Papers by Raymond S Turner
Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia... more Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia in older adults. With no known cures, there is a pressing need to find behavioral tasks and biomarkers that can accurately assess and/or predict disease progression in asymptotic patients, as treatment is likely to be most effective at an early stage of AD. On the other hand, artificial intelligence systems are powerful and critical tools to support early detection and diagnosis, treatment, as well as outcome prediction and prognosis evaluation in healthcare. In this study, standard neuropsychological tests and a simple 5.5-minute cognitive task were administered to patients with mild AD or mild cognitive impairment (MCI) (AD group, n=28) and cognitively normal older adults (Control group, n=50). Patients with mild AD or MCI were collapsed together as the AD group. Four different machine learning algorithms were applied to classify patients from healthy controls using the data collected from neuropsychological tests, or the cognitive task, or both. The results of the study revealed that machine learning technique has the potential to assist AD diagnosis using the neuropsychological data, and when combining the neuropsychological and cognitive data, the classification accuracy can be further improved.
Cortex
Barriers to healthcare access are widespread in elderly populations, with a major consequence tha... more Barriers to healthcare access are widespread in elderly populations, with a major consequence that older people are not benefiting from the latest technologies to diagnose disease. Recent advances in the automated analysis of speech show promising results in the identification of cognitive decline associated with Alzheimer's disease (AD), as well as its purported pre-clinical stage. We utilized automated methods to analyze speech recorded over the telephone in 91 community-dwelling older adults diagnosed with mild Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), or cognitively healthy. We asked whether natural language processing (NLP) and machine learning could more accurately identify groups than traditional screening tools and be sensitive to subtle differences in speech between the groups. Despite variable recording quality, NLP methods differentiated the three groups with greater accuracy than two traditional dementia screeners and a clinician who read transcripts of their speech. Imperfect speech data collected via a telephone is of sufficient quality to be examined with the latest speech technologies. Critically, these data reveal significant differences in speech that closely match the clinical diagnoses of AD, aMCI and healthy control.
Alzheimer's & Dementia, 2016
Study Activities of Daily Living; ADCS-ADL) scores. Threemonthly assessment included magnetic res... more Study Activities of Daily Living; ADCS-ADL) scores. Threemonthly assessment included magnetic resonance imaging (MRI) as a disease modifying outcome. Other secondary outcomes included ADCS-CGIC and MMSE. Results:A total of 891 patients were randomized, of whom 62% were female. Approved AD treatments were being taken in 85%. The mean age was 70.6 (SD 9.0) years and baseline MMSE score was 18.7 (SD 3.4). Dementia was of moderate severity (MMSE score 14-19) in 61%. The study efficacy and safety outcomes will be reported. Conclusions:The outcomes of this phase 3 trial will highlight the potential therapeutic value of tau aggregation inhibitor therapy in AD. A second phase 3 trial of LMTM for AD will be completed and reported later in 2016.
Frontiers in Aging Neuroscience, Mar 17, 2022
Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) is found in 30%-50% ... more Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) is found in 30%-50% of individuals with HIV infection. To date, no HIV1 individual has been reported to have a positive amyloid PET scan. We report a 71-year-old HIV1 individual with HAND. Clinical and neuropsychologic evaluations confirmed a progressive mild dementia. A routine brain MRI was normal for age. [18F]Fluorodeoxyglucose-PET revealed mild hypermetabolism in bilateral basal ganglia and hypometabolism of bilateral parietal cortex including the posterior cingulate/precuneus. Resting state functional MRI revealed altered connectivity as found with individuals with mild AD. CSF examination revealed a low Ab42/tau index but a low phospho-tau. An amyloid PET/CT with [18F]florbetaben revealed pronounced cortical radiotracer deposition. This case report suggests that progressive dementia in older HIV1 individuals may be due to HAND, AD, or both. HIV infection does not preclude CNS Ab/amyloid deposition. Amyloid PET imaging may be of value in distinguishing HAND from AD pathologies.
Alzheimers & Dementia, Jul 1, 2017
Alzheimer's & Dementia, 2018
from FCSRT alone at 3 (p1⁄40.04), 4 (p1⁄40.05) and 5 years (p1⁄40.02); but not from CRRSTalone (p... more from FCSRT alone at 3 (p1⁄40.04), 4 (p1⁄40.05) and 5 years (p1⁄40.02); but not from CRRSTalone (p>0.05). Conclusions:Examining CRRST retrieval speed and level of performance jointly with FCSRT level of performance improved prediction of future cognitive impairment over FCSRT level of performance alone. The addition of speed of performancemay account for the additional variance explained in the prediction models and may be a symptom of underlying brain function leading to early cognitive impairment.
