Fanny Elahi

A Critical Review of Dissociative Trance and Possession Disorders: Etiological, Diagnostic, Therapeutic, and Nosological Issues:

Objective: Although the Diagnostic and Statistical Manual of Mental Disorders (DSM), Fourth Edition, acknowledges the existence of dissociative trance and possession disorders, simply named dissociative trance disorder (DTD), it asks for further studies to assess its clinical utility in the DSM-5. To answer this question, we conducted the first review of the medical literature. Method: The MEDLINE, CINAHL, and PsycINFO databases were searched from 1988 to 2010, seeking case reports of DTD according to the DSM or the International Classification of Diseases definitions. For each article, we collected epidemiologic and clinical data, explanatory models used by authors, treatments, and information on the outcome. Results: We found 28 articles reporting 402 cases of patients with DTD worldwide. The data show an equal proportion of female and male patients, and a predominance of possession (69%), compared with trance (31%). Amnesia is reported by 20% of patients. Conversely, hallucinatory symptoms during possession episodes were found in 56% of patients and thus should feature as an important criterion. Somatic complaints are found in 34% of patients. Multiple explanatory models are simultaneously held and appear to be complementary. Conclusion: Data strongly suggest the inclusion of DTD in the DSM-5, provided certain adjustments are implemented. DTD is a widespread disorder that can be understood as a global idiom of distress, probably underdiagnosed in Western countries owing to cultural biases, whose incidence could increase given the rising flow of migration. Accurate diagnosis and appropriate management should result from a comprehensive evaluation both of sociocultural and of idiosyncratic issues, among which acculturation difficulties should systematically be considered, especially in cross-cultural settings.

A clinicopathological approach to the diagnosis of dementia

The most definitive classification systems for dementia are based on the underlying pathology which, in turn, is categorized largely according to the observed accumulation of abnormal protein aggregates in neurons and glia. These aggregates perturb molecular processes, cellular functions and, ultimately, cell survival, with ensuing disruption of large-scale neural networks subserving cognitive, behavioural and sensorimotor functions. The functional domains affected and the evolution of deficits in these domains over time serve as footprints that the clinician can trace back with various levels of certainty to the underlying neuropathology. The process of phenotyping and syndromic classification has substantially improved over decades of careful clinicopathological correlation, and through the discovery of in vivo biomarkers of disease. Here, we present an overview of the salient features of the most common dementia subtypes — Alzheimer disease, vascular dementia, frontotemporal dementia and related syndromes, Lewy body dementias, and prion diseases — with an emphasis on neuropathology, relevant epidemiology, risk factors, and signature signs and symptoms.

The concept of FDG-PET endophenotype in Alzheimer’s disease

Often viewed as a potential tool for preclinical diagnosis in early asymptomatic stages of Alzheimer’s disease (AD), the term “endophenotype” has acquired a recent popularity in the field. In this review, we analyze the construct of endophenotype—originally designed to discover genes, and examine the literature on potential endophenotypes for the late-onset form of AD (LOAD). We focus on the [18F]-fluoro-2-deoxyglucose (FDG) PET technique, which shows a characteristic pattern of hypometabolism in AD-related regions in asymptomatic carriers of the ApoE E4 allele and in children of AD mothers. We discuss the pathophysiological significance and the positive predictive accuracy of an FDG-endophenotype for LOAD in asymptomatic subjects, and discuss several applications of this endophenotype in the identification of both promoting and protective factors. Finally, we suggest that the term “endophenotype” should be reserved to the study of risk factors, and not to the preclinical diagnosis of LOAD.

The Longitudinal Trajectory of Default Mode Network Connectivity in Healthy Older Adults Varies as a Function of Age and is Associated with Changes in Episodic Memory and Processing Speed

