Sad Cases Research Articles

ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer’s disease

In sporadic Alzheimer’s disease (sAD) specific regions, layers and neurons accumulate hyperphosphorylated Tau (pTau) and degenerate early while others remain unaffected even in advanced disease. ApoER2-Dab1 signaling suppresses Tau phosphorylation as part of a four-arm pathway that regulates lipoprotein internalization and the integrity of actin, microtubules, and synapses; however, the role of this pathway in sAD pathogenesis is not fully understood. We previously showed that multiple ApoER2-Dab1 pathway components including ApoE, Reelin, ApoER2, Dab1, pP85αTyr607, pLIMK1Thr508, pTauSer202/Thr205 and pPSD95Thr19 accumulate together within entorhinal-hippocampal terminal zones in sAD, and proposed a unifying hypothesis wherein disruption of this pathway underlies multiple aspects of sAD pathogenesis. However, it is not yet known whether ApoER2-Dab1 disruption can help explain the origin(s) and early progression of pTau pathology in sAD. In the present study, we applied in situ hybridization and immunohistochemistry (IHC) to characterize ApoER2 expression and accumulation of ApoER2-Dab1 pathway components in five regions known to develop early pTau pathology in 64 rapidly autopsied cases spanning the clinicopathological spectrum of sAD. We found that (1) these selectively vulnerable neuron populations strongly express ApoER2; and (2) multiple ApoER2-Dab1 components representing all four arms of this pathway accumulate in abnormal neurons and neuritic plaques in mild cognitive impairment (MCI) and sAD cases and correlate with histological progression and cognitive deficits. Multiplex-IHC revealed that Dab1, pP85αTyr607, pLIMK1Thr508, pTauSer202/Thr205 and pPSD95Thr19 accumulate together within many of the same ApoER2-expressing neurons and in the immediate vicinity of ApoE/ApoJ-enriched extracellular plaques. Collective findings reveal that pTau is only one of many ApoER2-Dab1 pathway components that accumulate in multiple neuroanatomical sites in the earliest stages of sAD and provide support for the concept that ApoER2-Dab1 disruption drives pTau-associated neurodegeneration in human sAD.

Establishment of induced pluripotent stem cells IRMBi005-A from a patient with sporadic Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurological disorder and the most common form of dementia worldwide. Sporadic Alzheimer’s disease (sAD) cases are the main forms, over 95% of AD cases, but still poorly understood. Thereby there is a crucial need to develop in vitro models for studying this multifactorial disorder. Here, we report the reprogramming of skin fibroblasts from a 57-years-old male donor. The new generated iPSC cell line has a normal karyotype and, is pluripotent since it demonstrates the ability to differentiate in vitro into the three germ layers. This iPSC line will be used to understand pathological mechanisms of sAD.

Distinct Molecular Signatures of Amyloid-Beta and Tau in Alzheimer's Disease Associated with Down Syndrome.

Limited comparative data exist on the molecular spectrum of amyloid-beta (Aβ) and tau deposition in individuals with Down syndrome (DS) and sporadic Alzheimer's disease (sAD). We assessed Aβ and tau deposition severity in the temporal lobe and cerebellum of ten DS and ten sAD cases. Immunohistochemistry was performed using antibodies against eight different Aβ epitopes (6F/3D, Aβ38, Aβ39, Aβ40, Aβ42, Aβ43, pyroglutamate Aβ at third glutamic acid (AβNp3E), phosphorylated- (p-)Aβ at 8th serine (AβpSer8)), and six different pathological tau epitopes (p-Ser202/Thr205, p-Thr231, p-Ser396, Alz50, MC1, GT38). Findings were evaluated semi-quantitatively and quantitatively using digital pathology. DS cases had significantly higher neocortical parenchymal deposition (Aβ38, Aβ42, and AβpSer8), and cerebellar parenchymal deposition (Aβ40, Aβ42, AβNp3E, and AβpSer8) than sAD cases. Furthermore, DS cases had a significantly larger mean plaque size (6F/3D, Aβ42, AβNp3E) in the temporal lobe, and significantly greater deposition of cerebral and cerebellar Aβ42 than sAD cases in the quantitative analysis. Western blotting corroborated these findings. Regarding tau pathology, DS cases had significantly more severe cerebral tau deposition than sAD cases, especially in the white matter (p-Ser202/Thr205, p-Thr231, Alz50, and MC1). Greater total tau deposition in the white matter (p-Ser202/Thr205, p-Thr231, and Alz50) of DS cases was confirmed by quantitative analysis. Our data suggest that the Aβ and tau molecular signatures in DS are distinct from those in sAD.

Sad Cases and Success Stories: Representations of Multiple Sclerosis in Direct-to-Consumer Pharmaceutical Advertising

This article examines representations of multiple sclerosis in direct-to-consumer pharmaceutical advertisements televised during 2021 in the United States. Drawing on and developing Cultural Disability Studies theory, it highlights how advertising produced by pharmaceutical companies influences mass understandings, as well as personal experiences of, multiple sclerosis. The application of textual analysis to a small-sample of direct-to-consumer advertisements that promote drug therapies for multiple sclerosis (n. 4) uncovers the prevalence of profit-driven, rather than person-driven, medical neoliberal ideologies. On first impressions, the advertisements appear to challenge the metanarrative of multiple sclerosis as a life-limiting tragedy. However, the research findings reveal that multiple sclerosis is framed as the “hidden enemy” of the American dream, supposedly threatening individuals’ abilities to live productive and meaningful lives, while the consumption of pharmaceutical “wonder” drugs is treated as an act of self-empowerment.

