herring. The test’s deeper problem is its adoption of a standard of legality other than the Constitution. The paper also considers three possible defenses of the test, but finds all of them wanting.

In debates over the proper boundaries of free speech, we are naturally alert to the meanings of pivotal terms such as offensive speech, hate speech, and group libel. Alongside such contested concepts, however, stand peripheral terms whose misuse can be every bit as influential but whose ramifications go unnoticed. Because these terms are not consistently associated with particular substantive positions, we tend to assume that they are neutral tools of the debate's infrastructure. I argue that confusions concerning four such concepts - absolute, exception, censorship, and freedom - impede clear thinking and often lend the cover of respectability to unjustified restrictions of speech. The paper first offers examples of the misguided ways in which each term is frequently used and isolates the errors involved. It then explains the damage this inflicts, indicating how the confusions impede a logical understanding of the more substantive issues. Finally, it considers the deeper premises beneath the confusions, paying particular attention to the influence of utilitarian thinking. While the project is a modest one of conceptual clean-up, its stakes are large. For as long as we labor under blurred conceptual boundaries, we will protect speech that should not be protected and restrict speech that should not be restricted.

Ethanolamine plasmalogens (PlsEtn) are a class of glycerophospholipids characterized by a vinyl-ether bond at the sn-1 position that play an important role in the structure and function of membranes. Previous reports have suggested a link between reduced blood and brain PlsEtn levels and Parkinson's disease (PD). We recently reported that the DHA containing plasmalogen precursor PPI-1011 protected striatal dopamine (DA) against MPTP toxicity in mice. In this paper, we further investigate the specificity requirements of the lipid side chains by testing the oleic acid-containing plasmalogen precursor PPI-1025. Male mice were treated for 10days with daily oral administration of PPI-1025 (10, 50 or 200mg/kg). On day 5 mice received MPTP and were sacrificed on Day 11. Treatment with PPI-1025 prevented MPTP-induced decrease of DA and serotonin, as well as their metabolites. In addition, PPI-1025 treatment prevented the MPTP-induced decrease of the striatal dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) specific binding. Significant positive correlations were measured between striatal DA concentrations and DAT or VMAT2 specific binding, as well as with serum plasmalogen concentrations. The neuroprotective effect of PPI-1025 displayed a bell-curve dose-dependency losing effect at the highest dose tested. The similar protective response of oleic and docosahexaenoic acid (DHA)-containing plasmalogen precursors suggests that the neuroprotection observed is not only due to DHA but to the oleic substituent and the plasmalogen backbone.

Religious freedom is in the limelight. In recent years, religiously inspired violence has slaughtered thousands around the world and provoked calls for the repression of adherents of various faiths. Domestically, we have shrill debates: Should bakers be compelled to serve at gay weddings when they have religious objections to doing so? Should government officials be compelled to facilitate gay marriages when they have religious objections to doing so? Should employers have to provide workers with medical insurance for practices that they disapprove of on religious grounds? Prayer at town meetings, zoning exemptions for church property, embryonic stem cell research, workplace dress codes, beards on prisoners, recognition of religious organizations at state universities — a stream of contentious battles seems to pit religious freedom against equal protection. The liberation of some, many charge, is coming at the expense of others (e.g., his freedom to marry versus her freedom to practice her faith). Each side digs in — some with lawsuits, others with legislation. In 2015 alone, eighty-seven religious refusal bills were introduced in twenty-eight states. The aim of this paper is to step back from these controversies so as to consider the larger value at stake. Its question: What good is religious freedom? Why is it valuable? What is the source of its goodness and what is the benefit of respecting it? What does religious freedom add to a properly governed society?

Sports and the arts are alike, for their audiences, in their relative detachment from ordinary utilitarian concerns. Viewers’ lives remain essentially unchanged at the conclusion of the match or the drama. Yet the ubiquitous interest in sports and the arts, historically and globally, along with the intensity of passion that each can rouse, raise natural questions about the benefit of engagement with these artificial realms. This paper explores the respective values of sports and the arts for the viewer. After briefly registering some of the oft-remarked similarities in the appeal of each, the paper posits a more fundamental common dimension: the way in which both sports and the arts offer spiritual values by offering the material manifestation of important abstract ideas. It proceeds to outline the quite distinct ways in which sports and the arts do this. First, it identifies four respects in which artworks seem to offer a more philosophical “take” on life, effectively presenting a fundamental worldview. It then observes three important respects in which sports provide messages that the arts cannot. The paper’s overall aim is not to anoint either realm as definitively superior, but to better appreciate the exact rewards that each of them can offer to a flourishing human life.

