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Retrospective analysis of Braak stage- and APOE4 allele-dependent associations between MR spectroscopy and markers of tau and neurodegeneration in cognitively unimpaired elderly

Chen, Anna M; Gajdošík, Martin; Ahmed, Wajiha; Ahn, Sinyeob; Babb, James S; Blessing, Esther M; Boutajangout, Allal; de Leon, Mony J; Debure, Ludovic; Gaggi, Naomi; Gajdošík, Mia; George, Ajax; Ghuman, Mobeena; Glodzik, Lidia; Harvey, Patrick; Juchem, Christoph; Marsh, Karyn; Peralta, Rosemary; Rusinek, Henry; Sheriff, Sulaiman; Vedvyas, Alok; Wisniewski, Thomas; Zheng, Helena; Osorio, Ricardo; Kirov, Ivan I
PURPOSE/OBJECTIVE:The pathological hallmarks of Alzheimer's disease (AD), amyloid, tau, and associated neurodegeneration, are present in the cortical gray matter (GM) years before symptom onset, and at significantly greater levels in carriers of the apolipoprotein E4 (APOE4) allele. Their respective biomarkers, A/T/N, have been found to correlate with aspects of brain biochemistry, measured with magnetic resonance spectroscopy (MRS), indicating a potential for MRS to augment the A/T/N framework for staging and prediction of AD. Unfortunately, the relationships between MRS and A/T/N biomarkers are unclear, largely due to a lack of studies examining them in the context of the spatial and temporal model of T/N progression. Advanced MRS acquisition and post-processing approaches have enabled us to address this knowledge gap and test the hypotheses, that glutamate-plus-glutamine (Glx) and N-acetyl-aspartate (NAA), metabolites reflecting synaptic and neuronal health, respectively, measured from regions on the Braak stage continuum, correlate with: (i) cerebrospinal fluid (CSF) p-tau181 level (T), and (ii) hippocampal volume or cortical thickness of parietal lobe GM (N). We hypothesized that these correlations will be moderated by Braak stage and APOE4 genotype. METHODS:We conducted a retrospective imaging study of 34 cognitively unimpaired elderly individuals who received APOE4 genotyping and lumbar puncture from pre-existing prospective studies at the NYU Grossman School of Medicine between October 2014 and January 2019. Subjects returned for their imaging exam between April 2018 and February 2020. Metabolites were measured from the left hippocampus (Braak II) using a single-voxel semi-adiabatic localization by adiabatic selective refocusing sequence; and from the bilateral posterior cingulate cortex (PCC; Braak IV), bilateral precuneus (Braak V), and bilateral precentral gyrus (Braak VI) using a multi-voxel echo-planar spectroscopic imaging sequence. Pearson and Spearman correlations were used to examine the relationships between absolute levels of choline, creatine, myo-inositol, Glx, and NAA and CSF p-tau181, and between these metabolites and hippocampal volume or parietal cortical thicknesses. Covariates included age, sex, years of education, Fazekas score, and months between CSF collection and MRI exam. RESULTS:There was a direct correlation between hippocampal Glx and CSF p-tau181 in APOE4 carriers (Pearson's r = 0.76, p = 0.02), but not after adjusting for covariates. In the entire cohort, there was a direct correlation between hippocampal NAA and hippocampal volume (Spearman's r = 0.55, p = 0.001), even after adjusting for age and Fazekas score (Spearman's r = 0.48, p = 0.006). This relationship was observed only in APOE4 carriers (Pearson's r = 0.66, p = 0.017), and was also retained after adjustment (Pearson's r = 0.76, p = 0.008; metabolite-by-carrier interaction p = 0.03). There were no findings in the PCC, nor in the negative control (late Braak stage) regions of the precuneus and precentral gyrus. CONCLUSIONS:Our findings are in line with the spatially- and temporally-resolved Braak staging model of pathological severity in which the hippocampus is affected earlier than the PCC. The correlations, between MRS markers of synaptic and neuronal health and, respectively, T and N pathology, were found exclusively within APOE4 carriers, suggesting a connection with AD pathological change, rather than with normal aging. We therefore conclude that MRS has the potential to augment early A/T/N staging, with the hippocampus serving as a more sensitive MRS target compared to the PCC.
PMCID:11404707
PMID: 39029606
ISSN: 1095-9572
CID: 5695972

