CD19/CD22 targeting with cotransduced CAR T cells to prevent antigen-negative relapse after CAR T-cell therapy for B-cell ALL.

ABSTRACT: CD19-negative relapse is a leading cause of treatment failure after chimeric antigen receptor (CAR) T-cell therapy for acute lymphoblastic leukemia. We investigated a CAR T-cell product targeting CD19 and CD22 generated by lentiviral cotransduction with vectors encoding our previously described fast-off rate CD19 CAR (AUTO1) combined with a novel CD22 CAR capable of effective signaling at low antigen density. Twelve patients with advanced B-cell acute lymphoblastic leukemia were treated (CARPALL [Immunotherapy with CD19/22 CAR Redirected T Cells for High Risk/Relapsed Paediatric CD19+ and/or CD22+ Acute Lymphoblastic Leukaemia] study, NCT02443831), a third of whom had failed prior licensed CAR therapy. Toxicity was similar to that of AUTO1 alone, with no cases of severe cytokine release syndrome. Of 12 patients, 10 (83%) achieved a measurable residual disease (MRD)-negative complete remission at 2 months after infusion. Of 10 responding patients, 5 had emergence of MRD (n = 2) or relapse (n = 3) with CD19- and CD22-expressing disease associated with loss of CAR T-cell persistence. With a median follow-up of 8.7 months, there were no cases of relapse due to antigen-negative escape. Overall survival was 75% (95% confidence interval [CI], 41%-91%) at 6 and 12 months. The 6- and 12-month event-free survival rates were 75% (95% CI, 41%-91%) and 60% (95% CI, 23%-84%), respectively. These data suggest dual targeting with cotransduction may prevent antigen-negative relapse after CAR T-cell therapy.

Interleukin 9 alterations linked to alzheimer disease in african americans.

OBJECTIVE: Compared to older Caucasians, older African Americans have higher risks of developing Alzheimer disease (AD) and lower cerebrospinal fluid (CSF) tau biomarker levels. It is not known whether tau-related differences begin earlier in life or whether race modifies other AD-related biomarkers such as inflammatory proteins. METHODS: We performed multiplex cytokine analysis in a healthy middle-aged cohort with family history of AD (n = 68) and an older cohort (n = 125) with normal cognition (NC), mild cognitive impairment, or AD dementia. After determining baseline interleukin (IL)-9 level and AD-associated IL-9 change to differ according to race, we performed immunohistochemical analysis for proteins mechanistically linked to IL-9 in brains of African Americans and Caucasians (n = 38), and analyzed postmortem IL-9-related gene expression profiles in the publicly available Mount Sinai cohort (26 African Americans and 180 Caucasians). RESULTS: Compared to Caucasians with NC, African Americans with NC had lower CSF tau, p-Tau181 , and IL-9 levels in both living cohorts. Conversely, AD was only correlated with increased CSF IL-9 levels in African Americans but not Caucasians. Immunohistochemical analysis revealed perivascular, neuronal, and glial cells immunoreactive to IL-9, and quantitative analysis in independent US cohorts showed AD to correlate with molecular changes (upstream differentiation marker and downstream effector cell marker) of IL-9 upregulation only in African Americans but not Caucasians. INTERPRETATION: Baseline and AD-associated IL-9 differences between African Americans and Caucasians point to distinct molecular phenotypes for AD according to ancestry. Genetic and nongenetic factors need to be considered in future AD research involving unique populations. ANN NEUROL 2019;86:407-418.

Using tablet-based technology to deliver time-efficient ototoxicity monitoring.

OBJECTIVE: The goal of this article is to highlight mobile technology that is not yet standard of care but could be considered for use in an ototoxicity monitoring programme (OMP) as an adjunct to traditional audiometric testing. Current guidelines for ototoxicity monitoring include extensive test protocols performed by an audiologist in an audiometric booth. This approach is comprehensive, but it may be taxing for patients suffering from life-threatening illnesses and cost prohibitive if it requires serial clinical appointments. With the use of mobile technology, testing outside of the confines of the audiometric booth may be possible, which could create more efficient and less burdensome OMPs. DESIGN: A non-systematic review of new OMP technology was performed. Experts were canvassed regarding the impact of new technology on OMPs. STUDY SAMPLE: OMP devices and technologies that are commercially available and discussed in the literature. RESULTS: The benefits and limitations of portable, tablet-based technology that can be deployed for efficient ototoxicity monitoring are discussed. CONCLUSIONS: New mobile technology has the potential to influence the development and implementation of OMPs and lower barriers to patient access by providing time efficient, portable and self-administered testing options for use in the clinic and in the patient's home.

