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  • 1
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    Machine Learning Analysis Reveals Novel Neuroimaging and Clinical Signatures of Frailty in HIV
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  JAIDS Journal of Acquired Immune Deficiency Syndromes Vol. 84, No. 4 ( 2020-08-1), p. 414-421
    Details
    In: JAIDS Journal of Acquired Immune Deficiency Syndromes, Ovid Technologies (Wolters Kluwer Health), Vol. 84, No. 4 ( 2020-08-1), p. 414-421
    Abstract: Frailty is an important clinical concern for the aging population of people living with HIV (PLWH). The objective of this study was to identify the combination of risk features that distinguish frail from nonfrail individuals. Setting: Machine learning analysis of highly dimensional risk features was performed on a clinical cohort of PLWH. Methods: Participants included 105 older (average age = 55.6) PLWH, with at least a 3-month history of combination antiretroviral therapy (median CD4 = 546). Predictors included demographics, HIV clinical markers, comorbid health conditions, cognition, and neuroimaging (ie, volumetrics, resting-state functional connectivity, and cerebral blood flow). Gradient-boosted multivariate regressions were implemented to establish linear and interactive classification models. Model performance was determined by sensitivity/specificity (F1 score) with 5-fold cross validation. Results: The linear gradient-boosted multivariate regression classifier included lower current CD4 count, lower psychomotor performance, and multiple neuroimaging indices (volumes, network connectivity, and blood flow) in visual and motor brain systems (F1 score = 71%; precision = 84%; and sensitivity = 66%). The interactive model identified novel synergies between neuroimaging features, female sex, symptoms of depression, and current CD4 count. Conclusions: Data-driven algorithms built from highly dimensional clinical and brain imaging features implicate disruption to the visuomotor system in older PLWH designated as frail individuals. Interactions between lower CD4 count, female sex, depressive symptoms, and neuroimaging features suggest potentiation of risk mechanisms. Longitudinal data-driven studies are needed to guide clinical strategies capable of preventing the development of frailty as PLWH reach advanced age.
    Type of Medium: Online Resource
    ISSN: 1525-4135
    URL: Article
    DOI: 10.1097/QAI.0000000000002360
    RVK:
    XA 10000
    RVK:
    XA 51942
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2038673-4
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  • 2
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    Comparison of amyloid accumulation between Down syndrome and autosomal‐dominant Alzheimer disease
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S1 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S1 ( 2022-12)
    Abstract: Given the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development. Method We assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer’s Biomarker Consortium‐Down Syndrome (ABC‐DS) and 265 mutation‐carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) ( Table 1 ). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated‐years‐to‐symptom‐onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC‐DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40. Result The relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants ( Figure 1 ). We did not observe significant differences between MC and DS grouped by cognitive status ( Figure 2 ). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ ‐23 but was not elevated in DS until EYO ≥ ‐15 ( Figure 3 ). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region ( Figure 4 and 5 ). Conclusion These results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5‐10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S1
    DOI: 10.1002/alz.063959
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 3
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    Comparison of amyloid accumulation between Down syndrome and autosomal‐dominant Alzheimer disease
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S6 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S6 ( 2022-12)
    Abstract: Given the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development. Method We assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer’s Biomarker Consortium‐Down Syndrome (ABC‐DS) and 265 mutation‐carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) ( Table 1 ). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated‐years‐to‐symptom‐onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC‐DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40. Result The relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants ( Figure 1 ). We did not observe significant differences between MC and DS grouped by cognitive status ( Figure 2 ). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ ‐23 but was not elevated in DS until EYO ≥ ‐15 ( Figure 3 ). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region ( Figure 4 and 5 ). Conclusion These results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5‐10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S6
    DOI: 10.1002/alz.064684
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 4
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    11 Clinical Manifestations of Neuroaxonal Injury
    Cambridge University Press (CUP) ; 2023
    In:  Journal of Clinical and Translational Science Vol. 7, No. s1 ( 2023-04), p. 3-3
    Details
    In: Journal of Clinical and Translational Science, Cambridge University Press (CUP), Vol. 7, No. s1 ( 2023-04), p. 3-3
    Abstract: OBJECTIVES/GOALS: The preclinical stage of Alzheimer disease (AD) is a clinically silent period that can be detected through neuroimaging and biofluid biomarkers. The goal of this study was to determine whether performance of complex daily tasks is associated with plasma biomarkers of brain amyloidosis or neuroaxonal injury in cognitively normal (CN) older adults. METHODS/STUDY POPULATION: This is a cross-sectional analysis of an ongoing longitudinal cohort study. CN older adults performed three complex daily tasks (shopping, checkbook balancing, medication management) from the Performance Assessment of Self-Care Skills in their home. Tasks were scored for independence, with more assistance required indicating worse performance. Participants had a plasma sample obtained within two years of completing the tasks. Plasma amyloid (Aβ42 and Aβ40) were evaluated by high precision immunoprecipitation mass spectrometry assays and neurofilament light (NfL) was measured with single molecule array (Simoa) assays. Nonparametric partial correlations were used to quantify the associations between task performance and plasma AD biomarkers, controlling for age and gender. RESULTS/ANTICIPATED RESULTS: 105 CN participants (mean age 74.7 years, 55% female, 88% white) were included. After controlling for age and gender, worse performance of complex daily tasks (more assistance required) was associated with increased plasma NfL (Spearman’s: 0.23, p=0.04) but not plasma Aβ42/Aβ40. DISCUSSION/SIGNIFICANCE: This study suggests that worse performance of complex daily tasks in CN older adults may be associated with increased plasma NfL a marker of neuroaxonal injury, but not with plasma amyloid. These findings could lead to a better understanding of clinical changes that may occur prior to the onset of noticeable memory symptoms in AD or related dementias.