The neutrophil to lymphocyte ratio associates with markers of Alzheimer's disease pathology in cognitively unimpaired elderly people

Jacobs, Tovia; Jacobson, Sean R; Fortea, Juan; Berger, Jeffrey S; Vedvyas, Alok; Marsh, Karyn; He, Tianshe; Gutierrez-Jimenez, Eugenio; Fillmore, Nathanael R; Gonzalez, Moses; Figueredo, Luisa; Gaggi, Naomi L; Plaska, Chelsea Reichert; Pomara, Nunzio; Blessing, Esther; Betensky, Rebecca; Rusinek, Henry; Zetterberg, Henrik; Blennow, Kaj; Glodzik, Lidia; Wisniweski, Thomas M; de Leon, Mony J; Osorio, Ricardo S; Ramos-Cejudo, Jaime; ,
BACKGROUND:(p-tau), as well as the trajectories of these CSF measures obtained longitudinally. RESULTS:A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ + (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. CONCLUSIONS:We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.
PMID: 38760856
ISSN: 1742-4933
CID: 5733742

The neutrophil to lymphocyte ratio associates with markers of Alzheimer's disease pathology in cognitively unimpaired elderly people

Jacobs, Tovia; Jacobson, Sean R; Fortea, Juan; Berger, Jeffrey S; Vedvyas, Alok; Marsh, Karyn; He, Tianshe; Gutierrez-Jimenez, Eugenio; Fillmore, Nathanael R; Bubu, Omonigho M; Gonzalez, Moses; Figueredo, Luisa; Gaggi, Naomi L; Plaska, Chelsea Reichert; Pomara, Nunzio; Blessing, Esther; Betensky, Rebecca; Rusinek, Henry; Zetterberg, Henrik; Blennow, Kaj; Glodzik, Lidia; Wisniewski, Thomas M; Leon, Mony J; Osorio, Ricardo S; Ramos-Cejudo, Jaime
BACKGROUND/UNASSIGNED:(p-tau), as well as the trajectories of these CSF measures obtained longitudinally. RESULTS/UNASSIGNED:A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β=-12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ+ (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. CONCLUSIONS/UNASSIGNED:in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.
PMID: 38559231
ISSN: 2693-5015
CID: 5728992

Screening for PTSD and TBI in Veterans using Routine Clinical Laboratory Blood Tests

Xu, Mu; Lin, Ziqiang; Siegel, Carole E; Laska, Eugene M; Abu-Amara, Duna; Genfi, Afia; Newman, Jennifer; Jeffers, Michelle K; Blessing, Esther M; Flanagan, Steven R; Fossati, Silvia; Etkin, Amit; Marmar, Charles R
Post-traumatic stress disorder (PTSD) is a mental disorder diagnosed by clinical interviews, self-report measures and neuropsychological testing. Traumatic brain injury (TBI) can have neuropsychiatric symptoms similar to PTSD. Diagnosing PTSD and TBI is challenging and more so for providers lacking specialized training facing time pressures in primary care and other general medical settings. Diagnosis relies heavily on patient self-report and patients frequently under-report or over-report their symptoms due to stigma or seeking compensation. We aimed to create objective diagnostic screening tests utilizing Clinical Laboratory Improvement Amendments (CLIA) blood tests available in most clinical settings. CLIA blood test results were ascertained in 475 male veterans with and without PTSD and TBI following warzone exposure in Iraq or Afghanistan. Using random forest (RF) methods, four classification models were derived to predict PTSD and TBI status. CLIA features were selected utilizing a stepwise forward variable selection RF procedure. The AUC, accuracy, sensitivity, and specificity were 0.730, 0.706, 0.659, and 0.715, respectively for differentiating PTSD and healthy controls (HC), 0.704, 0.677, 0.671, and 0.681 for TBI vs. HC, 0.739, 0.742, 0.635, and 0.766 for PTSD comorbid with TBI vs HC, and 0.726, 0.723, 0.636, and 0.747 for PTSD vs. TBI. Comorbid alcohol abuse, major depressive disorder, and BMI are not confounders in these RF models. Markers of glucose metabolism and inflammation are among the most significant CLIA features in our models. Routine CLIA blood tests have the potential for discriminating PTSD and TBI cases from healthy controls and from each other. These findings hold promise for the development of accessible and low-cost biomarker tests as screening measures for PTSD and TBI in primary care and specialty settings.
PMCID:9944218
PMID: 36810280
ISSN: 2158-3188
CID: 5448152

