- Building D, Suite 177
4000 Reservoir Road, NW
Washington, DC 20057 - 2026877337
Raymond S Turner
Georgetown University, Neurology, Faculty Member
- The mission of the Georgetown University Memory Disorders Program is to prevent and treat Alzheimer's disease and rel... moreThe mission of the Georgetown University Memory Disorders Program is to prevent and treat Alzheimer's disease and related dementias by conducting innovative research, educating and training healthcare professionals and the public on research advances, and offering state-of-the-art clinical care.edit
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... 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.
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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... 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.
Research Interests: Medicine, Adam, Neuroinflammation, Resveratrol, Clinical Sciences, and 3 moreMMP, Elsevier, and Neurosciences
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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... 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.
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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... 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.
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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... 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.
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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... 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.
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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... 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.
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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... 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.
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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... 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.
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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... 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.
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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... 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.
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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... 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.
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Objective There is a critical need to develop rapid, inexpensive and easily accessible screening tools for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). We report on the efficacy of collecting speech via the telephone to... more
Objective There is a critical need to develop rapid, inexpensive and easily accessible screening tools for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). We report on the efficacy of collecting speech via the telephone to subsequently develop sensitive metrics that may be used as potential biomarkers by leveraging natural language processing methods. Methods Ninety-one older individuals who were cognitively unimpaired or diagnosed with MCI or AD participated from home in an audio-recorded telephone interview, which included a standard cognitive screening tool, and the collection of speech samples. In this paper we address six questions of interest: (1) Will elderly people agree to participate in a recorded telephone interview? (2) Will they complete it? (3) Will they judge it an acceptable approach? (4) Will the speech that is collected over the telephone be of a good quality? (5) Will the speech be intelligible to human raters? (6) Will transcriptions produced by aut...
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Introduction: The goal of this study was to investigate and compare the classification performance of machine learning with behavioral data from standard neuropsychological tests, a cognitive task, or both.Methods: A neuropsychological... more
Introduction: The goal of this study was to investigate and compare the classification performance of machine learning with behavioral data from standard neuropsychological tests, a cognitive task, or both.Methods: A neuropsychological battery and a simple 5-min cognitive task were administered to eight individuals with mild cognitive impairment (MCI), eight individuals with mild Alzheimer's disease (AD), and 41 demographically match controls (CN). A fully connected multilayer perceptron (MLP) network and four supervised traditional machine learning algorithms were used.Results: Traditional machine learning algorithms achieved similar classification performances with neuropsychological or cognitive data. MLP outperformed traditional algorithms with the cognitive data (either alone or together with neuropsychological data), but not neuropsychological data. In particularly, MLP with a combination of summarized scores from neuropsychological tests and the cognitive task achieved ~9...
Research Interests: Psychology and Medicine
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Resveratrol modulates β-amyloid levels and inflammatory markers in patients with Alzheimer's disease.
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Background Missing data are a notable problem in Alzheimer’s disease clinical trials. One cause of missing data is participant dropout. The Research Attitudes Questionnaire is a 7-item instrument that measures an individual’s attitudes... more
Background Missing data are a notable problem in Alzheimer’s disease clinical trials. One cause of missing data is participant dropout. The Research Attitudes Questionnaire is a 7-item instrument that measures an individual’s attitudes toward biomedical research, with higher scores indicating more favorable attitudes. The objective of this study was to describe the performance of the Research Attitudes Questionnaire over time and to examine whether Research Attitudes Questionnaire scores predict study dropout and other participant behaviors that affect trial integrity. Methods The Research Attitudes Questionnaire was collected at baseline and weeks 26 and 52 from each member of 119 participant/study partner dyads enrolled in a Phase 2, randomized, double-blind, placebo-controlled mild-to-moderate Alzheimer’s disease clinical trial. Within-subject longitudinal analyses examined change in Research Attitudes Questionnaire scores over time in each population. Logistic regression analyse...