The default mode network (DMN) supports memory functioning and may be sensitive to preclinical Alzheimers pathology. Little is known, however, about the longitudinal trajectory of this networks intrinsic functional connectivity (FC). In this study, we evaluated longitudinal FC in 111 cognitively normal older human adults (ages 49–87, 46 women/65 men), 92 of whom had at least three task-free fMRI scans (n = 353 total scans). Whole-brain FC and three DMN subnetworks were assessed: (1) within-DMN, (2) between anterior and posterior DMN, and (3) between medial temporal lobe network and posterior DMN. Linear mixed-effects models demonstrated significant baseline age × time interactions, indicating a nonlinear trajectory. There was a trend toward increasing FC between ages 50–66 and significantly accelerating declines after age 74. A similar interaction was observed for whole-brain FC. APOE status did not predict baseline connectivity or change in connectivity. After adjusting for network volume, changes in within-DMN connectivity were specifically associated with changes in episodic memory and processing speed but not working memory or executive functions. The relationship with processing speed was attenuated after covarying for white matter hyperintensities (WMH) and whole-brain FC, whereas within-DMN connectivity remained associated with memory above and beyond WMH and whole-brain FC. Whole-brain and DMN FC exhibit a nonlinear trajectory, with more rapid declines in older age and possibly increases in connectivity early in the aging process. Within-DMN connectivity is a marker of episodic memory performance even among cognitively healthy older adults. SIGNIFICANCE STATEMENT Default mode network and whole-brain connectivity, measured using task-free fMRI, changed nonlinearly as a function of age, with some suggestion of early increases in connectivity. For the first time, longitudinal changes in DMN connectivity were shown to correlate with changes in episodic memory, whereas volume changes in relevant brain regions did not. This relationship was not accounted for by white matter hyperintensities or mean whole-brain connectivity. Functional connectivity may be an early biomarker of changes in aging but should be used with caution given its nonmonotonic nature, which could complicate interpretation. Future studies investigating longitudinal network changes should consider whole-brain changes in connectivity.

Neurogranin, a synaptic protein, is associated with memory independent of Alzheimer biomarkers

Objective: To determine the association between synaptic functioning as measured via neurogranin in CSF and cognition relative to established Alzheimer disease (AD) biomarkers in neurologically healthy older adults. Methods: We analyzed CSF concentrations of neurogranin, β-amyloid (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) among 132 neurologically normal older adults (mean 64.5, range 55–85), along with bilateral hippocampal volumes and a measure of episodic memory (Auditory Verbal Learning Test, delayed recall). Univariable analyses examined the relationship between neurogranin and the other AD-related biomarkers. Multivariable regression models examined the relationship between neurogranin and delayed recall, adjusting for age and sex, and interaction terms (neurogranin × AD biomarkers). Results: Higher neurogranin concentrations were associated with older age (ρ = 0.20, p = 0.02), lower levels of p-tau and t-tau, and smaller hippocampal volumes (p < 0.03), but not with CSF Aβ42 (p = 0.18). In addition, CSF neurogranin demonstrated a significant relationship with memory performance independent of the AD-related biomarkers; individuals with the lowest CSF neurogranin concentrations performed better on delayed recall than those with medium or high CSF neurogranin concentrations (p < 0.01). Notably, CSF p-tau, t-tau, and Aβ42 and hippocampal volumes were not significantly associated with delayed recall scores (p > 0.40), and did not interact with neurogranin to predict memory (p > 0.10). Conclusions: Synaptic dysfunction (assessed via neurogranin) may be an early pathologic process in age-related neurodegeneration, and a sensitive marker of age-related cognitive abilities, potentially preceding or even acting independently from AD pathogenesis. Synaptic functioning may be a useful early marker of cognitive aging and possibly a target for future brain aging interventions.

Longitudinal white matter change in frontotemporal dementia subtypes and sporadic late onset Alzheimer's disease