Hippocampal Subfield Volumes Predict Disengagement from Maintenance Treatment in First Episode Schizophrenia

Qi, Wei; Marx, Julia; Zingman, Michael; Li, Yi; Petkova, Eva; Blessing, Esther; Ardekani, Babak; Sakalli Kani, Ayse; Cather, Corinne; Freudenreich, Oliver; Holt, Daphne; Zhao, Jingping; Wang, Jijun; Goff, Donald C
OBJECTIVES/OBJECTIVE:Disengagement from treatment is common in first episode schizophrenia (FES) and is associated with poor outcomes. Our aim was to determine whether hippocampal subfield volumes predict disengagement during maintenance treatment of FES. METHODS:FES patients were recruited from sites in Boston, New York, Shanghai, and Changsha. After stabilization on antipsychotic medication, participants were randomized to add-on citalopram or placebo and followed for 12 months. Demographic, clinical and cognitive factors at baseline were compared between completers and disengagers in addition to volumes of hippocampal subfields. RESULTS:Baseline data were available for 95 randomized participants. Disengagers (n = 38, 40%) differed from completers (n = 57, 60%) by race (more likely Black; less likely Asian) and in more alcohol use, parkinsonism, negative symptoms and more impairment in visual learning and working memory. Bilateral dentate gyrus (DG), CA1, CA2/3 and whole hippocampal volumes were significantly smaller in disengagers compared to completers. When all the eight volumes were entered into the model simultaneously, only left DG volume significantly predicted disengagement status and remained significant after adjusting for age, sex, race, intracranial volume, antipsychotic dose, duration of untreated psychosis, citalopram status, alcohol status, and smoking status (P < .01). Left DG volume predicted disengagement with 57% sensitivity and 83% specificity. CONCLUSIONS:Smaller left DG was significantly associated with disengagement status over 12 months of maintenance treatment in patients with FES participating in a randomized clinical trial. If replicated, these findings may provide a biomarker to identify patients at risk for disengagement and a potential target for interventions.
PMID: 36370124
ISSN: 1745-1701
CID: 5357702

Data-driven clustering of functional signals reveals gradients in processing both within the anterior hippocampus and across its long axis

Thorp, John N; Gasser, Camille; Blessing, Esther; Davachi, Lila
A particularly elusive puzzle concerning the hippocampus is how the structural differences along its long, anteroposterior axis might beget meaningful functional differences, particularly in terms of the granularity of information processing. One measure posits to quantify this granularity by calculating the average statistical independence of the BOLD signal across neighboring voxels, or inter-voxel similarity (IVS), and has shown the anterior hippocampus to process coarser-grained information than the posterior hippocampus. This measure, however, has yielded opposing results in studies of developmental and healthy aging samples, which also varied in fMRI acquisition parameters and hippocampal parcellation methods. In order to reconcile these findings, we measured IVS across two separate resting-state fMRI acquisitions and compared the results across many of the most widely used parcellation methods in a large young-adult sample of male and female humans (Acquisition 1, N = 233; Acquisition 2, N = 176). Finding conflicting results across acquisitions and parcellations, we reasoned that a data-driven approach to hippocampal parcellation is necessary. To this end, we implemented a group masked independent components analysis (mICA) to identify functional subunits of the hippocampus, most notably separating the anterior hippocampus into separate anterior-medial, anterior-lateral, and posteroanterior-lateral components. Measuring IVS across these components revealed a decrease in IVS along the medial-lateral axis of the anterior hippocampus but an increase from anterior to posterior. We conclude that inter-voxel similarity is deeply affected by parcellation, and that grounding one's parcellation in a functionally informed approach might allow for a more complex and reliable characterization of the hippocampus.SIGNIFICANCE STATEMENT:Processing information along hierarchical scales of granularity is critical for many of the feats of cognition considered most human. Recently, the changes in structure, cortical connectivity, and apparent functional properties across parcels of the hippocampal long axis have been hypothesized to underlie this hierarchical gradient in information processing. We show here, however, that the choice of parcellation method itself drastically affects one particular measure of granularity across the hippocampus, and that a functionally informed approach to parcellation reveals gradients both within the anterior hippocampus and in non-linear form across the long axis. These results point to the issue of parcellation as a critical one in the study of the hippocampus and reorient interpretation of existing results.
PMID: 36002264
ISSN: 1529-2401
CID: 5338262