Plasmalogens are a class of glycerophospholipids shown to play critical roles in membrane structure and function. Decreased plasmalogens are reported in the brain and blood of Parkinson's disease (PD) patients. The present study investigated the hypothesis that augmenting plasmalogens could protect striatal dopamine neurons that degenerate in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in mice, a PD model. First, in a pre-treatment experiment male mice were treated for 10 days with the docosahexaenoic acid (DHA)-plasmalogen precursor PPI-1011 (10, 50 and 200 mg/kg). On day 5 mice received MPTP and were killed on day 11. Next, in a post-treatment study, male mice were treated with MPTP and then received daily for 5 days PPI-1011 (5, 10 and 50 mg/kg). MPTP treatment reduced serum plasmalogen levels, striatal contents of dopamine (DA) and its metabolites, serotonin, DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2). Pre-treatment with PPI-1011 (10 and 50 mg/kg) prevented all MPTP-induced effects. Positive correlations were measured between striatal DA contents and serum plasmalogen levels as well as striatal DAT and VMAT2 specific binding. Post-treatment with PPI-1011 prevented all MPTP-induced effects at 50 mg/kg but not at lower doses. Positive correlations were measured between striatal DA contents and serum plasmalogen levels as well as striatal DAT and VMAT2 specific binding in the post-treatment experiment. PPI-1011 treatment (10 days at 5, 10 and 50 mg/kg) of intact mice left unchanged striatal biogenic amine contents. These data demonstrate that treatment with a plasmalogen precursor is capable of protecting striatal dopamine markers in an animal model of PD.

This paper seeks to demonstrate that religious exemptions are unjustified in theory and corrosive, in practice. By splintering the ultimate sovereignty of a legal system, they fracture its integrity and undermine its ability to fulfill its mission. My analysis proceeds from the function of the legal system – which is the basis of the system’s authority – to show how the practice of granting standing permission for some people to violate generally applicable laws is inimical to that system’s efficacy and an abuse of its authority. The injection of conflicting directives to the officials charged to enforce the law (Go by the law; Go by those people’s consciences) necessarily subjectivizes the use of the government’s coercive power, since those officials have no principled means of deciding between the two directives. The tremendous proliferation of exemptions over the years testifies to the absence of an objective standard for governing this. After establishing the central failings of exemptions, the paper takes up four specific arguments that are frequently offered in their defense: appeals to First Amendment text, the ideal of equality, the ideal of personal liberty, and the profound value of religious identity for many individuals. Careful examination demonstrates that none of these successfully justifies exemptions. Finally, the paper considers the grounds on which differential application of generally sound law might ever be appropriate, finding an important difference between religiously based exemptions and other legitimately exceptional treatment.

Presence of the Apolipoprotein E (ApoE) ε4 allele or low serum ethanolamine plasmalogen (PlsEtn) levels have been shown to be associated with Alzheimer's disease (AD) and decreased cognition.We investigated potential interactions between ApoE genotype and serum PlsEtn levels on cognition and AD. Using a community-based sample of 1196 well characterized elderly persons from the Rush University Religious Orders Study and Memory and Aging Project, the relationships between ApoE genotype, PlsEtn biosynthesis, cognition and AD diagnosis were investigated. A quantitative PlsEtn Biosynthesis Value (PBV) was generated for each person by combining the relative serum levels of three key PlsEtn species. Subjects were classified into one of three genotypes (ε2=ε2ε3, ε3=ε3ε3, ε4=ε3ε4+ε4ε4) and one of three metabotypes (Pls1=81-100th; Pls2=21-80th; Pls3=0-20th PBV percentiles). Higher PBV was associated with higher cognition (coef=0.66, p<0.001). Relative to ε3, ε2 was associated with higher (coef=0.19, p<0.001) and ε4 with lower (coef=-0.23, p<0.001) cognition. Relative to persons in ε3:Pls2, the odds of AD were higher for both low PBV (ε3:Pls3: OR=3.3 (95%CI 1.9-5.8), p<0.001)and ε4 (ε4:Pls2: OR=2.5 (95%CI 1.4-4.5), p=0.002); the odds of AD were lower in ε2 (ε2:Pls1-3: OR=0.18 (95%CI 0.04-0.78), p<0.05) and Pls1 (ε3:Pls1: OR=0.29 (95%CI 0.08-1.0), p<0.05). Relative to persons in ε3:Pls2, the odds of AD was increased in ε4:Pls3: OR=5.7 (95%CI 2.7-11.9), p<0.001) but not increased in ε4:Pls1 subjects. The Pls3 metabotype and ε4 genotype were observed to be independently associated with an increases odds of AD. The ApoE ε4 genotype did not result in an increased odds of AD in subjects wth a Pls1 metabotype. The odds of AD associated with ApoE genotype is dependent upon the underlying PlsEtn metabotype.