Characteristics and symptomatology of major depressive disorder with atypical features from symptom to syndromal level

ObjectiveTo explore clinical characteristics and symptomatology of major depressive disorder (MDD) with atypical features based on DSM criteria or only reversed vegetative symptoms. MethodA total of 3187 patients who met DSM-IV TR criteria for MDD were enrolled. Demographics and symptomatology covering multiple symptom domains were assessed and compared between three groups of cases: those who met DSM criteria for atypical specifier (the DAD group), those who had at least one reversed vegetative symptoms (hypersomnia or hyperphagia) (the SAD group) without meeting DSM atypical specifier criteria, and those without any reversed vegetative symptoms (the NAD group). ResultsThe DAD and SAD group accounted for 4.4% and 14.4% of the participants, respectively. The DAD cases were characterized by a highest proportion of hospitalizations, longest duration of current episode and worst quality of life. The DAD and SAD cases were more likely to adopt unhealthy behaviors (smoking and alcohol drinking). Most depressive symptoms related to higher illness severity and treatment resistance were more frequent in the DAD cases, followed by the SAD cases, and least frequent in the NAD cases. LimitationsA cross-sectional design and a non-validated questionnaire were used. ConclusionsThe findings support the role of DSM defined atypical depression as a valid MDD subtype and provide evidence for clinical utility of the simplified approach of defining atypical features based on only reversed vegetative symptoms. This has implications for illness screening, public health, suicide prevention and better treatment planning for depressed individuals with atypical features even below syndromal level.

Clinical and genetic features of Lewy body pathology in autosomal dominant and sporadic Alzheimer disease

AbstractBackgroundLewy body pathology (LBP) occurs in a substantial portion of individuals with autosomal dominant (ADAD) and sporadic Alzheimer disease (sAD) (Ringman, 2016; Cairns, 2015; Leverenz, 2007; Lippa, 1998). Whereas other non‐AD pathologies are frequent in sAD, LBP seems to be the most common co‐pathology in the relatively young ADAD population (Cairns, 2015). Knowledge of clinical and genetic characteristics of LBP in both ADAD and sAD is incomplete.MethodData from the National Alzheimer’s Coordinating Center, the Dominantly Inherited Alzheimer Network, the Queen Square Brain Bank at University College London and the Neurobiobank Munich were leveraged to compare individuals with ADAD and neuropathologically diagnosed sAD with and without LBP. Chi‐squared and Student’s t‐test were used for comparison of categorical and continuous variables respectively.ResultThe study included 139 ADAD and 4661 sAD autopsy cases. LBP occurred in 59% of ADAD and 38% of sAD cases. LBP was associated with a longer survival in both ADAD (10.1 vs. 8.6 years, p=0.024) and sAD (10.5 vs. 10.2 years, p=0.016). Memory disturbance occurred more frequently as the first clinical AD symptom in both AD variants when LBP was present (ADAD: 90 vs. 65%, p=0.005; sAD: 78 vs. 71%, p<0.001). In both ADAD and sAD, the presence of at least one APOE e4 allele was more common in individuals with LBP (ADAD: 40 vs. 21%, p=0.047; sAD: 57 vs. 46%, p<0.001). In ADAD, frequency of LBP did not differ between individuals with PSEN1 and APP mutations.ConclusionIn this investigation of 139 ADAD and 4661 sAD autopsy cases, LBP occurred in about 60% with ADAD and 40% with sAD. In both ADAD and sAD, the presence of LBP was associated with longer survival, higher frequency of memory disturbance as the first AD symptom and positive APOE e4 status. Further study of these associations may increase our understanding of the role of LBP in AD.

Effects of Practicing With and Obtaining Crowdsourced Feedback From the Video-Based Communication Assessment App on Resident Physicians' Adverse Event Communication Skills: Pre-post Trial.