Association between lower body temperature and increased tau pathology in cognitively normal older adults

Blessing, Esther M; Parekh, Ankit; Betensky, Rebecca A; Babb, James; Saba, Natalie; Debure, Ludovic; Varga, Andrew W; Ayappa, Indu; Rapoport, David M; Butler, Tracy A; de Leon, Mony J; Wisniewski, Thomas; Lopresti, Brian J; Osorio, Ricardo S
BACKGROUND:Preclinical studies suggest body temperature (Tb) and consequently brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD). Tau phosphorylation is substantially increased by small (<1 °C) decreases in temperature within the human physiological range, and thermoregulatory nuclei are affected by tau pathology early in the AD continuum. In this study we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults. METHODS:Tb was continuously measured with ingestible telemetry sensors for 48-h. This period also included two nights of nocturnal polysomnography to delineate whether Tb during waking vs sleep is differentially associated with tau pathology. Tau phosphorylation was assessed with plasma and cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (P-tau), sampled the day following Tb measurement. In addition, neurofibrillary tangle (NFT) burden in early Braak stage regions was imaged with PET-MR using the [18F]MK-6240 radiotracer on average one month later. RESULTS:Lower Tb was associated with increased NFT burden, as well as increased plasma and CSF P-tau levels (p < 0.05). NFT burden was associated with lower Tb during waking (p < 0.05) but not during sleep intervals. Plasma and CSF Ptau levels were highly correlated with each other (p < 0.05), and both variables were correlated with tau tangle radiotracer uptake (p < 0.05). CONCLUSIONS:These results, the first available for human, suggest that lower Tb in older adults may be associated with increased soluble and aggregated tau pathology. Our findings add to the substantial preclinical literature associating lower body and brain temperature with tau hyperphosphorylation. CLINICAL TRIAL NUMBER/BACKGROUND:NCT03053908.
PMID: 35550158
ISSN: 1095-953x
CID: 5214682

Pre-deployment risk factors for PTSD in active-duty personnel deployed to Afghanistan: a machine-learning approach for analyzing multivariate predictors