Intention-to-treat outcomes utilising a stringent event definition in children and young people treated with tisagenlecleucel for r/r ALL through a national access scheme.

CAR T-cell therapy has transformed relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukaemia (B-ALL) management and outcomes, but following CAR T infusion, interventions are often needed. In a UK multicentre study, we retrospectively evaluated tisagenlecleucel outcomes in all eligible patients, analysing overall survival (OS) and event-free survival (EFS) with standard and stringent definitions, the latter including measurable residual disease (MRD) emergence and further anti-leukaemic therapy. Both intention-to-treat and infused cohorts were considered. We collected data on feasibility of delivery, manufacture, toxicity, cause of therapy failure and followed patients until death from any cause. Of 142 eligible patients, 125 received tisagenlecleucel, 115/125 (92%) achieved complete remission (CR/CRi). Severe cytokine release syndrome and neurotoxicity occurred in 16/123 (13%) and 10/123 (8.1%), procedural mortality was 3/126 (2.4%). The 2-year intent to treat OS and EFS were 65.2% (95%CI 57.2-74.2%) and 46.5% (95%CI 37.6-57.6%), 2-year intent to treat stringent EFS was 35.6% (95%CI 28.1-44.9%). Median OS was not reached. Sixty-two responding patients experienced CAR T failure by the stringent event definition. Post failure, 1-year OS and standard EFS were 61.2% (95%CI 49.3-75.8) and 55.3% (95%CI 43.6-70.2). Investigation of CAR T-cell therapy for B-ALL delivered on a country-wide basis, including following patients beyond therapy failure, provides clinicians with robust outcome measures. Previously, outcomes post CAR T-cell therapy failure were under-reported. Our data show that patients can be successfully salvaged in this context with good short-term survival.

A retrospective cohort study of Libmeldy (atidarsagene autotemcel) for MLD: What we have accomplished and what opportunities lie ahead.

Metachromatic leukodystrophy (MLD) results from ARSA gene mutations. Affected individuals meet early milestones before neurological deterioration and early death. Atidarsagene autotemcel (arsa-cel), an autologous haematopoietic stem cell gene therapy (HSC-GT) product, has demonstrated sustained clinical benefits in MLD. Arsa-cel was approved for NHS treatment in February 2022 for asymptomatic late infantile or early juvenile disease, or early symptomatic early juvenile MLD. We evaluate the impact of this approval in the largest real-world dataset of MLD HSC-GT. Hospital records were reviewed for all patients referred for NHS treatment following arsa-cel approval. Information was gathered about disease phenotype, presentation, eligibility, and affected siblings. In the year following NHS approval, 17 UK MLD patients were referred for treatment. Four patients met eligibility criteria and have been treated, including 1 infant who weighed 5 kg at leukapheresis. Eleven patients failed screening: 10 symptomatic patients with late infantile disease and 1 with early juvenile disease and cognitive decline. Two further patients with later onset subtypes did not meet the approval criteria. Three out of four treated patients were diagnosed by screening after MLD was diagnosed in a symptomatic older sibling. The success of HSC-GT for MLD has heralded a new era of hope for families affected by this devastating disease, yet currently, most patients are ineligible for treatment at diagnosis. The feasibility of apheresis in infants and the availability of a licenced, effective HSC-GT product highlights the urgent need for newborn screening to ensure that patients can be diagnosed and treated before symptom onset.

The Words-in-Noise Test (WIN), list 3: a practice list.