BackgroundUS residents require practice and feedback to meet Accreditation Council for Graduate Medical Education mandates and patient expectations for effective communication after harmful errors. Current instructional approaches rely heavily on lectures, rarely provide individualized feedback to residents about communication skills, and may not assure that residents acquire the skills desired by patients. The Video-based Communication Assessment (VCA) app is a novel tool for simulating communication scenarios for practice and obtaining crowdsourced assessments and feedback on physicians’ communication skills. We previously established that crowdsourced laypeople can reliably assess residents’ error disclosure skills with the VCA app. However, its efficacy for error disclosure training has not been tested.ObjectiveWe aimed to evaluate the efficacy of using VCA practice and feedback as a stand-alone intervention for the development of residents’ error disclosure skills.MethodsWe conducted a pre-post study in 2020 with pathology, obstetrics and gynecology, and internal medicine residents at an academic medical center in the United States. At baseline, residents each completed 2 specialty-specific VCA cases depicting medical errors. Audio responses were rated by at least 8 crowdsourced laypeople using 6 items on a 5-point scale. At 4 weeks, residents received numerical and written feedback derived from layperson ratings and then completed 2 additional cases. Residents were randomly assigned cases at baseline and after feedback assessments to avoid ordinal effects. Ratings were aggregated to create overall assessment scores for each resident at baseline and after feedback. Residents completed a survey of demographic characteristics. We used a 2×3 split-plot ANOVA to test the effects of time (pre-post) and specialty on communication ratings.ResultsIn total, 48 residents completed 2 cases at time 1, received a feedback report at 4 weeks, and completed 2 more cases. The mean ratings of residents’ communication were higher at time 2 versus time 1 (3.75 vs 3.53; P<.001). Residents with prior error disclosure experience performed better at time 1 compared to those without such experience (ratings: mean 3.63 vs mean 3.46; P=.02). No differences in communication ratings based on specialty or years in training were detected. Residents’ communication was rated higher for angry cases versus sad cases (mean 3.69 vs mean 3.58; P=.01). Less than half of all residents (27/62, 44%) reported prior experience with disclosing medical harm to patients; experience differed significantly among specialties (P<.001) and was lowest for pathology (1/17, 6%).ConclusionsResidents at all training levels can potentially improve error disclosure skills with VCA practice and feedback. Error disclosure curricula should prepare residents for responding to various patient affects. Simulated error disclosure may particularly benefit trainees in diagnostic specialties, such as pathology, with infrequent real-life error disclosure practice opportunities. Future research should examine the effectiveness, feasibility, and acceptability of VCA within a longitudinal error disclosure curriculum.

Coenzyme A-Dependent Tricarboxylic Acid Cycle Enzymes Are Decreased in Alzheimer's Disease Consistent With Cerebral Pantothenate Deficiency.

Sporadic Alzheimer’s disease (sAD) is the commonest cause of age-related neurodegeneration and dementia globally, and a leading cause of premature disability and death. To date, the quest for a disease-modifying therapy for sAD has failed, probably reflecting our incomplete understanding of aetiology and pathogenesis. Drugs that target aggregated Aβ/tau are ineffective, and metabolic defects are now considered to play substantive roles in sAD pathobiology. We tested the hypothesis that the recently identified, pervasive cerebral deficiency of pantothenate (vitamin B5) in sAD, might undermine brain energy metabolism by impairing levels of tricarboxylic acid (TCA)-cycle enzymes and enzyme complexes, some of which require the pantothenate-derived cofactor, coenzyme A (CoA) for their normal functioning. We applied proteomics to measure levels of the multi-subunit TCA-cycle enzymes and their cytoplasmic homologues. We analysed six functionally distinct brain regions from nine sAD cases and nine controls, measuring 33 cerebral proteins that comprise the nine enzymes of the mitochondrial-TCA cycle. Remarkably, we found widespread perturbations affecting only two multi-subunit enzymes and two enzyme complexes, whose function is modulated, directly or indirectly by CoA: pyruvate dehydrogenase complex, isocitrate dehydrogenase, 2-oxoglutarate dehydrogenase complex, and succinyl-CoA synthetase. The sAD cases we studied here displayed widespread deficiency of pantothenate, the obligatory precursor of CoA. Therefore, deficient cerebral pantothenate can damage brain-energy metabolism in sAD, at least in part through impairing levels of these four mitochondrial-TCA-cycle enzymes.

Lipid Peroxidation Induced ApoE Receptor-Ligand Disruption as a Unifying Hypothesis Underlying Sporadic Alzheimer's Disease in Humans.

Sporadic Alzheimer's disease (sAD) lacks a unifying hypothesis that can account for the lipid peroxidation observed early in the disease, enrichment of ApoE in the core of neuritic plaques, hallmark plaques and tangles, and selective vulnerability of entorhinal-hippocampal structures. We hypothesized that 1) high expression of ApoER2 (receptor for ApoE and Reelin) helps explain this anatomical vulnerability; 2) lipid peroxidation of ApoE and ApoER2 contributes to sAD pathogenesis, by disrupting neuronal ApoE delivery and Reelin-ApoER2-Dab1 signaling cascades. In vitro biochemical experiments; Single-marker and multiplex fluorescence-immunohistochemistry (IHC) in postmortem specimens from 26 individuals who died cognitively normal, with mild cognitive impairment or with sAD. ApoE and ApoER2 peptides and proteins were susceptible to attack by reactive lipid aldehydes, generating lipid-protein adducts and crosslinked ApoE-ApoER2 complexes. Using insitu hybridization alongside IHC, we observed that: 1) ApoER2 is strongly expressed in terminal zones of the entorhinal-hippocampal 'perforant path' projections that underlie memory; 2) ApoE, lipid aldehyde-modified ApoE, Reelin, ApoER2, and the downstream Reelin-ApoER2 cascade components Dab1 and Thr19-phosphorylated PSD95 accumulated in the vicinity of neuritic plaques in perforant path terminal zones in sAD cases; 3) several ApoE/Reelin-ApoER2-Dab1 pathway markers were higher in sAD cases and positively correlated with histological progression and cognitive deficits. Results demonstrate derangements in multiple ApoE/Reelin-ApoER2-Dab1 axis components in perforant path terminal zones in sAD and provide proof-of-concept that ApoE and ApoER2 are vulnerable to aldehyde-induced adduction and crosslinking. Findings provide the foundation for a unifying hypothesis implicating lipid peroxidation of ApoE and ApoE receptors in sAD.