    Type of Medium: Online Resource
    ISSN: 2059-8661
    URL: Article
    DOI: 10.1017/cts.2023.112
    Language: English
    Publisher: Cambridge University Press (CUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2898186-8
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  • 5
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    Comparison of [11C]-PBR28 Binding Between Persons Living With HIV and HIV-Uninfected Individuals
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  JAIDS Journal of Acquired Immune Deficiency Syndromes Vol. 85, No. 2 ( 2020-10-1), p. 244-251
    Details
    In: JAIDS Journal of Acquired Immune Deficiency Syndromes, Ovid Technologies (Wolters Kluwer Health), Vol. 85, No. 2 ( 2020-10-1), p. 244-251
    Abstract: Despite combined antiretroviral therapy, neuroinflammation may persist in persons living with HIV (PLWH) and contribute to cognitive impairment in this population. Positron emission tomography (PET) imaging targeting 18 kDa translocator protein (TSPO) has been used to localize neuroinflammation. We aimed to use TSPO-PET imaging to evaluate neuroinflammation in PLWH. Design: Twenty-four virologically suppressed PLWH on combined antiretroviral therapy and 13 HIV-negative (HIV−) controls completed TSPO-PET imaging using the radiotracer [ 11 C]PBR28. Because of tracer complexity and differing procedures used in previous studies, we employed an expansive methodological approach, using binding potential (BP) and standard uptake value ratio and multiple different reference regions to estimate [ 11 C]PBR28 binding. Methods: [ 11 C]PBR28 binding was measured in 30 cortical and subcortical regions and compared between PLWH and HIV− controls. Pearson correlation evaluated the association between [ 11 C]PBR28 binding and cognition and clinical measures of HIV. Results: Analyses conducted using multiple reference regions and measures of tracer uptake revealed no significant differences between [ 11 C]PBR28 binding in PLWH compared with HIV− controls. In addition, [ 11 C]PBR28 binding in PLWH was not significantly associated with clinical measures of HIV or plasma biomarkers of inflammation. [ 11 C]PBR28 binding was not significantly elevated in cognitively impaired PLWH compared with unimpaired PLWH, but there were inverse relationships between cognitive performance (executive and global function) and [ 11 C]PBR28 binding in PLWH. Conclusions: Our results suggest that neuroinflammation may play a role in cognitive deficits, but overall neuroinflammatory levels as measured by TSPO-PET imaging in PLWH are not significantly different from those seen in HIV− controls.
    Type of Medium: Online Resource
    ISSN: 1525-4135
    URL: Article
    DOI: 10.1097/QAI.0000000000002435
    RVK:
    XA 10000
    RVK:
    XA 51942
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2038673-4
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  • 6
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    Socioeconomic status largely explains integrase inhibitors-related body composition differences in chronically infected men living with HIV
    SAGE Publications ; 2022
    In:  Antiviral Therapy Vol. 27, No. 3 ( 2022-06), p. 135965352211097-
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 27, No. 3 ( 2022-06), p. 135965352211097-
    Abstract: Substantial body composition alterations have been reported after starting combined antiretroviral therapy (cART). We characterized a cohort of chronically infected and virologically suppressed (VL 〈 50 copies/ml) men (≥50 years old) living with HIV (MLWH) who were switched to integrase inhibitors (INSTI), and compared their body composition parameters and proinflammatory/endocrine profiles to age-matched MLWH on integrase inhibitor free (non-INSTI) regimens, taking into account neighborhood-level measures of socioeconomic status (SES). In addition, we used previously published HIV-seronegative men of the same age as controls. Methods We used dual energy X-ray absorptiometry to quantify body composition parameters, and measured plasma proinflammatory/endocrine markers in 56 MLWH. We compared body composition to a publicly available dataset of 450 HIV-seronegative men of similar age. Within the MLWH group, body composition and plasma proinflammatory/endocrine markers were compared between individuals on INSTI and non-INSTI regimens, accounting for SES. Results Men living with HIV tended to have a greater android/gynoid ratio compared to HIV-seronegative men ( p 〈 0.001). INSTI usage in MLWH was associated with lower adiposity measures when compared to non-INSTI, although these differences largely disappeared after controlling for SES. Proinflammatory/endocrine markers were similar for INSTI and non-INSTI MLWH. Conclusions Among cART-experienced MLWH, those receiving INSTI-containing regimens had modestly lower adiposity compared to non-INSTI MLWH, although these differences were explained by SES. Future studies examining the relationship between INSTI use and body composition should consider the impact of SES.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/13596535221109748
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2022
    detail.hit.zdb_id: 2118396-X
    SSG: 15,3
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  • 7