Background Degradation of white matter microstructure has been demonstrated in frontotemporal lobar degeneration (FTLD) and Alzheimers disease (AD). In preparation for clinical trials, ongoing studies are investigating the utility of longitudinal brain imaging for quantification of disease progression. To date only one study has examined sample size calculations based on longitudinal changes in white matter integrity in FTLD. Objective To quantify longitudinal changes in white matter microstructural integrity in the three canonical subtypes of frontotemporal dementia (FTD) and AD using diffusion tensor imaging (DTI). Methods 60 patients with clinical diagnoses of FTD, including 27 with behavioral variant frontotemporal dementia (bvFTD), 14 with non-fluent variant primary progressive aphasia (nfvPPA), and 19 with semantic variant PPA (svPPA), as well as 19 patients with AD and 69 healthy controls were studied. We used a voxel-wise approach to calculate annual rate of change in fractional anisotropy (FA) and mean diffusivity (MD) in each group using two time points approximately one year apart. Mean rates of change in FA and MD in 48 atlas-based regions-of-interest, as well as global measures of cognitive function were used to calculate sample sizes for clinical trials (80% power, alpha of 5%). Results All FTD groups showed statistically significant baseline and longitudinal white matter degeneration, with predominant involvement of frontal tracts in the bvFTD group, frontal and temporal tracts in the PPA groups and posterior tracts in the AD group. Longitudinal change in MD yielded a larger number of regions with sample sizes below 100 participants per therapeutic arm in comparison with FA. SvPPA had the smallest sample size based on change in MD in the fornix (n = 41 participants per study arm to detect a 40% effect of drug), and nfvPPA and AD had their smallest sample sizes based on rate of change in MD within the left superior longitudinal fasciculus (n = 49 for nfvPPA, and n = 23 for AD). BvFTD generally showed the largest sample size estimates (minimum n = 140 based on MD in the corpus callosum). The corpus callosum appeared to be the best region for a potential study that would include all FTD subtypes. Change in global measure of functional status (CDR box score) yielded the smallest sample size for bvFTD (n = 71), but clinical measures were inferior to white matter change for the other groups. Conclusions All three of the canonical subtypes of FTD are associated with significant change in white matter integrity over one year. These changes are consistent enough that drug effects in future clinical trials could be detected with relatively small numbers of participants. While there are some differences in regions of change across groups, the genu of the corpus callosum is a region that could be used to track progression in studies that include all subtypes.

Lipid associated polygenic enrichment in Alzheimer's disease

Cardiovascular (CV) and lifestyle associated risk factors (RFs) are increasingly recognized as important for Alzheimer’s disease (AD) pathogenesis. Beyond the ∊4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV associated genes also increase risk for AD (genetic pleiotropy). Using large genome-wide association studies (GWASs) (total n > 500,000 cases and controls) and validated tools to quantify genetic pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 57 SNPs on 19 different chromosomes that were jointly associated with AD and CV outcomes including APOA4, ABCA1, ABCG5, LIPG, and MTCH2/SPI1. We found that common genetic variants influencing AD are associated with multiple CV RFs, at times with a different directionality of effect. Expression of these AD/CV pleiotropic genes was enriched for lipid metabolism processes, over-represented within astrocytes and vascular structures, highly co-expressed, and differentially altered within AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid associated RFs. Rather than a single causal link between genetic loci, RF and the outcome, we found that common genetic variants influencing AD are associated with multiple CV RFs. Our collective findings suggest that a network of genes involved in lipid biology also influence Alzheimer’s risk.

New Antibody-Free Mass Spectrometry-Based Quantification Reveals That C9ORF72 Long Protein Isoform Is Reduced in the Frontal Cortex of Hexanucleotide-Repeat Expansion Carriers

Frontotemporal dementia (FTD) is a fatal neurodegenerative disease characterized by behavioral and language disorders. The main genetic cause of FTD is an intronic hexanucleotide repeat expansion (G4C2)n in the C9ORF72 gene. A loss of function of the C9ORF72 protein associated with the allele-specific reduction of C9ORF72 expression is postulated to contribute to the disease pathogenesis. To better understand the contribution of the loss of function to the disease mechanism, we need to determine precisely the level of reduction in C9ORF72 long and short isoforms in brain tissue from patients with C9ORF72 mutations. In this study, we developed a sensitive and robust mass spectrometry (MS) method for quantifying C9ORF72 isoform levels in human brain tissue without requiring antibody or affinity reagent. An optimized workflow based on surfactant-aided protein extraction and pellet digestion was established for optimal recovery of the two isoforms in brain samples. Signature peptides, common or specific to the isoforms, were targeted in brain extracts by multiplex MS through the parallel reaction monitoring mode on a Quadrupole–Orbitrap high resolution mass spectrometer. The assay was successfully validated and subsequently applied to frontal cortex brain samples from a cohort of FTD patients with C9ORF72 mutations and neurologically normal controls without mutations. We showed that the C9ORF72 short isoform in the frontal cortices is below detection threshold in all tested individuals and the C9ORF72 long isoform is significantly decreased in C9ORF72 mutation carriers.

A comparison of biofluid cytokine markers across platform technologies: Correspondence or divergence?