Multi-omics data integration reveals clinically meaningful molecular profiles of Alzheimer disease.

Alzheimer disease (AD) is a complex polygenic disease in which multiple molecular pathways and biological processes are affected in distinct cell-types of the brain. Increasingly, novel machine learning approaches have been applied in other areas of similarly high complexity (e.g., cancer) to integrate different modalities of "-omics" data and provide novel insights. We sought to apply high-throughput "multi-omics" and machine learning approaches to a large assembly of clinically and neuropathologically well-characterized brain samples to identify genes and biological pathways that may lead to new biomarkers and therapies for AD. We analyzed high-throughput transcriptomics, proteomics, metabolomics and lipidomics profiles of postmortem parietal cortex samples from the Knight ADRC (n=328) and the DIAN (n =21) participants including APP, PSEN1 and PSEN2 autosomal dominant AD mutation carriers (ADAD, n=28), sporadic AD (sAD, n=282), presymptomatic AD (preAD, n=14), and controls with minimal neuropathologic changes (n=25). We applied a Bayesian integrative clustering method (iClusterBayes), designed to identify disease subtypes, to cluster sAD samples on the basis of 2,676 transcripts, 1,067 proteins, 350 metabolites, and 277 lipids. Our analyses identified four different molecular signatures among sAD cases (Figure 1A). Cluster 4 was associated with higher Clinical Dementia Rating (CDR; p=2.2 x10-20) scores and shorter life span (p=5.6 x10-3, HR=1.6; Figure 1B). In particular, alpha-synuclein (SNCA) transcriptomic and proteomic levels were differentially expressed between samples in cluster 4 and others representing sAD, ADAD, preAD, and controls (Figure 1C) suggesting a unique role for SNCA in sAD cases with unfavorable outcomes. The lower levels of soluble SNCA protein in AD samples may be associated with insoluble aggregated SNCA (Lewy bodies) reported in 50-60% of sAD. By applying machine learning approaches to sAD samples with high-throughput multi-omic profiles, we identified novel molecular signatures missed by single layer analyses. These signatures are associated with clinical phenotypes and offer new insights into which molecules may wax or wane as cognition declines. The association of SNCA with poor outcomes suggests that concomitant Lewy bodies may be a negative prognostic factor in sAD. Currently, we are extending these analyses to incorporate replication cohorts and to perform downstream pathway and enrichment analyses.

Amyloid, tau, and astrocyte pathology in autosomal-dominant Alzheimer\u2019s disease variants: A\u03b2PParc and PSEN1DE9

Autosomal-dominant Alzheimer’s disease (ADAD) may be associated with atypical amyloid beta deposits in the brain. In vivo amyloid imaging using 11C-Pittsburgh compound B (PiB) tracer has shown differences in binding between brains from ADAD and sporadic Alzheimer’s disease (sAD) patients. To gain further insight into the various pathological characteristics of these genetic variants, we performed large frozen hemisphere autoradiography and brain homogenate binding assays with 3H-PiB, 3H-MK6240-3H-THK5117, and 3H-deprenyl for detection of amyloid fibrils, tau depositions, and activated astrocytes, respectively, in two AβPParc mutation carriers, one PSEN1ΔE9 mutation carrier, and three sAD cases. The results were compared with Abeta 40, Abeta 42, AT8, and GFAP immunostaining, respectively, as well as with Congo red and Bielschowsky. PiB showed a very low binding in AβPParc. A high binding was observed in PSEN1ΔE9 and in sAD tissues but with different binding patterns. Comparable 3H-THK5117 and 3H-deprenyl brain homogenate binding was observed for AβPParc, PSEN1ΔE9, and sAD, respectively. Some differences were observed between 3H-MK6240 and 3H-THK5117 in ADAD. A positive correlation between 3H-deprenyl and 3H-THK5117 binding was observed in AβPParc, while no such correlation was found in PSEN1ΔE9 and sAD. Our study demonstrates differences in the properties of the amyloid plaques between two genetic variants of AD and sAD. Despite the lack of measurable amyloid fibrils by PiB in the AβPParc cases, high regional tau and astrocyte binding was observed. The lack of correlation between 3H-deprenyl and 3H-THK5117 binding in PSEN1ΔE9 and sAD in contrast of the positive correlation observed in the AβPParc cases suggest differences in the pathological cascade between variants of AD that warrant further exploration in vivo.

Investigation of pathology, expression and proteomic profiles in human TREM2 variant postmortem brains with and without Alzheimer's disease.