BACKGROUND: The Words-in-Noise Test (WIN) was developed as an instrument to quantify the ability of listeners to understand monosyllabic words in background noise using multitalker babble (Wilson, 2003). The 50% point, which is calculated with the Spearman-Kärber equation (Finney, 1952), is used as the evaluative metric with the WIN materials. Initially, the WIN was designed as a 70-word instrument that presented ten unique words at each of seven signal-to-noise ratios from 24 to 0 dB in 4 dB decrements. Subsequently, the 70-word list was parsed into two 35-word lists that achieved equivalent recognition performances (Wilson and Burks, 2005). This report involves the development of a third list (WIN List 3) that was developed to serve as a practice list to familiarize the participant with listening to words presented in background babble. PURPOSE: To determine-on young listeners with normal hearing and on older listeners with sensorineural hearing loss-the psychometric properties of the WIN List 3 materials. RESEARCH DESIGN: A quasi-experimental, repeated-measures design was used. STUDY SAMPLE: Twenty-four young adult listeners (M = 21.6 yr) with normal pure-tone thresholds (≤ 20 dB HL at 250 to 8000 Hz) and 24 older listeners (M = 65.9 yr) with sensorineural hearing loss participated. DATA COLLECTION AND ANALYSIS: The level of the babble was fixed at 80 dB SPL with the level of the words varied from 104 to 80 dB SPL in 4 dB decrements. RESULTS: For listeners with normal hearing, the 50% points for Lists 1 and 2 were similar (4.3 and 5.1 dB S/N, respectively), both of which were lower than the 50% point for List 3 (7.4 dB S/N). A similar relation was observed with the listeners with hearing loss, 50% points for Lists 1 and 2 of 12.2 and 12.4 dB S/N, respectively, compared to 15.8 dB S/N for List 3. The differences between Lists 1 and 2 and List 3 were significant. The relations among the psychometric functions and the relations among the individual data both reflected these differences. CONCLUSIONS: The significant ∼3 dB difference between performances on WIN Lists 1 and 2 and on WIN List 3 by the listeners with normal hearing and the listeners with hearing loss dictates caution with the use of List 3. The use of WIN List 3 should be reserved for ancillary purposes in which equivalent recognition performances are not required, for example, as a practice list or a stand alone measure.

The Revised Speech Perception in Noise Test (R-SPIN) in a multiple signal-to-noise ratio paradigm.

BACKGROUND: The Revised Speech Perception in Noise Test (R-SPIN; Bilger, 1984b) is composed of 200 target words distributed as the last words in 200 low-predictability (LP) and 200 high-predictability (HP) sentences. Four list pairs, each consisting of two 50-sentence lists, were constructed with the target word in a LP and HP sentence. Traditionally the R-SPIN is presented at a signal-to-noise ratio (SNR, S/N) of 8 dB with the listener task to repeat the last word in the sentence. PURPOSE: The purpose was to determine the practicality of altering the R-SPIN format from a single SNR paradigm into a multiple SNR paradigm from which the 50% points for the HP and LP sentences can be calculated. RESEARCH DESIGN: Three repeated measures experiments were conducted. STUDY SAMPLE: Forty listeners with normal hearing and 184 older listeners with pure-tone hearing loss participated in the sequence of experiments. DATA COLLECTION AND ANALYSIS: The R-SPIN sentences were edited digitally (1) to maintain the temporal relation between the sentences and babble, (2) to establish the SNRs, and (3) to mix the speech and noise signals to obtain SNRs between -1 and 23 dB. All materials were recorded on CD and were presented through an earphone with the responses recorded and analyzed at the token level. For reference purposes the Words-in-Noise Test (WIN) was included in the first experiment. RESULTS: In Experiment 1, recognition performances by listeners with normal hearing were better than performances by listeners with hearing loss. For both groups, performances on the HP materials were better than performances on the LP materials. Performances on the LP materials and on the WIN were similar. Performances at 8 dB S/N were the same with the traditional fixed level presentation and the descending presentation level paradigms. The results from Experiment 2 demonstrated that the four list pairs of R-SPIN materials produced good first approximation psychometric functions over the -4 to 23 dB S/N range, but there were irregularities. The data from Experiment 2 were used in Experiment 3 to guide the selection of the words to be used at the various SNRs that would provide homogeneous performances at each SNR and would produce systematic psychometric functions. In Experiment 3, the 50% points were in good agreement for the LP and HP conditions within both groups of listeners. The psychometric functions for List Pairs 1 and 2, 3 and 4, and 5 and 6 had similar characteristics and maintained reasonable separations between the HP and LP functions, whereas the HP and LP functions for List Pair 7 and 8 bisected one another at the lower SNRs. CONCLUSIONS: This study indicates that the R-SPIN can be configured into a multiple SNR paradigm. A more in-depth study with the R-SPIN materials is needed to develop lists that are systematic and reasonably equivalent for use on listeners with hearing loss. The approach should be based on the psychometric characteristics of the 200 HP and 200 LP sentences with the current R-SPIN lists discarded. Of importance is maintaining the synchrony between the sentences and their accompanying babble.

The effects of energetic and informational masking on The Words-in-Noise Test (WIN).

