Authors: Cimino, Nicolas | Kang, Min Suk | Honig, Lawrence S. | Rutherford, Bret R.
Article Type: Research Article
Abstract: Background: Posttraumatic stress disorder (PTSD) is associated with cognitive decline and risk for dementia, but the neuropathology involved is unclear. Objective: The aim of this study was to determine whether PTSD is associated with increased levels of Alzheimer’s disease (AD) blood-based biomarkers. Methods: Individuals aged 50 years and older with PTSD were compared to trauma-exposed healthy controls (TEHCs) at baseline on serum measures of amyloid-β (Aβ ) 42 and 40 levels, the Aβ 42 /Aβ 40 ratio, and total tau. Serum was analyzed using ultrasensitive Simoa Human Neurology 3-Plex A assay (N3PA). Linear regressions modeling each AD biomarker as a …function of group were used to investigate between-group differences, controlling for age, sex, and educational attainment (years). Results: TEHC participants (N = 26) were 53.8% male with mean age 66.8±10.7, whereas PTSD participants (N = 44) were 47.7% male and aged 62.5±9.1 years. No between-group differences were noted on demographic characteristics or cognitive performance measured with the NIH Toolbox Cognition Battery. There were no significant between-group differences in serum Aβ 40 (TEHC 105.8±51.6 versus PTSD 93.2±56.1, p = 0.46), Aβ 42 (TEHC 8.1±4.6 versus PTSD 7.8±4.6, p = 0.63), Aβ 42 /Aβ 40 (TEHC 0.08±0.03 versus PTSD 0.09±0.03, p = 0.27), or total tau (TEHC 0.5±0.3 versus PTSD 0.5±0.4, p = 0.77). Likewise, there were no significant interaction effects of amyloid or tau serum concentrations and PTSD group status on cognitive functioning. Conclusion: Findings from cognitive assessments and serum analyses do not support PTSD-induced neurodegeneration of the Alzheimer’s type as a pathway linking PTSD to increased incidence of dementia in older adults. Show more
Keywords: Alzheimer’s disease, dementia, posttraumatic stress disorder, trauma
DOI: 10.3233/ADR-210048
Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 49-56, 2022
Authors: Seifan, Alon | Marder, Karen S. | Mez, Jesse | Noble, James M. | Cortes, Etty P. | Vonsattel, Jean Paul | Honig, Lawrence S.
Article Type: Research Article
Abstract: Background: Cerebral deposition of phospho-tau in Alzheimer's disease (AD) occurs with varying patterns within hippocampus. Lamina-specific tau changes in AD may reflect trans-synaptic propagation of phospho-tau along neuroanatomical pathways. Objective: To study patterns of tau deposition within inner (IML) and outer (OML) molecular layers of dentate gyrus and their clinical and neuropathological correlates. Methods: 98 consecutive autopsied brains from the Columbia University Brain Bank were stained for phospho-tau using AT-8. Staining density was rated as High versus Low within IML and OML. Four patterns were observed among the 98 brains: High IML&OML, n = 44; High OML Only (n = …35); High IML Only (n = 5); and Low IML&OML (n = 14). Demographic, clinical, and neuropathological characteristics of these four groups were compared. Results: High IML&OML subjects, versus High OML Only, were more likely to fulfill CERAD criteria for Definite AD (93% versus 66%, p < 0.01) and to have higher median Braak stage (6 versus 5, p < 0.01) and earlier mean age of onset (65.9 versus 73.7 y, p = 0.02), with similar symptom duration. Using logistic regression, the association between High IML&OML and AD remained significant after adjustment for demographics but not symptom duration. In the 70 subjects with Definite AD, High IML&OML was associated with younger age of onset (mean difference 3.7 years, 95%CI −6.7 to −0.7, p < 0.01), after adjustment for demographics and symptom duration. Conclusions: Phospho-tau pathology, when prominent within both IML and OML, is associated with CERAD diagnosis of Definite AD and earlier age of onset in AD. Laminar patterns of tau deposition reflect regional involvements during disease course. Show more
Keywords: Alzheimer's disease, dentate gyrus, hippocampus, perforant pathway, tau proteins
DOI: 10.3233/JAD-140279
Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 315-324, 2015
Authors: Tariciotti, Leonardo | Casadei, Matthew | Honig, Lawrence S. | Teich, Andrew F. | McKhann II, Guy M. | Tosto, Giuseppe | Mayeux, Richard