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To determine if older patients with breast cancer have cognitive impairment before systemic therapy. Participants were patients with newly diagnosed nonmetastatic breast cancer and matched friend or community controls age > 60 years... more
To determine if older patients with breast cancer have cognitive impairment before systemic therapy. Participants were patients with newly diagnosed nonmetastatic breast cancer and matched friend or community controls age > 60 years without prior systemic treatment, dementia, or neurologic disease. Participants completed surveys and a 55-minute battery of 17 neuropsychological tests. Biospecimens were obtained for APOE genotyping, and clinical data were abstracted. Neuropsychological test scores were standardized using control means and standard deviations (SDs) and grouped into five domain z scores. Cognitive impairment was defined as any domain z score two SDs below or ≥ two z scores 1.5 SDs below the control mean. Multivariable analyses evaluated pretreatment differences considering age, race, education, and site; comparisons between patient cases also controlled for surgery. The 164 patient cases and 182 controls had similar neuropsychological domain scores. However, among pa...
Research Interests: Neuropsychology, Dementia, Cognition, Breast Cancer, Mild Cognitive Impairment, and 15 moreMedicine, Comorbidity, Executive Function, Anxiety, Humans, Internal Medicine, Female, Clinical oncology, Aged, Cognitive impairment, Educational Status, ANXIETY, Neuropsychological Tests, Breast Neoplasms, and Neoplasm staging
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OBJECTIVE Nearly half of individuals living with HIV in the USA are now 50 or older. This rapidly aging populace may be at an increasingly greater risk of Alzheimer's disease (AD). However, the potential interaction between... more
OBJECTIVE Nearly half of individuals living with HIV in the USA are now 50 or older. This rapidly aging populace may be at an increasingly greater risk of Alzheimer's disease (AD). However, the potential interaction between HIV-disease and AD pathogenesis (i.e., AD genetic risk factors) on brain function remains an open question. The present study aimed to investigate the impact of APOE ε4 on brain function in middle-aged to older PWH, as well as the putative interaction between ε4 and HIV disease severity. METHODS Ninety-nine PWH participated in a cross-sectional study (56.3 ± 6.5yrs, range 41-70yrs, 27 females, 26 ε4 carriers and 73 noncarriers). Structural MRI and resting-state functional MRI were collected to assess alterations in brain structure and functional connectivity (FC), respectively. RESULTS APOE ε4 was associated with worse memory performance and reduced FC in the memory network. The FC reduction was centered at the caudate nucleus rather than hippocampus and correlated with worse memory performance. In ε4 carriers, low CD4 nadir was associated with reduced FC in the memory network, but this association was absent in noncarriers. Furthermore, there was an indirect detrimental impact of ε4 on memory performance through memory network FC. However, this indirect effect was contingent on CD4 nadir - that is, the indirect effect of ε4 on memory was only significant when CD4 nadir was low. INTERPRETATION APOE ε4 is associated with reduced memory and reduced FC within the memory network, and low CD4 nadir-indicating a history of severe immunosuppression-may exacerbate the effects of ε4.
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ABSTRACTSpatial inhibition of return (IOR) refers to the phenomenon by which individuals are slower to respond to stimuli appearing at a previously cued location compared to un-cued locations. Here we provide evidence supporting that... more
ABSTRACTSpatial inhibition of return (IOR) refers to the phenomenon by which individuals are slower to respond to stimuli appearing at a previously cued location compared to un-cued locations. Here we provide evidence supporting that spatial IOR is mildly impaired in individuals with mild cognitive impairment (MCI) or mild Alzheimer’s disease (AD), and the impairment is readily detectable using a novel double cue paradigm. Furthermore, reduced spatial IOR in high-risk healthy older individuals is associated with reduced memory and other neurocognitive task performance, suggesting that the novel double cue spatial IOR paradigm may be useful in detecting MCI and early AD.SIGNIFICANCE STATEMENTNovel double cue spatial inhibition of return (IOR) paradigm revealed a robust effect IOR deficits in individuals with mild cognitive impairment (MCI) or mild Alzheimer’s disease (AD)Spatial IOR effect correlates with memory performance in healthy older adults at a elevated risk of Alzheimer’s di...
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Preclinical evidence with nilotinib, a US Food and Drug Administration (FDA)‐approved drug for leukemia, indicates improvement in Alzheimer's disease phenotypes. We investigated whether nilotinib is safe, and detectable in... more
Preclinical evidence with nilotinib, a US Food and Drug Administration (FDA)‐approved drug for leukemia, indicates improvement in Alzheimer's disease phenotypes. We investigated whether nilotinib is safe, and detectable in cerebrospinal fluid, and alters biomarkers and clinical decline in Alzheimer's disease.