BACKGROUND: In certain masking paradigms, the masker can have two components, energetic and informational. Energetic masking is the traditional peripheral masking, whereas informational masking involves confusions (uncertainty) between the signal and masker that originate more centrally in the auditory system. Sperry et al (1997) used Northwestern University Auditory Test No. 6 (NU-6) words in multitalker babble to study the differential effects of energetic and informational masking using babble played temporally forward (FB) and backward (BB). The FB and BB are the same except BB is void of the contextual and semantic content cues that are available in FB. It is these informational cues that are thought to fuel informational masking. Sperry et al found 15% better recognition performance (∼3 dB) on BB than on FB, which can be interpreted as the presence of informational masking in the FB condition and not in the BB condition (Dirks and Bower, 1969). The Words-in-Noise Test (WIN) (Wilson, 2003; Wilson and McArdle, 2007) uses NU-6 words as the signal and multitalker babble as the masker, which is a combination of stimuli that potentially could produce informational masking. The WIN presents 5 or 10 words at each of seven signal-to-noise ratios (S/N, SNR) from 24 to 0 dB in 4 dB decrements with the 50% correct point being the metric of interest. The same recordings of the NU-6 words and multitalker babble used by Sperry et al are used in the WIN. PURPOSE: To determine whether informational masking was involved with the WIN. RESEARCH DESIGN: Descriptive, quasi-experimental designs were conducted in three experiments using FB and BB in various paradigms in which FB and BB varied from 4.3 sec concatenated segments to essentially continuous. STUDY SAMPLE: Eighty young adults with normal hearing and 64 older adults with sensorineural hearing losses participated in a series of three experiments. DATA COLLECTION AND ANALYSIS: Experiment 1 compared performance on the normal WIN (FB) with performance on the WIN in which the babble segment with each word was reversed temporally (BB). Experiment 2 examined the effects of continuous FB and BB segments on WIN performance. Experiment 3 replicated the Sperry et al (1997) experiment at 4 and 0 dB S/N using NU-6 words in the FB and BB conditions. RESULTS: Experiment 1-with the WIN paradigm, recognition performances on FB and BB were the same for listeners with normal hearing and listeners with hearing loss, except at the 0 dB S/N with the listeners with normal hearing at which performance was significantly better on BB than FB. Experiment 2-recognition performances on FB and BB were the same at all SNRs for listeners with normal hearing using a slightly modified WIN paradigm. Experiment 3-there was no difference in performances on the FB and BB conditions with either of the two SNRs. CONCLUSIONS: Informational masking was not involved in the WIN paradigm. The Sperry et al results were not replicated, which is thought to be related to the way in which the Sperry et al BB condition was produced.

Development of the Listening Self-Efficacy Questionnaire (LSEQ).

OBJECTIVE: Listening self-efficacy refers to the beliefs, or confidence, that listeners have in their capability to successfully listen in specific situations, which may influence audiologic rehabilitation outcomes. The objective of this study was to develop and validate the Listening Self-Efficacy Questionnaire (LSEQ), which quantifies listening self-efficacy in a variety of situations where the goal of the listener is to understand speech. STUDY SAMPLE: Older listeners with hearing loss (N = 169) participated in the study. DESIGN: A factor analysis showed that the LSEQ has three subscales, with beliefs about listening capabilities relating to the following situations: (1) dialogue in quiet, (2) focusing attention on a single source, and (3) complex auditory scenes. Internal consistency reliability was excellent (Chronbach's α > .80). RESULTS: The validity of the LSEQ was demonstrated by comparing the LSEQ scores to audiologic measures, responses on questionnaires, and to the scores for reference groups of younger and older listeners with normal hearing. CONCLUSION: The findings indicate that the LSEQ is a valid and reliable measure of listening self-efficacy with good potential for use in clinical and research settings.

High-resolution metabolomic profiling of Alzheimer's disease in plasma.