Apolipoprotein E (ApoE) genotype and serum ethanolamine plasmalogen (PlsEtn) levels have been associated with cognitive status and Alzheimer's disease (AD) diagnosis. The association of ApoE genotype, and serum PlsEtn with the conversion from No Cognitive Impairment (NCI) to either Mild Cognitive Impairment (MCI) or AD or from MCI to AD in elderly persons was investigated. Serum PlsEtn, ApoE genotype, and cognition were determined in 713 persons aged 55-98 (80.5+/-7.3) and diagnosed as having either NCI (n=551) or MCI (n=162) at baseline (Rush University Religious Orders Study and Memory and Aging Project). Subjects were re-examined at follow-up (3.9+/-1.4 years later) and their diagnosis, cognition, and serum PlsEtn levels re-determined. A quantitative PlsEtn Biosynthesis Value (PBV) was generated for each person by combining the relative serum levels of three key PlsEtn species. Odds ratios of continuous variables expressed per standard deviation (SD). During the follow-up period 85 subjects converted from NCI to MCI, 19 from NCI to AD, and 39 from MCI to AD (collectively, “Converters”) and 447 NCI and 65 MCI subjects remained NCI and MCI, respectively and 58 MCI subjects were re-classified as NCI at follow-up (collectively, “Non-Converters”). After adjusting for gender, education, and years from baseline, Age at baseline (OR=1.52, p<0.001), ApoE ε3ε4/ε4ε4 genotype (relative to ε3ε3; OR=1.30, p=0.006), and a decrease in PBV from baseline (OR=1.45, p=0.002) were associated with a higher odds of being a Converter and a higher PBV at baseline (OR=0.63, p<0.001) was associated with a lower odds of being a Converter. The presence of a ApoE ε4 allele, a low PBV at baseline, or a decrease in PBV from baseline was associated with a higher odds of NCI persons becoming cognitively impaired and MCI persons converting to AD.

Presence of the ApoE ε4 allele, ethanolamine plasmalogen (PlsEtn) levels, and amyloid plaques or neurofibrillary tangles density in the brain are associated with the severity of dementia and AD pathology. The independent and combined associations of these factors on cognition and AD pathology was investigated. PlsEtn, amyloid, tangles, ApoE genotype, and mRNA transcripts for enzyme, and transport proteins involved in plasmalogen synthesis were determined in the temporal cortex of 100 subjects who had completed comprehensive cognitive testing prior to death. Subjects were grouped into one of three ApoE subgroups (ε2=ε2ε3, ε3=ε3ε3, ε4=ε3ε4+ ε4ε4) and ε3 was used as the reference. After adjusting for only demographic variables (age, education, gender), the key variables associated with cognition were: docosahexaenoic acid (DHA)-PlsEtn (Coef:0.620, p=8.7E-09, r2=0.329, n=99), tangles (Coef: -0.552, p=4.0E-06, r2=0.267, n=99), amyloid (Coef: -0.394, p=1.1E-04, r2=0.150, n=99), ApoE ε4 (Coef: -0.369, p=4.2E-03, r2=0.131, n=91), Dihydroxyacetone phosphate alkyltransferase (DHAPAT, Coef: 0.307, p=2.7E-02, r2=0.109, n=94). Neither amyloid nor ApoE ε4 was associated with cognition in combined models of these variables where brain DHA-PlsEtn level, tangle density and age showed independent associations with cognition. ApoE ε4 was the dominant variable associated with amyloid (Coef: 1.185, p=5.3E-07, r2=0.297, n=91). Overall, 46% of the variance in cognition was associated with DHA-PlsEtn, tangles, DHAPAT, and age. Amyloid (Coef:-0.025 p=1.4E-03, r2=0.084, n=99), ApoE ε4 (Coef: -0.044, p=2.1E-02, r2=0.081, n=92), and tangles (Coef:-0.044 p=1.1E-04, r2=0.153, n=100) were associated with DHA-PlsEtn levels. Of the variables investigated, temporal cortex DHA-PlsEtn level exhibited the strongest association with cognition. Only tangles and age were associated with cognition independent of brain DHA-PlsEtn levels.