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Purpose To determine treatment and aging-related effects on longitudinal cognitive function in older breast cancer survivors. Methods Newly diagnosed nonmetastatic breast cancer survivors (n = 344) and matched controls without cancer (n =... more
Purpose To determine treatment and aging-related effects on longitudinal cognitive function in older breast cancer survivors. Methods Newly diagnosed nonmetastatic breast cancer survivors (n = 344) and matched controls without cancer (n = 347) 60 years of age and older without dementia or neurologic disease were recruited between August 2010 and December 2015. Data collection occurred during presystemic treatment/control enrollment and at 12 and 24 months through biospecimens; surveys; self-reported Functional Assessment of Cancer Therapy-Cognitive Function; and neuropsychological tests that measured attention, processing speed, and executive function (APE) and learning and memory (LM). Linear mixed-effects models tested two-way interactions of treatment group (control, chemotherapy with or without hormonal therapy, and hormonal therapy) and time and explored three-way interactions of ApoE (ε4+ v not) by group by time; covariates included baseline age, frailty, race, and cognitive r...
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This study examined the maintenance of anomia treatment effects in primary progressive aphasia (PPA). Following baseline testing, a phonological treatment and an orthographic treatment were administered over the course of six months. The... more
This study examined the maintenance of anomia treatment effects in primary progressive aphasia (PPA). Following baseline testing, a phonological treatment and an orthographic treatment were administered over the course of six months. The treatment stimuli consisted of nouns that were consistently named correctly at baseline (Prophylaxis items) and/or nouns that were consistently named incorrectly at baseline (Remediation items). Naming accuracy was measured at baseline, and it was measured at 1 month, 8 months, and 15 months post-treatment. The change in naming accuracy from baseline to each post-treatment evaluation was calculated within each treatment condition, and within a matched untrained condition. The change in naming accuracy was then compared between the three conditions. The results of these analyses indicate that phonological and orthographic treatments are both effective in the Prophylaxis and Remediation of anomia in all three variants of PPA. For Prophylaxis items, so...
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Changes in neuropsychological testing, neuroimaging, and cerebrospinal fluid may precede mild cognitive impairment (MCI). However, these markers are not routinely performed in outpatient clinical visits. To evaluate whether a simple... more
Changes in neuropsychological testing, neuroimaging, and cerebrospinal fluid may precede mild cognitive impairment (MCI). However, these markers are not routinely performed in outpatient clinical visits. To evaluate whether a simple clinical index, consisting of questions given to patients and their informants, could predict the onset of symptoms of MCI among cognitively normal individuals. Two hundred twenty-two participants in the BIOCARD study received a detailed history, physical examination, and neuropsychological testing annually. An index was calculated by including questions about memory problems, depression, age, education, history of cerebrovascular disease risk factors, and brain injury, family history of dementia, and the Mini-Mental State examination score. Cox regression analyses were used to determine if this index score was related to diagnosis of MCI. The BIOCARD Index score mean for individuals who progressed to MCI was 20.3 (SD=2.9), whereas the score for individu...
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Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) is a neurodegenerative disorder with cognitive deficits.... more
Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) is a neurodegenerative disorder with cognitive deficits. Amyloidogenic processing of amyloid precursor protein (APP) produces amyloid β (Aβ), the major component of hallmark AD plaques. Synaptic activity stimulates APP cleavage, whereas APP promotes excitatory synaptic transmission, suggesting APP participates in neuronal homeostasis. However, mechanisms linking synaptic activity to APP processing are unclear. Here we show that Polo-like kinase 2 (Plk2), an activity-inducible regulator of homeostatic plasticity, directly binds and phosphorylates threonine-668 and serine-675 of APP in vitro and associates with APP in vivo. Plk2 accelerates APP amyloidogenic cleavage by β-secretase at synapses and is required for neuronal overactivity-stimulated Aβ secretion. These findings implicate Plk2 as a novel mediator of activity-dependent APP amyloidogenic processing.