BACKGROUND: Alzheimer's disease (AD) is a complex neurological disorder with contributions from genetic and environmental factors. High-resolution metabolomics (HRM) has the potential to identify novel endogenous and environmental factors involved in AD. Previous metabolomics studies have identified circulating metabolites linked to AD, but lack of replication and inconsistent diagnostic algorithms have hindered the generalizability of these findings. Here we applied HRM to identify plasma metabolic and environmental factors associated with AD in two study samples, with cerebrospinal fluid (CSF) biomarkers of AD incorporated to achieve high diagnostic accuracy. METHODS: Liquid chromatography-mass spectrometry (LC-MS)-based HRM was used to identify plasma and CSF metabolites associated with AD diagnosis and CSF AD biomarkers in two studies of prevalent AD (Study 1: 43 AD cases, 45 mild cognitive impairment [MCI] cases, 41 controls; Study 2: 50 AD cases, 18 controls). AD-associated metabolites were identified using a metabolome-wide association study (MWAS) framework. RESULTS: An MWAS meta-analysis identified three non-medication AD-associated metabolites in plasma, including elevated levels of glutamine and an unknown halogenated compound and lower levels of piperine, a dietary alkaloid. The non-medication metabolites were correlated with CSF AD biomarkers, and glutamine and the unknown halogenated compound were also detected in CSF. Furthermore, in Study 1, the unknown compound and piperine were altered in MCI patients in the same direction as AD dementia. CONCLUSIONS: In plasma, AD was reproducibly associated with elevated levels of glutamine and a halogen-containing compound and reduced levels of piperine. These findings provide further evidence that exposures and behavior may modify AD risks.

Ototoxicity: Visualized in Concept Maps.

Ototoxicity refers to the damage to structures and function of the auditory-vestibular system caused by exogenous agents such as pharmaceuticals, chemicals, and ionizing radiation. There are many potentially ototoxic substances. For example, depending on how ototoxicity is defined, there are 200 to 600 medications that can cause damage to hearing and/or balance. Ototoxicity encompasses cochleotoxicity, vestibulotoxicity, and neurotoxicity. A variety of professional disciplines are involved in determining causation, prevention, and management of ototoxic effects. Research to identify and develop otoprotectants and otorescue agents is emerging and will translate basic scientific discovery into applications for use in hearing conservation programs, safety operations, and clinical care. Original concept maps are presented here to visually represent knowledge pathways, domains, and relationships essential to the understanding of ototoxicity.

Effects of low-frequency biasing on spontaneous otoacoustic emissions: amplitude modulation.

The dynamic effects of low-frequency biasing on spontaneous otoacoustic emissions (SOAEs) were studied in human subjects under various signal conditions. Results showed a combined suppression and modulation of the SOAE amplitudes at high bias tone levels. Ear-canal acoustic spectra demonstrated a reduction in SOAE amplitude and growths of sidebands while increasing the bias tone level. These effects varied depending on the relative strength of the bias tone to a particular SOAE. The SOAE magnitudes were suppressed when the cochlear partition was biased in both directions. This quasi-static modulation pattern showed a shape consistent with the first derivative of a sigmoid-shaped nonlinear function. In the time domain, the SOAE amplitudes were modulated with the instantaneous phase of the bias tone. For each biasing cycle, the SOAE envelope showed two peaks each corresponded to a zero crossing of the bias tone. The temporal modulation patterns varied systematically with the level and frequency of the bias tone. These dynamic behaviors of the SOAEs are consistent with the shifting of the operating point along the nonlinear transducer function of the cochlea. The results suggest that the nonlinearity in cochlear hair cell transduction may be involved in the generation of SOAEs.

Development of the Warfighter's Hearing Health Instructional (WHHIP) Primer App.

The Warfighter's Hearing Health Instructional Primer (WHHIP) is a supplemental tool for military hearing conservation programs (MHCPs) and can be accessed by the warfighter on his/her own personal mobile phone. A gap was identified for a supplement to MHCPs that is easily accessible by warfighters to improve hearing health knowledge. The WHHIP aims to instruct the warfighter in best hearing health practices. To do so, four activities are included: Learn, Demos, HPD Check, and Glossary. Learn and Glossary allow the warfighter to scroll through various informational topics related to hearing conservation - including videos, descriptions of noise, and results of hearing tests. In the Demos activity, the warfighter can explore the difficulties that hearing loss and tinnitus pose to sound and speech identification. The HPD Check feature allows the warfighter to take a picture of the fit of hearing protection devices (HPDs) in his/her own ears then compare the images to ones that he/she had previously taken or of standard images of good fitting devices. The WHHIP is an easily accessed reference tool available for free via Google Play; if a warfighter has a question or concern regarding his/her hearing health, the WHHIP can be used to verify or improve knowledge.

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes.