Triggering receptor expressed on myeloid cells 2 TREM2 was identified as a risk factor for late onset Alzheimer’s disease (AD). Here we compared TREM2 cases with a variant (TREM2+) and cases without a TREM2 variant (TREM2−), considering pathological burden, inflammatory response and altered canonical pathways and biochemical functions between the cohorts. We hypothesised that TREM2+ cases would have a loss of function, indicating an altered inflammatory profile compared to TREM2− cases. Immunohistochemistry was performed using antibodies against Aβ, tau and microglia markers in TREM2+ cases, with and without AD, which were compared to sporadic TREM2− AD, familial AD and neurologically normal control cases. Aβ and tau load were measured along with the composition of Aβ plaques, in addition to microglial load and circularity. Expression and proteomic profiles were determined from the frontal cortex of selected cases. TREM2+ control cases had no Aβ or tau deposition. No differences in the amount of Aβ or tau, or the composition of Aβ plaques were observed between TREM2+ and TREM2− SAD cases. There were no differences in microglial load observed between disease groups. However, the TREM2+ SAD cases showed more amoeboid microglia than the TREM2− SAD cases, although no differences in the spatial relationship of microglia and Aβ plaques were identified. Visualisation of the canonical pathways and biological functions showed differences between the disease groups and the normal controls, clearly showing a number of pathways upregulated in TREM2+ SAD, TREM2− SAD and FAD groups whilst, the TREM2+ controls cases showed a downregulation of the majority of the represented pathways. These findings suggest that the TREM2+ control group, although carrying the TREM2+ variant, have no pathological hallmarks of AD, have altered microglial and expression profiles compared to the TREM2+ SAD cases. This indicates that other unknown factors may initiate the onset of AD, with TREM2 influencing the microglial involvement in disease pathogenesis.

Precursor-Independent Overproduction of Beta-Amyloid in AD: Mitochondrial Dysfunction as Possible Initiator of Asymmetric RNA-Dependent βAPP mRNA Amplification. An Engine that Drives Alzheimer’s Disease

The present study defines RNA-dependent amplification of βAPP mRNA as a molecular basis of beta-amyloid overproduction in Alzheimer's disease. In this process, βAPP mRNA serves as a template for RNA-dependent RNA polymerase, RdRp complex. The resulting antisense RNA self-primes its extension utilizing two complementary elements: 3'-terminal and internal, located within an antisense segment corresponding to the coding portion of βAPP mRNA. The extension produces 3'-terminal fragment of βAPP mRNA, a part of a hairpin-structured antisense/sense RNA molecule. Cleavage at the 3' end of the hairpin loop produces RNA end product encoding a C-terminal fragment of βAPP. Since each conventional βAPP mRNA can be used repeatedly as a template, the process constitutes an asymmetric mRNA amplification. The 5'-most translation initiation codon of the amplified mRNA is the AUG preceding immediately and in-frame the Aβ-coding segment. Translation from this codon overproduces Aβ independently of βAPP. Such process can occur in humans but not in mice and other animals where segments of βAPP antisense RNA required for self-priming have little, if any, complementarity. This explains why Alzheimer's disease occurs exclusively in humans and implies that βAPP mRNA amplification is requisite in AD. In AD, therefore, there are two pathways of beta-amyloid production: βAPP proteolytic pathway and βAPP mRNA amplification pathway independent of βAPP and insensitive to beta-secretase inhibition. This implies that in healthy humans, where only the proteolytic pathway is in operation, Aβ production should be suppressed by the BACE inhibition, and indeed it is. However, since βAPP-independent pathway operating in AD is by far the predominant one, BACE inhibition has no effect in Alzheimer's disease. It appears that, physiologically, the extent of beta-amyloid overproduction sufficient to trigger amyloid cascade culminating in AD requires asymmetric RNA-dependent amplification of βAPP mRNA and cannot be reached without it. In turn, the occurrence of mRNA amplification process depends on the activation of inducible components of RdRp complex by certain stresses, for example the ER stress in case of amplification of mRNA encoding extracellular matrix proteins. In case of Alzheimer's disease, such an induction appears to be triggered by stresses associated with mitochondrial dysfunction, a phenomenon closely linked to AD. The cause-and-effect relationships between mitochondrial dysfunction and AD appear to be very different in familial, FAD, and sporadic, SAD cases. In FAD, increased levels or more toxic species of Aβ resulting from the abnormal proteolysis of βAPP trigger mitochondrial dysfunction, activate mRNA amplification and increase the production of Aβ, reinforcing the cycle. Thus in FAD, mitochondrial dysfunction is an intrinsic component of the amyloid cascade. The reverse sequence is true in SAD where aging-related mitochondrial dysfunction activates amplification of βAPP mRNA and enhances the production of Aβ. This causes further mitochondrial dysfunction, the cycle repeats and degeneration increases. Thus in SAD, the initial mitochondrial dysfunction arises prior to the disease, independently of and upstream from the increased Aβ production, i.e. in SAD, mitochondrial pathology hierarchically supersedes Aβ pathology. This is the primary reason for the formulation of the Mitochondrial Cascade Hypothesis. But even in terms of the MCH, the core of the disease is the amyloid cascade as defined in the amyloid cascade hypothesis, ACH. The role of mitochondrial dysfunction in relation to this core is causative in SAD and auxiliary in FAD. In FAD, the initial increase in the production of Aβ is mutations-based and occurs relatively early in life, whereas in SAD it is coerced by an aging-contingent component, but both lead to mechanistically identical self-perpetuating mutual Aβ/mitochondrial dysfunction feedback cycles, an engine that drives, via RNA-dependent βAPP mRNA amplification, overproduction of beta-amyloid and, consequently, AD; hence drastic difference in the age of onset, yet profound pathological and symptomatic similarity in the progression, of familial and sporadic forms of Alzheimer's disease. Interestingly, the recent findings that mitochondrial microprotein PIGBOS interacts with the ER in mitigating the unfolded protein response indicate a possible connection between mitochondrial dysfunction and ER stress, implicated in activation of RNA-dependent mRNA amplification pathway. The possible involvement of mitochondrial dysfunction in βAPP mRNA amplification makes it a promising therapeutic target. Recent successes in mitigating, and even reversing, Aβ-induced metabolic defects with anti-diabetes drug metformin are encouraging in this respect.