Article Type: Research Article
Abstract: Background: Elevated total tau (tTau), 181-phosphorylated phosphorylated tau (pTau), and low amyloid-β42 (Aβ42 ) in cerebrospinal fluid (CSF) represent a diagnostic biomarker for Alzheimer’s disease (AD). Objective: The goal was to determine the overall accuracy of CSF Aβ42 , tTau, pTau, and the Aβ42 /total tau index (ATI) in a non-research, clinical setting for the diagnosis of AD. Methods: From medical records in 1,016 patients that had CSF studies for dementia over a 12-year period (2005 to 2017), we calculated the sensitivity and specificity of CSF Aβ42 , tTau, and pTau and the ATI in relation to the final clinical …diagnosis. Results: Compared with non-demented patients and patients with other dementias or mild cognitive impairment (MCI), the sensitivity and specificity of the recommended ATI and pTau cut-offs (ATI < 1.0 and pTau >61 pg/ml) for the diagnosis of AD were 0.88 and 0.72, respectively. Similar results were obtained comparing AD with non-demented patients only (0.88, 0.82) and AD with other types of dementia (0.81, 0.77). A subgroup of patients with presumed normal pressure hydrocephalus (n = 154) were biopsied at the time of shunt placement. Using the pathological manifestations of AD as the standard, the sensitivity was 0.83 while the specificity was 0.72. Conclusions: In a non-research setting, CSF biomarkers for AD showed a high sensitivity in accordance with previous studies, but modest specificity differentiating AD from other types of dementia or MCI. This study of unselected patients provides a valid and realistic assessment of the diagnostic accuracy of these CSF biomarkers in clinical practice. Show more
Keywords: Aβ42, accuracy, Alzheimer’s disease, CSF biomarkers, pTau, sensitivity, specificity, tTau
DOI: 10.3233/JAD-180548
Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1417-1425, 2018
Authors: Gulisano, Walter | Maugeri, Daniele | Baltrons, Marian A. | Fà, Mauro | Amato, Arianna | Palmeri, Agostino | D’Adamio, Luciano | Grassi, Claudio | Devanand, D.P. | Honig, Lawrence S. | Puzzo, Daniela | Arancio, Ottavio
Article Type: Correction
DOI: 10.3233/JAD-189015
Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 415-415, 2019
Authors: Klein, Julia | Yan, Xinyu | Johnson, Aubrey | Tomljanovic, Zeljko | Zou, James | Polly, Krista | Honig, Lawrence S. | Brickman, Adam M. | Stern, Yaakov | Devanand, D.P. | Lee, Seonjoo | Kreisl, William C.
Article Type: Research Article
Abstract: Background: Olfactory impairment is evident in Alzheimer’s disease (AD); however, its precise relationships with clinical biomarker measures of tau pathology and neuroinflammation are not well understood. Objective: To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation. Methods: Cognitively normal and cognitively impaired participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent 18 F-MK-6240 PET (measuring tau pathology) and fifty-three underwent …11 C-PBR28 PET (measuring TSPO, present in activated microglia). Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ42 ). Results: Low UPSIT performance was associated with greater18 F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex, and posterior cingulate cortex (p < 0.05). Similar relationships were seen for 11 C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (p < 0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (p < 0.01). Conclusion: Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. The independent association of amyloid-positivity and cognitive impairment with odor identification suggests that low UPSIT performance may be a marker for AD pathophysiology in cognitive normal individuals, although impaired odor identification is associated with both AD and non-AD related neurodegeneration. NCT Registration Numbers: NCT03373604; NCT02831283 Show more
Keywords: Alzheimer’s disease, anosmia, microglia, olfaction, tau proteins
DOI: 10.3233/JAD-201149
Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1051-1065, 2021
Authors: Gulisano, Walter | Maugeri, Daniele | Baltrons, Marian A. | Fà, Mauro | Amato, Arianna | Palmeri, Agostino | D’Adamio, Luciano | Grassi, Claudio | Devanand, D.P. | Honig, Lawrence S. | Puzzo, Daniela | Arancio, Ottavio
Article Type: Review Article