Alzheimers & Dementia, Jul 1, 2017
J Neuroinfl, 2023
Discoidin Domain Receptor (DDR)-1 is activated by collagen. Nilotinib is a tyrosine kinase inhibi... more Discoidin Domain Receptor (DDR)-1 is activated by collagen. Nilotinib is a tyrosine kinase inhibitor that is FDAapproved for leukemia and potently inhibits DDR-1. Individuals diagnosed with mild-moderate Alzheimer's disease (AD) treated with nilotinib (versus placebo) for 12 months showed reduction of amyloid plaque and cerebrospinal fluid (CSF) amyloid, and attenuation of hippocampal volume loss. However, the mechanisms are unclear. Here, we explored unbiased next generation whole genome miRNA sequencing from AD patients CSF and miRNAs were matched with their corresponding mRNAs using gene ontology. Changes in CSF miRNAs were confirmed via measurement of CSF DDR1 activity and plasma levels of AD biomarkers. Approximately 1050 miRNAs are detected in the CSF but only 17 miRNAs are specifically altered between baseline and 12-month treatment with nilotinib versus placebo. Treatment with nilotinib significantly reduces collagen and DDR1 gene expression (upregulated in AD brain), in association with inhibition of CSF DDR1. Pro-inflammatory cytokines, including interleukins and chemokines are reduced along with caspase-3 gene expression. Specific genes that indicate vascular fibrosis, e.g., collagen, Transforming Growth Factors (TGFs) and Tissue Inhibitors of Metalloproteases (TIMPs) are altered by DDR1 inhibition with nilotinib. Specific changes in vesicular transport, including the neurotransmitters dopamine and acetylcholine, and autophagy genes, including ATGs, indicate facilitation of autophagic flux and cellular trafficking. Inhibition of DDR1 with nilotinib may be a safe and effective adjunct treatment strategy involving an oral drug that enters the CNS and adequately engages its target. DDR1 inhibition with nilotinib exhibits multi-modal effects not only on amyloid and tau clearance but also on anti-inflammatory markers that may reduce cerebrovascular fibrosis.
Frontiers in Neuroscience, 2023
Alzheimer's Disease (AD) and related dementias are a leading cause of death globally and are pred... more Alzheimer's Disease (AD) and related dementias are a leading cause of death globally and are predicted to increase in prevalence. Despite this expected increase in the prevalence of AD, we have yet to elucidate the causality of the neurodegeneration observed in AD and we lack effective therapeutics to combat the progressive neuronal loss. Throughout the past 30 years, several nonmutually exclusive hypotheses have arisen to explain the causative pathologies in AD: amyloid cascade, hyper-phosphorylated tau accumulation, cholinergic loss, chronic neuroinflammation, oxidative stress, and mitochondrial and cerebrovascular dysfunction. Published studies in this field have also focused on changes in neuronal extracellular matrix (ECM), which is critical to synaptic formation, function, and stability. Two of the greatest non-modifiable risk factors for development of AD (aside from autosomal dominant familial AD gene mutations) are aging and APOE status, and two of the greatest modifiable risk factors for AD and related dementias are untreated major depressive disorder (MDD) and obesity. Indeed, the risk of developing AD doubles for every 5 years after ≥ 65, and the APOE4 allele increases AD risk with the greatest risk in homozygous APOE4 carriers. In this review, we will describe mechanisms by which excess ECM accumulation may contribute to AD pathology and discuss pathological ECM alterations that occur in AD as well as conditions that increase the AD risk. We will discuss the relationship of AD risk factors to chronic central nervous system and peripheral inflammation and detail ECM changes that may follow. In addition, we will discuss recent data our lab has obtained on ECM components and effectors in APOE4/4 and APOE3/3 expressing murine brain lysates, as well as human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 expressing AD individuals. We will describe the principal molecules that function in ECM turnover as well as abnormalities in these molecular systems that have been observed in AD. Finally, we will communicate therapeutic interventions that have the potential to modulate ECM deposition and turnover in vivo.
Alzheimer's and Dementia, 2023
OBJECTIVE: Investigation of learning slopes in early-onset dementias has been limited. The curren... more OBJECTIVE: Investigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without β-amyloid positivity METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses. K E Y W O R D S early-onset Alzheimer's disease, learning slopes, memory Highlights • Learning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. • Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants.