Growing up during the Israeli-Palestinian conflict: The interplay of sense of coherence and the psychological and psychoendocrine consequences of traumatic stress

Pulsatile ultradian secretion of cortisol, rarely studied in salivary data, has functional importance in hypothalamic pituitary adrenal (HPA) axis regulation. The first daily ultradian episode, the cortisol awakening response (CAR), was examined in healthy adults, in 5-min secretion rates of salivary cortisol from electronically monitored awakening time to 1.25 h. Aggregated rates revealed a cubic trend, with wave-length of almost exactly 1 h, as predicted from known ultradian periodicity. Peak secretion rate occurred 20-min post-awakening. Peak (20-min) to trough (59-min) amplitude (PTA) expressed a salient signal shape. Rates rose steeply to and from peak, and major secretion was packaged into a few 5-min intervals, inconsistent with normal or uniform distribution of 5-min rates, but consistent with known pulsatile cortisol delivery. Null hypotheses asserting normal or uniform distributions were rejected. Maximal rates overwhelmingly occurred before and minimal rates after 30-mins, with degree of extremity at each polarity significantly positively correlated.To demonstrate utility and reliability of PTA estimation in a clinically relevant domain, re- analyses of a previously published study were conducted. Data from only three saliva samples were used, given importance of cost considerations for many CAR researchers. Difference between mean rates before and after 30-min yielded a simple salience index, highly correlated with PTA derived from full 5-min interval data. CAR salience performed significantly better than traditional AUCi magnitude in discriminating control cases (higher inferred amplitude) and cases with Seasonal Affective Disorder (lower inferred amplitude). Evidence suggested that low AUCi may be more sensitive in identifying within-subject changes (e.g. more depressed mood in winter among SAD cases) and low CAR salience better at revealing enduring between-subjects associations (e.g. underlying disorder vulnerability). Since both PTA salience and AUCi magnitude can be analysed and compared using exactly the same data from the same commonly used saliva sampling points, further research is warranted into the importance of individual differences in patterns of cortisol delivery, not just how much is delivered.

Feeling like a winner: Affective state, emotional state, and hormone monitoring in division I athletes

Pulsatile ultradian secretion of cortisol, rarely studied in salivary data, has functional importance in hypothalamic pituitary adrenal (HPA) axis regulation. The first daily ultradian episode, the cortisol awakening response (CAR), was examined in healthy adults, in 5-min secretion rates of salivary cortisol from electronically monitored awakening time to 1.25 h. Aggregated rates revealed a cubic trend, with wave-length of almost exactly 1 h, as predicted from known ultradian periodicity. Peak secretion rate occurred 20-min post-awakening. Peak (20-min) to trough (59-min) amplitude (PTA) expressed a salient signal shape. Rates rose steeply to and from peak, and major secretion was packaged into a few 5-min intervals, inconsistent with normal or uniform distribution of 5-min rates, but consistent with known pulsatile cortisol delivery. Null hypotheses asserting normal or uniform distributions were rejected. Maximal rates overwhelmingly occurred before and minimal rates after 30-mins, with degree of extremity at each polarity significantly positively correlated.To demonstrate utility and reliability of PTA estimation in a clinically relevant domain, re- analyses of a previously published study were conducted. Data from only three saliva samples were used, given importance of cost considerations for many CAR researchers. Difference between mean rates before and after 30-min yielded a simple salience index, highly correlated with PTA derived from full 5-min interval data. CAR salience performed significantly better than traditional AUCi magnitude in discriminating control cases (higher inferred amplitude) and cases with Seasonal Affective Disorder (lower inferred amplitude). Evidence suggested that low AUCi may be more sensitive in identifying within-subject changes (e.g. more depressed mood in winter among SAD cases) and low CAR salience better at revealing enduring between-subjects associations (e.g. underlying disorder vulnerability). Since both PTA salience and AUCi magnitude can be analysed and compared using exactly the same data from the same commonly used saliva sampling points, further research is warranted into the importance of individual differences in patterns of cortisol delivery, not just how much is delivered.