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Research Interests: Caenorhabditis elegans, Biology, Membrane Proteins, Biological Chemistry, Medicine, and 15 moreProtein Targeting, Biological Sciences, Cell line, Brain, Humans, Mice, Animals, Biological, Proteins, CHEMICAL SCIENCES, Transfection, Amino Acid Sequence, Molecular Sequence Data, conserved sequence , and Medical and Health Sciences
Treatment of mild-moderate Alzheimer's disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aβ40 levels and activities of daily... more
Treatment of mild-moderate Alzheimer's disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aβ40 levels and activities of daily living (ADL) scores. For this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Aβ42 <600 ng/ml (biomarker-confirmed AD) at baseline (N = 19 resveratrol-treated and N = 19 placebo-treated). We utilized multiplex Xmap technology to measure markers of neurodegenerative disease and metalloproteinases (MMPs) in parallel in CSF and plasma samples. Compared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated decline...
Research Interests: Immunology, Cytokines, Inflammation, Medicine, Activities of Daily Living, and 15 moreHumans, Adaptive Immunity, Female, Neuroinflammation, Male, Fibroblast Growth Factor, Resveratrol, Clinical Sciences, Stilbenes, Encephalitis, Alzheimer Disease, Neurosciences, Cognition disorders, Matrix Metalloproteinase, and Tau proteins
We sought to determine whether patients with posterior cortical atrophy (PCA) demonstrate a pattern of binding to translocator protein 18 kDa, a marker of microglial activation, that is distinct from that in patients with amnestic... more
We sought to determine whether patients with posterior cortical atrophy (PCA) demonstrate a pattern of binding to translocator protein 18 kDa, a marker of microglial activation, that is distinct from that in patients with amnestic presentation of Alzheimer's disease (AD). Eleven PCA patients, 11 amnestic AD patients, and 15 age-matched controls underwent positron emission tomography with (11)C-PBR28 to measure translocator protein 18 kDa. PCA patients showed greater (11)C-PBR28 binding than controls in occipital, posterior parietal, and temporal regions. In contrast, amnestic AD patients showed greater (11)C-PBR28 binding in inferior and medial temporal cortex. Increased (11)C-PBR28 binding overlapped with reduced cortical volume for both PCA and amnestic AD patients, and with areas of reduced glucose metabolism in PCA patients. While both patient groups showed diffuse amyloid binding, PCA patients showed greater binding than amnestic AD patients in bilateral occipital cortex. T...
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A 66-year-old woman with probable Alzheimer disease (AD) enrolled in National Institute of Mental Health protocols 09-M-0198 and 08-M-0066. The protocols were approved by the Combined Neurosciences Institutional Review Board, and the... more
A 66-year-old woman with probable Alzheimer disease (AD) enrolled in National Institute of Mental Health protocols 09-M-0198 and 08-M-0066. The protocols were approved by the Combined Neurosciences Institutional Review Board, and the patient gave informed consent before entering the study. Brian MRI showed diffuse atrophy and a small T2 hyperintensity in the right posterior temporal region (0.4 × 1.4 cm) interpreted as nonspecific gliosis (figure). 18Fluorodeoxyglucose PET revealed bilateral temporo-parietal hypometabolism (with no hypermetabolism in the area of the T2 hyperintensity) and 11C-Pittsburgh compound B PET imaging showed fibrillar β-amyloid retention, both consistent with AD pathophysiology. PET imaging with 11C-PBR28, a radioligand for the 18 kDa translocator protein (TSPO), was performed to measure microglial activation. Diffuse 11C-PBR28 binding was found in gray matter, with a small focus of increased binding colocalized to the T2 hyperintensity. 11C-PR28 binding was 19% greater in the T2 hyperintensity than in an identical volume in contralateral brain (figure).
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This longitudinal study sought to determine whether the 18 kDa translocator protein (TSPO), a marker of neuroinflammation, increases over time in Alzheimer's disease. Positron emission tomography imaging with the TSPO radioligand... more
This longitudinal study sought to determine whether the 18 kDa translocator protein (TSPO), a marker of neuroinflammation, increases over time in Alzheimer's disease. Positron emission tomography imaging with the TSPO radioligand (11)C-PBR28 was performed at baseline and after a median follow-up of 2.7 years in 14 amyloid-positive patients and 8 amyloid-negative controls. Patients had a greater increase in TSPO binding than controls in inferior parietal lobule, precuneus, occipital cortex, hippocampus, entorhinal cortex, and combined middle and inferior temporal cortex. TSPO binding in temporoparietal regions increased from 3.9% to 6.3% per annum in patients, but ranged from -0.5% to 1% per annum in controls. The change in TSPO binding correlated with cognitive worsening on clinical dementia rating scale-sum of boxes and reduced cortical volume. The annual rate of increased TSPO binding in temporoparietal regions was about 5-fold higher in patients with clinical progression (n =...