Alzheimer's and Dementia, 2023
Introduction: We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a la... more Introduction: We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS). Methods: Baseline NPS (Neuropsychiatric Inventory-Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups-amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n = 70). Results: Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Alzheimer's and Dementia, 2023
Introduction: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to de... more Introduction: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD). Methods: Cerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated.
Alzheimer's and Dementia, 2023
INTRODUCTION: We used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of patho... more INTRODUCTION: We used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD). METHODS: We included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden. RESULTS: EOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non-carriers also had greater gray matter atrophy than female ε4 carriers.
Annals Clin Transl Neurology, 2023
Objective: The objective of this study was to examine clinicians' patient selection and result in... more Objective: The objective of this study was to examine clinicians' patient selection and result interpretation of a clinically validated mass spectrometry test measuring amyloid beta and ApoE blood biomarkers combined with patient age (PrecivityADâ blood test) in symptomatic patients evaluated for Alzheimer's disease (AD) or other causes of cognitive decline. Methods: The Quality Improvement and Clinical Utility PrecivityAD Clinician Survey (QUIP I, ClinicalTrials.gov Identifier: NCT05477056) was a prospective, single-arm cohort study among 366 patients evaluated by neurologists and other cognitive specialists. Participants underwent blood biomarker testing and received an amyloid probability score (APS), indicating the likelihood of a positive result on an amyloid positron emission tomography (PET) scan. The primary study outcomes were appropriateness of patient selection as well as result interpretation associated with PrecivityAD blood testing. Results: A 95% (347/366) concordance rate was noted between clinicians' patient selection and the test's intended use criteria. In the final analysis including these 347 patients (median age 75 years, 56% women), prespecified test result categories incorporated 133 (38%) low APS, 162 (47%) high APS, and 52 (15%) intermediate APS patients. Clinicians' pretest and posttest AD diagnosis probability changed from 58% to 23% in low APS patients and 71% to 89% in high APS patients (p < 0.0001). Anti-AD drug therapy decreased by 46% in low APS patients (p < 0.0001) and increased by 57% in high APS patients (p < 0.0001). Interpretation: These findings demonstrate the clinical utility of the PrecivityAD blood test in clinical care and may have added relevance as new AD therapies are introduced.
Alzheimer''s and Dementia, 2023
INTRODUCTION: We compared white matter hyperintensities (WMHs) in early-onset Alzheimer's disease... more INTRODUCTION: We compared white matter hyperintensities (WMHs) in early-onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early-onset amyloidnegative cognitively impaired (EOnonAD) groups in the Longitudinal Early-Onset Alzheimer's Disease Study. METHODS: We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t-tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden. RESULTS: EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group.
Alzheimer's and Dementia, 2023
Objective: The Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) seeks to provide compre... more Objective: The Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early-onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data-collection mid-point. Methods: Data from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid-positive EOAD [n = 212], and amyloid-negative early-onset non-Alzheimer's disease [EOnonAD; n = 70]). Results: Cognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures. Conclusions: We present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive
The APOE4 allele increases the risk for Alzheimer's disease (AD) in a dose-dependent manner and i... more The APOE4 allele increases the risk for Alzheimer's disease (AD) in a dose-dependent manner and is also associated with cognitive decline in non-demented elderly controls. In mice with targeted gene replacement (TR) of murine APOE with human APOE3 or APOE4, the latter show reduced neuronal dendritic complexity and impaired learning. APOE4 TR mice also show reduced gamma oscillation power, a neuronal population activity which is important to learning and memory. Published work has shown that brain extracellular matrix (ECM) can reduce neuroplasticity as well as gamma power, while attenuation of ECM can instead enhance this endpoint. In the present study we examine human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 individuals and brain lysates from APOE3 and APOE4 TR mice for levels of ECM effectors that can increase matrix deposition and restrict neuroplasticity. We find that CCL5, a molecule linked to ECM deposition in liver and kidney, is increased in CSF samples from APOE4 individuals. Levels of tissue inhibitor of metalloproteinases (TIMPs), which inhibit the activity of ECM-degrading enzymes, are also increased in APOE4 CSF as well as astrocyte supernatants brain lysates from APOE4 TR mice. Importantly, as compared to APOE4/wild-type heterozygotes, APOE4/CCR5 knockout heterozygotes show reduced TIMP levels and enhanced EEG gamma power. The latter also show improved learning and memory, suggesting that the CCR5/CCL5 axis could represent a therapeutic target for APOE4 individuals.