Developmental origins of the human hypothalamic-pituitary-adrenal axis

Pulsatile ultradian secretion of cortisol, rarely studied in salivary data, has functional importance in hypothalamic pituitary adrenal (HPA) axis regulation. The first daily ultradian episode, the cortisol awakening response (CAR), was examined in healthy adults, in 5-min secretion rates of salivary cortisol from electronically monitored awakening time to 1.25 h. Aggregated rates revealed a cubic trend, with wave-length of almost exactly 1 h, as predicted from known ultradian periodicity. Peak secretion rate occurred 20-min post-awakening. Peak (20-min) to trough (59-min) amplitude (PTA) expressed a salient signal shape. Rates rose steeply to and from peak, and major secretion was packaged into a few 5-min intervals, inconsistent with normal or uniform distribution of 5-min rates, but consistent with known pulsatile cortisol delivery. Null hypotheses asserting normal or uniform distributions were rejected. Maximal rates overwhelmingly occurred before and minimal rates after 30-mins, with degree of extremity at each polarity significantly positively correlated.To demonstrate utility and reliability of PTA estimation in a clinically relevant domain, re- analyses of a previously published study were conducted. Data from only three saliva samples were used, given importance of cost considerations for many CAR researchers. Difference between mean rates before and after 30-min yielded a simple salience index, highly correlated with PTA derived from full 5-min interval data. CAR salience performed significantly better than traditional AUCi magnitude in discriminating control cases (higher inferred amplitude) and cases with Seasonal Affective Disorder (lower inferred amplitude). Evidence suggested that low AUCi may be more sensitive in identifying within-subject changes (e.g. more depressed mood in winter among SAD cases) and low CAR salience better at revealing enduring between-subjects associations (e.g. underlying disorder vulnerability). Since both PTA salience and AUCi magnitude can be analysed and compared using exactly the same data from the same commonly used saliva sampling points, further research is warranted into the importance of individual differences in patterns of cortisol delivery, not just how much is delivered.

Salience versus magnitude in the measurement of the cortisol awakening response

Pulsatile ultradian secretion of cortisol, rarely studied in salivary data, has functional importance in hypothalamic pituitary adrenal (HPA) axis regulation. The first daily ultradian episode, the cortisol awakening response (CAR), was examined in healthy adults, in 5-min secretion rates of salivary cortisol from electronically monitored awakening time to 1.25 h. Aggregated rates revealed a cubic trend, with wave-length of almost exactly 1 h, as predicted from known ultradian periodicity. Peak secretion rate occurred 20-min post-awakening. Peak (20-min) to trough (59-min) amplitude (PTA) expressed a salient signal shape. Rates rose steeply to and from peak, and major secretion was packaged into a few 5-min intervals, inconsistent with normal or uniform distribution of 5-min rates, but consistent with known pulsatile cortisol delivery. Null hypotheses asserting normal or uniform distributions were rejected. Maximal rates overwhelmingly occurred before and minimal rates after 30-mins, with degree of extremity at each polarity significantly positively correlated.To demonstrate utility and reliability of PTA estimation in a clinically relevant domain, re- analyses of a previously published study were conducted. Data from only three saliva samples were used, given importance of cost considerations for many CAR researchers. Difference between mean rates before and after 30-min yielded a simple salience index, highly correlated with PTA derived from full 5-min interval data. CAR salience performed significantly better than traditional AUCi magnitude in discriminating control cases (higher inferred amplitude) and cases with Seasonal Affective Disorder (lower inferred amplitude). Evidence suggested that low AUCi may be more sensitive in identifying within-subject changes (e.g. more depressed mood in winter among SAD cases) and low CAR salience better at revealing enduring between-subjects associations (e.g. underlying disorder vulnerability). Since both PTA salience and AUCi magnitude can be analysed and compared using exactly the same data from the same commonly used saliva sampling points, further research is warranted into the importance of individual differences in patterns of cortisol delivery, not just how much is delivered.

The intact postsynaptic protein neurogranin is reduced in brain tissue from patients with familial and sporadic Alzheimer\u2019s disease

Synaptic degeneration and neuronal loss are early events in Alzheimer’s disease (AD), occurring long before symptom onset, thus making synaptic biomarkers relevant for enabling early diagnosis. The postsynaptic protein neurogranin (Ng) is a cerebrospinal fluid (CSF) biomarker for AD, also in the prodromal phase. Here we tested the hypothesis that during AD neurodegeneration, processing of full-length Ng into endogenous peptides in the brain is increased. We characterized Ng in post-mortem brain tissue and investigated the levels of endogenous Ng peptides in relation to full-length protein in brain tissue of patients with sporadic (sAD) and familial Alzheimer’s disease (fAD), healthy controls and individuals who were cognitively unaffected but amyloid-positive (CU-AP) in two different brain regions. Brain tissue from parietal cortex [sAD (n = 10) and age-matched controls (n = 10)] and temporal cortex [sAD (n = 9), fAD (n = 10), CU-AP (n = 13) and controls (n = 9)] were included and all the samples were analyzed by three different methods. Using high-resolution mass spectrometry, 39 endogenous Ng peptides were identified while full-length Ng was found to be modified including disulfide bridges or glutathione. In sAD parietal cortex, the ratio of peptide-to-total full-length Ng was significantly increased for eight endogenous Ng peptides compared to controls. In the temporal cortex, several of the peptide-to-total full-length Ng ratios were increased in both sAD and fAD cases compared to controls and CU-AP. This finding was confirmed by western blot, which mainly detects full-length Ng, and enzyme-linked immunosorbent assay, most likely detecting a mix of peptides and full-length Ng. In addition, Ng was significantly associated with the degree of amyloid and tau pathology. These results suggest that processing of Ng into peptides is increased in AD brain tissue, which may reflect the ongoing synaptic degeneration, and which is also mirrored as increased levels of Ng peptides in CSF.