Schultebraucks, Katharina; Qian, Meng; Abu-Amara, Duna; Dean, Kelsey; Laska, Eugene; Siegel, Carole; Gautam, Aarti; Guffanti, Guia; Hammamieh, Rasha; Misganaw, Burook; Mellon, Synthia H; Wolkowitz, Owen M; Blessing, Esther M; Etkin, Amit; Ressler, Kerry J; Doyle, Francis J; Jett, Marti; Marmar, Charles R
Active-duty Army personnel can be exposed to traumatic warzone events and are at increased risk for developing post-traumatic stress disorder (PTSD) compared with the general population. PTSD is associated with high individual and societal costs, but identification of predictive markers to determine deployment readiness and risk mitigation strategies is not well understood. This prospective longitudinal naturalistic cohort study-the Fort Campbell Cohort study-examined the value of using a large multidimensional dataset collected from soldiers prior to deployment to Afghanistan for predicting post-deployment PTSD status. The dataset consisted of polygenic, epigenetic, metabolomic, endocrine, inflammatory and routine clinical lab markers, computerized neurocognitive testing, and symptom self-reports. The analysis was computed on active-duty Army personnel (N = 473) of the 101st Airborne at Fort Campbell, Kentucky. Machine-learning models predicted provisional PTSD diagnosis 90-180 days post deployment (random forest: AUC = 0.78, 95% CI = 0.67-0.89, sensitivity = 0.78, specificity = 0.71; SVM: AUC = 0.88, 95% CI = 0.78-0.98, sensitivity = 0.89, specificity = 0.79) and longitudinal PTSD symptom trajectories identified with latent growth mixture modeling (random forest: AUC = 0.85, 95% CI = 0.75-0.96, sensitivity = 0.88, specificity = 0.69; SVM: AUC = 0.87, 95% CI = 0.79-0.96, sensitivity = 0.80, specificity = 0.85). Among the highest-ranked predictive features were pre-deployment sleep quality, anxiety, depression, sustained attention, and cognitive flexibility. Blood-based biomarkers including metabolites, epigenomic, immune, inflammatory, and liver function markers complemented the most important predictors. The clinical prediction of post-deployment symptom trajectories and provisional PTSD diagnosis based on pre-deployment data achieved high discriminatory power. The predictive models may be used to determine deployment readiness and to determine novel pre-deployment interventions to mitigate the risk for deployment-related PTSD.
PMID: 32488126
ISSN: 1476-5578
CID: 4469032

Sleep Disorders in Adults with Down Syndrome

Giménez, Sandra; Altuna, Miren; Blessing, Esther; Osorio, Ricardo M; Fortea, Juan
Sleep disorders, despite being very frequent in adults with Down syndrome (DS), are often overlooked due to a lack of awareness by families and physicians and the absence of specific clinical sleep guidelines. Untreated sleep disorders have a negative impact on physical and mental health, behavior, and cognitive performance. Growing evidence suggests that sleep disruption may also accelerate the progression to symptomatic Alzheimer's disease (AD) in this population. It is therefore imperative to have a better understanding of the sleep disorders associated with DS in order to treat them, and in doing so, improve cognition and quality of life, and prevent related comorbidities. This paper reviews the current knowledge of the main sleep disorders in adults with DS, including evaluation and management. It highlights the existing gaps in knowledge and discusses future directions to achieve earlier diagnosis and better treatment of sleep disorders most frequently found in this population.
PMCID:8306783
PMID: 34300177
ISSN: 2077-0383
CID: 5011482

Effect of citalopram on hippocampal volume in first-episode schizophrenia: Structural MRI results from the DECIFER trial

Qi, Wei; Blessing, Esther; Li, Chenxiang; Ardekani, Babak A; Hart, Kamber L; Marx, Julia; Freudenreich, Oliver; Cather, Corinne; Holt, Daphne; Bello, Iruma; Diminich, Erica D; Tang, Yingying; Worthington, Michelle; Zeng, Botao; Wu, Renrong; Fan, Xiaoduo; Troxel, Andrea; Zhao, Jingping; Wang, Jijun; Goff, Donald C
Hippocampal volume loss is prominent in first episode schizophrenia (FES) and has been associated with poor clinical outcomes and with BDNF genotype; antidepressants are believed to reverse hippocampal volume loss via release of BDNF. In a 12-month, placebo-controlled add-on trial of the antidepressant, citalopram, during the maintenance phase of FES, negative symptoms were improved with citalopram. We now report results of structural brain imaging at baseline and 6 months in 63 FES patients (34 in citalopram group) from the trial to assess whether protection against hippocampal volume loss contributed to improved negative symptoms with citalopram. Hippocampal volumetric integrity (HVI) did not change significantly in the citalopram or placebo group and did not differ between treatment groups, whereas citalopram was associated with greater volume loss of the right CA1 subfield. Change in cortical thickness was associated with SANS change in 4 regions (left rostral anterior cingulate, right frontal pole, right cuneus, and right transverse temporal) but none differed between treatment groups. Our findings suggest that minimal hippocampal volume loss occurs after stabilization on antipsychotic treatment and that citalopram's potential benefit for negative symptoms is unlikely to result from protection against hippocampal volume loss or cortical thinning.
PMID: 33857750
ISSN: 1872-7506
CID: 4851292