AIDS Research and Human Retroviruses
Neurologic complications of the human immunodeficiency virus (HIV) are common in treated individu... more Neurologic complications of the human immunodeficiency virus (HIV) are common in treated individuals, and toxicity of certain antiretroviral therapies (ART) may contribute to cognitive impairment. We investigated exposures to specific ART and cognition among women living with HIV (WLWH). Virologically suppressed (viral load <200 copies/mL during at least two semi-annual visits) WLWH and age/race matched HIV-seronegative controls enrolled in the Women's Interagency HIV Study who completed at least two biennial cognitive assessments were included. Analysis of WLWH was restricted to those with exposure to the drug class of interest and a nucleoside reverse transcriptase inhibitor (NRTI) backbone. Generalized estimating equations were used to evaluate repeated measures of cognition over time in association with ART class exposure. Among 1,242 eligible WLWH, 20% (n = 247) had isolated drug exposure to non-nucleoside reverse transcriptase inhibitors (NNRTI), 18% (n = 219) to protease inhibitors (PIs), and 6% (n = 79) to integrase inhibitors with a NRTI backbone. Cognitive assessments were performed at a median of 3 biennial visits {IQR 2-4 visits}. At the index assessment, 21% of WLWH demonstrated global cognitive impairment versus 29% at their last cognitive assessment. In multivariable analyses adjusted for hypertension, depression, diabetes mellitus, history of AIDS-defining illness, alcohol use, number of medications, and time on ART, WLWH exposed to NNRTIs demonstrated verbal learning improvements (mean T-score change 1.3, p = .020) compared to other treated women. Compared to HIV-seronegative women, WLWH exposed to PIs had worse verbal learning (mean T-score difference-2.62, p = .002) and verbal memory performance (mean T-score difference-1.74, p = .032) at baseline. Compared to HIV-seronegative women, WLWH exposed to PIs had improvements in verbal learning (mean T-score slope difference 0.36, p = .025) and verbal memory (mean T-score slope difference 0.32, p = .042). The index T-score and slope of change in the T-score were similar among other treated groups and the HIV-seronegative group. We noted emerging trends in cognition in WLWH exposed to specific drug classes. Ongoing study of this relatively young group is important to characterize long-term cognitive outcomes and effect of antiretrovirals as treatment guidelines evolve.
Frontiers in Neurology, Mar 23, 2022
Second-generation anti-amyloid monoclonal antibodies are emerging as a viable therapeutic option ... more Second-generation anti-amyloid monoclonal antibodies are emerging as a viable therapeutic option for individuals with prodromal and mild dementia due to Alzheimer's disease (AD). Passive immunotherapy with aducanumab (Aduhelm), lecanemab, donanemab, and gantenerumab all lower CNS amyloid (Aβ) burden but come with a significant risk of amyloid-related imaging abnormality (ARIA)-the most common side effect of this class of drugs. While usually asymptomatic and detected only on brain MRI, ARIA may lead to new signs and symptoms including headache, worsening confusion, dizziness, visual disturbances, nausea, and seizures. In addition, one fatality related to ARIA-E (edema) with aducanumab and one fatality due to ARIA-H (hemorrhage) with donanemab are reported to date. ARIA-E may be associated with excessive neuroinflammation and saturation of perivascular clearance pathways, while ARIA-H may be related to vascular amyloid clearance with weakening and rupture of small blood vessels. The risk of ARIA-E is higher at treatment initiation, in ApoE4 carriers, with higher dosage, and with >4 of microhemorrhages on a baseline MRI. The risk of ARIA-H increases with age and cerebrovascular disease. Dose titration mitigates the risk of ARIA, and contraindications include individuals with >4 microhemorrhages and those prescribed anti-platelet or anti-coagulant drugs. A brain MRI is required before aducanumab is initiated, before each scheduled dose escalation, and with any new neurologic sign or symptom. Management of ARIA ranges from continued antibody treatment with monthly MRI monitoring for asymptomatic individuals to temporary or permanent suspension for symptomatic individuals or those with moderate to severe ARIA on MRI. Controlled studies regarding prevention and treatment of ARIA are lacking, but anecdotal evidence suggests that a pulse of intravenous corticosteroids may be of benefit, as well as a course of anticonvulsant for seizures.
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Papers by Raymond S Turner