Incidence of cardiac fibrosis in SUDEP and control cases.

Since cardic fibrosis was previously found more frequently in patients with sudden unexpected death in epilepsy (SUDEP) than control cases, we compared blinded and quantitative reviews of cardiac pathology in SUDEP to multiple control groups. We adjudicated causes of death in epilepsy patients as part of consecutive out-of-hospital sudden cardiac deaths (SCDs) from the Postmortem Systematic Investigation of Sudden Cardiac Death (POSTSCD) study. Blinded cardiac gross and microscopic examinations were performed by forensic and cardiac pathologists. Of 541 SCDs over 37 months (mean age 62.8 years, 69% male), 525 (97%) were autopsied; 25/525 (4.8%) had epilepsy (mean age 56.4 years ± 15.4, range 27-92; 67% male). The 25 epilepsy patients died of definite SUDEP/definite SUDEP-plus (n = 8), possible SUDEP (n = 10), or other causes (n = 7). Comparison groups included autopsy-defined sudden arrhythmic death (SAD; n = 285) and trauma (n = 104) and we adjusted for age, sex, HIV, coronary artery disease, congestive heart failure, and cardiomyopathy in the analyses. Compared to SAD cases, SUDEP cases had less gross and histologic evidence of cardiac pathology; significant for cardiac mass (p < 0.0011), coronary artery disease (p < 0.0024), total cardiac fibrosis (CF) (p = 0.022), and interstitial CF (p = 0.013). Compared to trauma cases, SUDEP cases had similar cardiac pathology including CF. Among SUDEP cases, cardiac pathology was less severe than in SAD cases but similar to trauma and epilepsy controls. Our data do not support prior studies finding elevated rates of CF among SUDEP cases compared to controls. Larger studies including molecular analyses would further our understanding of cardiac changes associated with SUDEP.

Goldfish, and: Gold Donkey

Goldfish, and: Gold Donkey Ted Mathys (bio) Goldfish Sometimes a ping pong ballricochets in the improbable honeycomb of fishbowls—liplip—before rimming out and you are grateful to physicsfor saving you from having to adopt a distressed carnival petand send your child off on her first, slowpilgrimage to grief. But sometimes a package dealleaves you stuck with a full bucket of balls. You put a littleEnglish on a throw, and the wind’s sorcery provides a direct hit,the splash unnerving the skittish creature your child declaresis a girl named Marvin. Eighty dollars laterMarvin is in an aquarium on your child’s dresserdarting in all that water, [End Page 46] all that LED light. Sometimesdiagnoses of shock proliferate for one who no longer recognizesthe system in which she lives— lack of appetite, bottom sitting,black spots, skin flukes, slow mouth and gill movement,a decline from golden sheen to sallow white—until a protective impulse grows animal in your core.Sometimes there’s a protest on the radio when you enter your child’s roomto retrieve her ladybug rain boots and find your wife in her bathrobesitting on the bed alone, watching Marvin swallow a descending flakeand there’s no need to ask why. [End Page 47] Gold Donkey —Cripple Creek, Colorado The canary in the gold minespent her nights above groundand days 1000 feet downthe same cool shaftI descend in a metal cageto the crosscuts and driftsblasted into Independence Lodeand hung in her little cagelow between ore cart wheelswhere she could die sacrificiallyin an updraft of monoxide. But the donkey in the gold minewas born down here, and hermother before her, a lineageaccustomed to hauling rockwith flecks of quartz and goldthrough blackness interruptedonly by a candle strappedto the mucker’s hator a calcium carbide lamphot with acetylene flamethat leapt at the wind of a sledge,burnt off a tenderfoot’s eyebrowsand singed a black starinto the donkey’s hide. A politician legislated lightinto the donkey’s livesbut the asses kicked like madwhen the nippers—kidsat 5 cents a shift—strung themfrom the cage’s base in slingsand sent them up the shaftinto sun they’d never known.Like all good ideas, this oneburnt out the retinas in seconds. [End Page 48] While I’m below, a sunset above.I rise along a wall of oxidized ironthe color of tobacco spit, emerge.There are twelve donkeys at largein town, the bartender says, directdescendants of those from below.I search for them for an hourbut find only a coyote trottingthe Family Dollar parking lot. In rain, in the donkeys’ honor,I choose from the strip of casinosThe Brass Ass, wade throughthe usual sad cases to roulette.At the only game with no strategymy only job is to bet on black, odd,and constellations of birthdaysthen wait like an ass for the houseto place the dolly and rake my chips. The dealer spins the ballagainst the spinning wheeland sweeps her arm to end all bets.The bottled water I ordered arrives.The brand is Eldorado. The ball fallsinto 29 black. I win hundreds.When a donkey bucked and contortedhard enough to slip free on ascentit plummeted like a bullet reversingto explode in its own chamber.Chips in stacks float to me on felt.They are not gold but powder blue.The ball falls into 15 black. Again,I win. When a donkey fell it fellto the nippers at the bottomto clean up the mess. [End Page 49] Ted Mathys Ted Mathys is the author of Null Set (Coffee House Press, 2015) and two previous collections of poetry. Copyright © 2018 Pleiades and Pleiades Press