OBJECTIVE: Frontotemporal lobar degeneration (FTLD) is the second most prevalent dementia in young patients and is characterized by the presence of two main protein aggregates in the brain, tau (FTLD-Tau) or TDP43 (FTLD-TDP), which likely require distinct pharmacological therapy. However, specific diagnosis of FTLD and its subtypes remains challenging due to largely overlapping clinical phenotypes. Here, we aimed to assess the clinical performance of novel cerebrospinal fluid (CSF) biomarkers for discrimination of FTLD and its pathological subtypes. METHODS: YKL40, FABP4, MFG-E8, and the activities of catalase and specific lysosomal enzymes were analyzed in patients with FTLD-TDP (n = 30), FTLD-Tau (n = 20), AD (n = 30), DLB (n = 29), and nondemented controls (n = 29) obtained from two different centers. Models were validated in an independent CSF cohort (n = 188). RESULTS: YKL40 and catalase activity were increased in FTLD-TDP cases compared to controls. YKL40 levels were also higher in FTLD-TDP compared to FTLD-Tau. We identified biomarker models able to discriminate FTLD from nondemented controls (MFG-E8, tTau, and Aß 42; 78% sensitivity and 83% specificity) and non-FTLD dementia (YKL40, pTau, p/tTau ratio, and age; 90% sensitivity, 78% specificity), which were validated in an independent cohort. In addition, we identified a biomarker model differentiating FTLD-TDP from FTLD-Tau (YKL40, MFGE-8, ßHexA together with ßHexA/tHex and p/tTau ratios and age) with 80% sensitivity and 82% specificity. INTERPRETATION: This study identifies CSF protein signatures distinguishing FTLD and the two main pathological subtypes with optimal accuracy (specificity/sensitivity > 80%). Validation of these models may allow appropriate selection of cases for clinical trials targeting the accumulation of Tau or TDP43, thereby increasing their efficiency and facilitating the development of successful therapies.

Non-beta-amyloid/tau cerebrospinal fluid markers inform staging and progression in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by neuropathologic changes involving beta-amyloid (Aß), tau, neuronal loss, and other associated biological events. While levels of cerebrospinal fluid (CSF) Aß and tau peptides have enhanced the antemortem detection of AD-specific changes, these two markers poorly reflect the severity of cognitive and functional deficits in people with altered Aß and tau levels. While multiple previous studies identified non-Aß, non-tau proteins as candidate neurodegenerative markers to inform the A/T/N biomarker scheme of AD, few have advanced beyond association with clinical AD diagnosis. Here we analyzed nine promising neurodegenerative markers in a three-centered cohort using independent assays to identify candidates most likely to complement Aß and tau in the A/T/N framework. METHODS: CSF samples from 125 subjects recruited at the three centers were exchanged such that each of the nine previously identified biomarkers can be measured at one of the three centers. Subjects were classified according to cognitive status and CSF AD biomarker profiles as having normal cognition and normal CSF (n = 31), normal cognition and CSF consistent with AD (n = 13), mild cognitive impairment and normal CSF (n = 13), mild cognitive impairment with CSF consistent with AD (n = 23), AD dementia (n = 32; CSF consistent with AD), and other non-AD dementia (n = 13; CSF not consistent with AD). RESULTS: Three biomarkers were identified to differ among the AD stages, including neurofilament light chain (NfL; p < 0.001), fatty acid binding protein 3 (Fabp3; p < 0.001), and interleukin (IL)-10 (p = 0.033). Increased NfL levels were most strongly associated with the dementia stage of AD, but increased Fabp3 levels were more sensitive to milder AD stages and correlated with both CSF tau markers. IL-10 levels did not correlate with tau biomarkers, but were associated with rates of longitudinal cognitive decline in mild cognitive impairment due to AD (p = 0.006). Prefreezing centrifugation did not influence measured CSF biomarker levels. CONCLUSION: CSF proteins associated with AD clinical stages and progression can complement Aß and tau markers to inform neurodegeneration. A validated panel inclusive of multiple biomarker features (etiology, stage, progression) can improve AD phenotyping along the A/T/N framework.

Clinical and MRI correlates of autoreactive antibodies in multiple sclerosis patients.