Abstract: The “Amyloid Cascade Hypothesis” has dominated the Alzheimer’s disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of Aβ and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms …between the two proteins in all of these phenomena. We discuss novel findings showing binding of both Aβ and tau oligomers to amyloid-β protein precursor (AβPP), and the requirement for the presence of this protein for both Aβ and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of Aβ and tau act in parallel and upstream of AβPP. Such a view will call for a reconsideration of therapeutic approaches directed against Aβ and tau, paving the way to an increased interest toward AβPP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies. Show more
Keywords: Amyloid-β peptide, amyloid-β protein precursor, oligomers, synaptic dysfunction, tau
DOI: 10.3233/JAD-179935
Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S611-S631, 2018
Authors: Guthrie, Heather | Honig, Lawrence S. | Lin, Helen | Sink, Kaycee M. | Blondeau, Kathleen | Quartino, Angelica | Dolton, Michael | Carrasco-Triguero, Montserrat | Lian, Qinshu | Bittner, Tobias | Clayton, David | Smith, Jillian | Ostrowitzki, Susanne
Article Type: Research Article
Abstract: Background: Crenezumab is a fully humanized, monoclonal anti-amyloid-β immunoglobulin G4 antibody. Objective: This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of crenezumabat doses of ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity and exploratory biomarkers were also evaluated. Methods: In this multicenter, double-blind study, participants (aged 50–90 years) with mild-to-moderate Alzheimer’s disease (AD) and amyloid-positive positron emission tomography (PET) scan were randomized to receive crenezumab 30 or 45 mg/kg (Cohort 1, n = 21), 60 mg/kg (Cohort 2, n = 21), or 120 mg/kg (Cohort 3, n = 19) or corresponding placebo (n = 14) intravenously q4w for 13 weeks. Seventy-one participants were subsequently …enrolled in an optional open-label extension (OLE) and received crenezumab at the originally assigned dose level, except for Cohort 3 (crenezumab 60 mg/kg during OLE). Participants received regular brain MRIs to assess amyloid-related imaging abnormalities (ARIA). Results up to Week 133 are reported. Results: Approximately 94% of participants experienced ≥1 adverse event (AE). Most AEs were mild or moderate; 15.5% experienced a Grade ≥3 AE. No ARIA-edema/effusion (ARIA-E) events were observed. New ARIA-micro hemorrhages and hemosiderosis (ARIA-H) were reported in 4.9% (double-blind treatment period) and 9.9% (combined double-blind treatment and OLE periods) of participants. Steady-state trough concentrations of crenezumab were dose-proportional and maintained for each dose level. Conclusion: Crenezumab doses of ≤120 mg/kg intravenously q4w were well tolerated. The observed safety profile for ≤133 weeks of treatment in a mild-to-moderate AD population was similar to that seen in previous trials. Show more
Keywords: Alzheimer’s disease, amyloid positron emission tomography, amyloid-β peptide, crenezumab, humanized monoclonal antibody, infusion site adverse event, magnetic resonance imaging, safety
DOI: 10.3233/JAD-200134
Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 967-979, 2020
Authors: Salloway, Stephen P. | Sperling, Reisa | Fox, Nick C. | Sabbagh, Marwan N. | Honig, Lawrence S. | Porsteinsson, Anton P. | Rofael, Hany | Ketter, Nzeera | Wang, Daniel | Liu, Enchi | Carr, Stephen | Black, Ronald S. | Brashear, H. Robert
Article Type: Research Article
Abstract: Background: A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer’s disease dementia (apolipoprotein (APOE ) ɛ 4 carriers and noncarriers) is summarized. Objectives: The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab. Methods: A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the …parent studies. Results: A total of 1,462 (688 were APOE ɛ 4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups. Conclusions: Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies. Show more
Keywords: Alzheimer’s disease, amyloid-related imaging abnormality with edema/effusions, bapineuzumab, long-term safety
DOI: 10.3233/JAD-171157
Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 689-707, 2018