Background Quantification of biofluid cytokines is a rapidly growing area of translational research. However, comparability across the expanding number of available assay platforms for detection of the same proteins remains to be determined. We aimed to directly compare a panel of commonly measured cytokines in plasma of typically aging adults across two high sensitivity quantification platforms, Meso Scale Discovery high performance electrochemiluminiscence (HPE) and single‐molecule immunosorbent assays (Simoa) by Quanterix. Methods 57 community‐dwelling older adults completed a blood draw, neuropsychological assessment, and brain MRI as part of a healthy brain aging study. Plasma samples from the same draw dates were analyzed for IL‐10, IP‐10, IL‐6, TNF&agr;, and IL‐1&bgr; on HPE and Simoa, separately. Reliable detectability (coefficient of variance (CV) < 20% and outliers 3 interquartiles above the median removed), intra‐assay precision, absolute concentrations, reproducibility across platforms, and concurrent associations with external variables of interest (e.g., demographics, peripheral markers of vascular health, and brain health) were examined. Results The proportion of cytokines reliably measured on HPE (87.7–93.0%) and Simoa (75.4–93.0%) did not differ (ps > 0.32), with the exception of IL‐1&bgr; which was only reliably measured using Simoa (68.4%). On average, CVs were acceptable at <8% across both platforms. Absolute measured concentrations were higher using Simoa for IL‐10, IL‐6, and TNF&agr; (ps < 0.05). HPE and Simoa shared only small‐to‐moderate proportions of variance with one another on the same cytokine proteins (range: r = 0.26 for IL‐10 to r = 0.64 for IL‐6), though platform agreement did not dependent on cytokine concentrations. Cytokine ratios within each platform demonstrated similar relative patterns of up‐ and down‐regulation across HPE and Simoa, though still significantly differed (ps < 0.001). Supporting concurrent validity, all 95% confidence intervals of the correlations between cytokines and external variables overlapped between the two platforms. Moreover, most associations were in expected directions and consistently so across platforms (e.g., IL‐6 and TNF&agr;), though with several notable exceptions for IP‐10 and IL‐10. Conclusions HPE and Simoa showed comparable detectability and intra‐assay precision measuring a panel of commonly examined cytokine proteins, with the exception of IL‐1&bgr; which was not reliably detected on HPE. However, Simoa demonstrated overall higher concentrations and the two platforms did not show agreement when directly compared against one another. Relative cytokine ratios and associations demonstrated similar patterns across platforms. Absolute cytokine concentrations may not be directly comparable across platforms, may be analyte dependent, and interpretation may be best limited to discussion of relative associations. HighlightsMSD HPE and Quanterix Simoa are analytic platforms to detect biofluid cytokines.Detectability and reliability of the same cytokines did not differ across platforms.Absolute cytokine concentrations were higher using Simoa vs. HPE.Cross‐platform correlations were low, but cytokine ratios showed similar patterns.Cytokine measurement is platform‐specific and is best interpreted in relative terms.

Perceived Stress is Associated with Accelerated Monocyte/Macrophage Aging Trajectories in Clinically Normal Adults

OBJECTIVES Chronic stress is associated with poorer age-related cognition, but the mechanisms of this relationship are not well understood. Aging increases expression of activated macrophages, leading to exacerbated immune responses to stressors. We examined the impact of stress and aging on macrophage-related inflammation and cognition in clinically normal adults. METHODS Three hundred eighty clinically normal adults were followed longitudinally (age M = 73 years; visit range: 1-8; M = 2.5 visits). Participants completed the Perceived Stress Scale, a neuropsychological battery, and blood draws. Plasma was analyzed for cytokines related to macrophage function (interleukin 6, tumor necrosis factor alpha, macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta). Linear mixed-effects examined the effects of age, baseline stress, and their interaction predicting macrophage cytokines, adjusting for sex, education, and depressive symptoms. Latent growth curve models assessed the mediating role of macrophage cytokines in the relationship between age and cognition in high or low stress. RESULTS Baseline perceived stress interacted with age to predict macrophage cytokines longitudinally. Specifically, high-stress adults demonstrated accelerated age-related elevations in macrophage cytokines across time. Macrophage cytokines negatively tracked with executive functioning longitudinally. Macrophage cytokines mediated 19% of the relationship between age and executive function in high-stress, but not low-stress, adults. CONCLUSIONS Our data provide evidence of accelerated immune aging among individuals with high stress. Elevated macrophage cytokine trajectories mediated the effect of age on executive function only in individuals with high stress, suggesting these constructs may be more tightly linked in elevated stress contexts. Stress interventions are warranted to optimize immune aging, with possible downstream cognitive benefits among even clinically normal adults.