BACKGROUND: Autoreactive antibodies (ARAB) occur more frequently in patients with multiple sclerosis (MS) than in general population and the presence of these antibodies often causes uncertainty regarding the disease course, response to therapy and the diagnosis of MS. METHODS: Retrospective analyses of the ARAB, clinical and MRI data of a consecutive patient cohort of MS and clinically isolated syndrome (CIS) patients were conducted. The patients were evaluated for an extensive panel that included various subtypes of antiphospholipid antibody (APLA) including anti-phosphatidylethanolamine (APE), anti-phosphatidylserine (APS), anti-beta-2-glycoprotein-1 (ABGP), anti-cardiolipin (ACA), and several other ARAB such as antinuclear antibody (ANA), anti-neutrophilic cytoplasmic antibodies (ANCA), anti-thyroid peroxidase antibodies (ATA), anti-SS-A, and anti-SS-B antibodies. Quantitative MRI analysis was performed in a subgroup of MS patients measuring T2-lesion volume (LV), T1 black hole LV and brain parenchymal fraction (BPF). RESULTS: A total of 137 patients (mean age 44.7, 84% female) with either MS (n=111; age: mean 46.5+/-S.D. 10.3 years; disease duration: mean 13.0+/-S.D. 10.4 years; EDSS: mean 3.2+/-S.D. 1.9) or CIS (n=26; age: mean 37.7+/-S.D. 7.8 years; disease duration: mean 1.3+/-S.D. 1.1 years; EDSS: mean 1.0+/-S.D. 0.7) were enrolled. Among MS patients, 82 were RRMS, 26 SPMS, and 3 had PPMS. Seventy-seven (69%) of MS patients showed presence of one or more ARAB. The proportion of MS patients with APLA was 55% (61 patients); IgM subtype was most frequent. Co-occurrence of ACA and APE was more frequent in SPMS as compared to RRMS (15.4% vs. 1.2%, p=0.012). The proportion of CIS patients with ARAB was 75% with IgM subtype being the most frequent. However, the ARAB in majority of CIS patients (9 out of 14, 64%) were transient on repeated testing. In a subgroup of 62 MS patients, quantitative MRI analysis showed significantly higher T2-LV in patients with positive APLA (15.1 ml for APLA positive vs. 6.75 ml for APLA negative) after correcting for the disease duration (p=0.048). The patients with ATA also had significantly higher T2-LV after correction for disease duration (19.0 ml vs.8.5, p=0.044). CONCLUSIONS: ARAB were present in more than two thirds of MS and CIS patients although most of APLA in CIS were transient. The presence of APLA in MS patients was associated with higher T2-LV.

Fear and Uncertainty Do Not Influence Reported Willingness to Undergo Lumbar Punctures in a U.S. Multi-Cultural Cohort.

Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease and related disorders can provide early and accurate prediction of underlying neuropathology even when the clinical symptoms are mild, but lumbar punctures (LP) to obtain CSF can be perceived as frightening and invasive. We previously demonstrated that this negative perception of the LP is strongly associated with a negative LP experience in terms of discomfort and complications, but it is not known what factors can lead to a negative perception of the LP. It has also been proposed that LP is less well-perceived by adults in the U.S. compared to Europe and elsewhere, although there is a paucity of primary data to support this. To address these knowledge gaps, we conducted a survey of 237 younger and older adults in the Atlanta area including a significant number born outside of the U.S. (n = 82, 34%) to determine demographic, medical, and experiential factors associated with the perception of LP as well as the willingness to undergo LP for medical or research purposes. Our results show that one in four respondents in this cohort with limited first-hand LP experience viewed the LP as a frightening invasive procedure, but the majority (89%) were willing to undergo LP for medical reasons. General awareness of the LP was associated with both standard and negative views of the LP, but perception did not influence willingness to undergo the procedure. Multi-variate models showed that higher annual household income, not place of birth or past experience, was associated with greater willingness to undergo LPs. We conclude that Americans (born in the U.S. or abroad) are not resistant to LPs if there is useful information to improve their health, although there is limited enthusiasm to undergo LPs solely for research purposes. At the same time, we failed to find modifiable factors to improve the perception of LP among those who already perceive it as frightening and invasive. Future recruitment effort should target adults with no preconceived notion of the LP with emphasis on data related to safety and tolerability.

Race modifies the relationship between cognition and Alzheimer's disease cerebrospinal fluid biomarkers.