Research Interests: Neuroimaging, Magnetic Resonance Imaging, Biomarkers, Positron Emission Tomography, Medicine, and 15 moreBrain, Humans, GABA receptors, Female, Male, Clinical Sciences, Aged, Middle Aged, Longitudinal Studies, Disease Progression, Elsevier, Protein Binding, Alzheimer Disease, Neurosciences, and Acetamides
Research Interests:
The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Understanding the pathogenicity of amyloid-beta (Ab) peptides constitutes a major goal in research on Alzheimer’s disease (AD). One hypothesis... more
The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Understanding the pathogenicity of amyloid-beta (Ab) peptides constitutes a major goal in research on Alzheimer’s disease (AD). One hypothesis entails that Ab peptides induce uncontrolled, neurotoxic ion flux through cellular membranes. The exact biophysical mechanism of this ion flux is, however, a subject of an ongoing controversy which has attenuated progress toward understanding the importance of Ab-induced ion flux in AD. The work presented here addresses two prevalent controversies regarding the nature of transmembrane ion flux induced by Ab peptides. First, the results clarify that Ab can induce stepwise ion flux across planar lipid bilayers as opposed to a gradual increase in transmembrane current; they show that the previously repor-ted gradual thinning of membranes with concomitant increase in transmembrane current arises from residues of the solvent hexafluoroisopropanol, which is ...
Our recent study demonstrated that an amyloid-β binding molecule, BTA-EG4, increases dendritic spine number via Ras-mediated signaling. To potentially optimize the potency of the BTA compounds, we synthesized and evaluated an amyloid-β... more
Our recent study demonstrated that an amyloid-β binding molecule, BTA-EG4, increases dendritic spine number via Ras-mediated signaling. To potentially optimize the potency of the BTA compounds, we synthesized and evaluated an amyloid-β binding analog of BTA-EG4 with increased solubility in aqueous solution, BTA-EG6. We initially examined the effects of BTA-EG6 on dendritic spine formation and found that BTA-EG6-treated primary hippocampal neurons had significantly increased dendritic spine number compared to control treatment. In addition, BTA-EG6 significantly increased the surface level of AMPA receptors. Upon investigation into the molecular mechanism by which BTA-EG6 promotes dendritic spine formation, we found that BTA-EG6 may exert its effects on spinogenesis via RasGRF1-ERK signaling, with potential involvement of other spinogenesis-related proteins such as Cdc42 and CDK5. Taken together, our data suggest that BTA-EG6 boosts spine and synapse number, which may have a benefici...
Research Interests:
This study had two goals (1) to evaluate changes in neuropsychological performance among cognitively normal individuals that might precede the onset of clinical symptoms, and (2) to examine the impact of Apolipoprotein E (ApoE) genotype... more
This study had two goals (1) to evaluate changes in neuropsychological performance among cognitively normal individuals that might precede the onset of clinical symptoms, and (2) to examine the impact of Apolipoprotein E (ApoE) genotype on these changes. Longitudinal neuropsychological, clinical assessments and consensus diagnoses were completed prospectively in 268 cognitively normal individuals. The mean duration of follow-up was 9.2 years (+/- 3.3). 208 participants remained normal and 60 developed cognitive decline, consistent with a diagnosis of MCI or dementia. Cox regression analyses were completed, for both baseline scores and rate of change in scores, in relation to time to onset of clinical symptoms. Analyses were completed both with and without ApoE-4 status included. Interactions with ApoE-4 status were also examined. Lower baseline test scores, as well as greater rate of change in test scores, were associated with time to onset of clinical symptoms (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). The mean time from baseline to onset of clinical symptoms was 6.15 (+/- 3.4) years. The presence of an ApoE-4 allele doubled the risk of progression. The rate of change in two of the test scores was significantly different in ApoE-4 carriers vs. non-carriers. Cognitive performance declines prior to the onset of clinical symptoms that are a harbinger of a diagnosis of MCI. Cognitive changes in normal individuals who will subsequently decline may be observed at least 6.5 years prior to symptom onset. In addition, the risk of decline is doubled among individuals with an ApoE-4 allele.