BACKGROUND: African Americans have been reported to have a higher prevalence of Alzheimer's disease (AD) than Caucasians, but etiology-specific AD biomarkers have not been systematically analyzed in older African Americans. Coexisting cerebrovascular disease may also contribute to this increased prevalence. We hypothesized that cerebrospinal fluid (CSF) biomarkers of amyloid, neurodegeneration, and endothelial dysfunction would differ between older African Americans and Caucasians with normal cognition and cognitive impairment associated with AD. METHODS: We prospectively recruited 135 older Americans to undergo detailed clinical, neuropsychological, genetic, magnetic resonance imaging (MRI), and CSF analysis from 2013 to 2015 at Emory University (Atlanta, GA, USA). We compared levels of CSF markers for ß-amyloid (Aß42, Aß40), total and phosphorylated tau (t-tau and p-tau181, respectively), endothelial dysfunction (soluble vascular cell adhesion molecule 1, soluble intercellular adhesion molecule 1), α-synuclein, and neurodegeneration (neurofilament light chain [NfL]), as well as MRI markers, for hippocampal atrophy and cerebrovascular disease (white matter hyperintensity [WMH] volume). RESULTS: Sixty-five older African Americans (average age, 69.1 years) and 70 older Caucasians (average age, 70.8 years) were included. After adjusting for demographic variables, AD risk alleles, and cognitive function, older African Americans had lower CSF levels of p-tau181 (difference of 7.4 pg/ml; 95% CI, 3.7-11.2 pg/ml; p < 0.001), t-tau (difference of 23.6 pg/ml; 95% CI, 9.5-37.7; p = 0.001), and Aß40 (difference of 1.35 ng/ml; 95% CI, 0.29-2.42 ng/ml; p = 0.013) despite similar levels of Aß42, NfL, WMH volume, and hippocampal volume. Cognitively impaired African Americans also had lower CSF t-tau/Aß42 (difference of 0.255 per 1-SD change in composite cognition; 95% CI, 0.100-0.409; p = 0.001) and p-tau181/Aß42 (difference of 0.076 per 1-SD change in composite cognition; 95% CI, 0.031-0.122; p = 0.001). These could not be explained by measured biomarkers of non-AD processes, but African Americans may be more susceptible than Caucasians to the cognitive effects of WMH. CONCLUSIONS: Despite comparable levels of CSF Aß42 and Aß42/Aß40, cognitive impairment in African Americans is associated with smaller changes in CSF tau markers but greater impact from similar WMH burden than Caucasians. Race-associated differences in CSF tau markers and ratios may lead to underdiagnosis of AD in African Americans. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02089555 . Retrospectively registered on 14 March 2014.

Effect of MRI coregistration on serial short-term brain volume changes in multiple sclerosis.

OBJECTIVE: To test the effect of serial magnetic resonance (MR) coregistration on short-term brain volume changes using different semiautomated and automated brain volume techniques in patients with relapsing-remitting (RR) multiple sclerosis (MS). Coregistration is frequently used to increase precision in serial MR imaging (MRI) analyses. However, the effect of coregistration on measurement of whole brain volume changes from serial scans in the short term has not been tested in MS patients. METHODS: Twenty-eight patients with RR MS [mean disease duration: 4.9 years, mean age: 34.4 years and mean expanded disability status scale (EDSS): 1.4] were scanned at baseline and monthly for a period of 3 months with 2D spin-echo T1-weighted sequences obtained with nongapped 3 mm axial slices. Percent brain parenchymal fraction change (PBPFC) was calculated by a semiautomated (Buffalo) and, separately, by two automated (Buffalo automated and SIENAX) techniques, whereas percent brain volume change (PBVC) was calculated by the SIENA technique. For coregistration of serial images we used a robust, fully automated linear image coregistration tool. PBPFC and PBVC were calculated before and after coregistration, comparing scans from the following time periods: (1) baseline to month 3; (2) baseline to month 1; (3) month 1 to 2 and (4) month 2 to 3. RESULTS: The highest median PBPFCs measured on non-coregistered images were detected for the baseline-to-month-3 time period and ranged from -0.11% for Buffalo semiautomated to -0.45% for Buffalo automated (p = ns). On coregistered images, the highest PBPFCs were detected for the baseline-to-month-3 time period and ranged from 0.3% for Buffalo semiautomated, -0.3% for Buffalo automated, 0.02% for SIENAX and -0.02% for SIENA (PBVC). At all time points of the study, no significant differences of median volume changes were measured on coregistered and non-coregistered images when comparing the results among the segmentation algorithms. CONCLUSIONS: Over a 3 month period we did not detect short-term changes in normalized brain volumes using different measurement techniques. A longer observation period is needed to assess whether coregistration can affect the measurement of long-term brain volume changes.