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    Dynamic Characteristics of a Pressure-Compensated Inlet-Metered Pump
    ASME International ; 2017
    In:  Journal of Dynamic Systems, Measurement, and Control Vol. 139, No. 6 ( 2017-06-01)
    Details
    In: Journal of Dynamic Systems, Measurement, and Control, ASME International, Vol. 139, No. 6 ( 2017-06-01)
    Abstract: Pressure-compensated pumps are routinely used for supplying fluid power for hydraulic control systems. These pumps traditionally exhibit significant overshoot and oscillation before reaching a steady-state pressure condition, thus requiring the use of downstream safety valves to prevent over pressurization. In addition to over pressurizing the hydraulic control system, the response of the traditional pressure-compensated pump often induces excessive noise and creates instability for other components within the system. In this paper, a nontraditional pressure-compensated hydraulic pump is studied based upon the paradigm that has been offered by diesel-engine technology. This technology uses an inlet-metered pump to provide pressurized fuel for the high-pressure, fuel-injector rail. The analysis of this paper shows that a system of this type may be used to produce a first-order pressure response with no overshoot and oscillation, and that the characteristic time constant and settling time may be designed by specifying parameters that are identified in this research. The problem of cavitation damage is also discussed based upon preliminary testing done at the University of Missouri, and it is suggested that by using hardened machine parts cavitation damage may be prevented in these machines. In conclusion, this paper shows that continued development of the inlet-metered pump may be warranted for those applications where pressure overshoot and oscillation cannot be tolerated due to safety, noise, or other dynamical considerations.
    Type of Medium: Online Resource
    ISSN: 0022-0434 , 1528-9028
    URL: Article
    DOI: 10.1115/1.4035298
    Language: English
    Publisher: ASME International
    Publication Date: 2017
    detail.hit.zdb_id: 240760-7
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  • 8
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    Adverse driving behaviors increase over time as a function of preclinical Alzheimer's disease biomarkers
    Wiley ; 2023
    In:  Alzheimer's & Dementia Vol. 19, No. 5 ( 2023-05), p. 2014-2023
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 19, No. 5 ( 2023-05), p. 2014-2023
    Abstract: We investigated the relationship between preclinical Alzheimer's disease (AD) biomarkers and adverse driving behaviors in a longitudinal analysis of naturalistic driving data. Methods Naturalistic driving data collected using in‐vehicle dataloggers from 137 community‐dwelling older adults (65+) were used to model driving behavior over time. Cerebrospinal fluid (CSF) biomarkers were used to identify individuals with preclinical AD. Additionally, hippocampal volume and cognitive biomarkers for AD were investigated in exploratory analyses. Results CSF biomarkers predicted the longitudinal trajectory of the incidence of adverse driving behavior. Abnormal amyloid beta (Aβ 42 /Aβ 40 ) ratio was associated with an increase in adverse driving behaviors over time compared to ratios in the normal/lower range. Discussion Preclinical AD is associated with increased adverse driving behavior over time that cannot be explained by cognitive changes. Driving behavior as a functional, neurobehavioral marker may serve as an early detection for decline in preclinical AD. Screening may also help prolong safe driving as older drivers age.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v19.5
    DOI: 10.1002/alz.12852
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2201940-6
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  • 9
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    Comparing neuroimaging and cerebrospinal fluid markers of amyloid, tau, and neurodegenerative biomarkers: implications for understanding the biology of the disease
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S1 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S1 ( 2022-12)
    Abstract: Alzheimer disease (AD) is a complex disorder characterized by changes in amyloid, tau, as well as neurodegeneration. Neuroimaging and cerebrospinal fluid (CSF) assays provide complimentary measures of these pathologies although the Correspondence between such biomarkers is not well elucidated. Methods Data from 313 cognitively unimpaired and 59 impaired individuals aged 45 to 91 was drawn from the Charles F. and Joanne Knight Alzheimer Disease Research Center. Participants had neuroimaging, CSF, and clinical data acquired within one year. Neuroimaging variables included summary measures of amyloid (Centiloids from either PiB or Florebetapir), tau (Flortaucipir), and atrophy (MRI cortical signature). CSF variables were the Aβ 42/40 ratio, ptau 181 , and neurofilament light chain (NfL). Biomarker cutoffs were determined using Gaussian‐Mixture modeling as well as a Youden Index to maximally separate cognitively unimpaired individuals from those with a clinical AD diagnosis. Rank order congruence between biomarkers was determined using Kendall correlations (t). Results Gaussian Mixture Modeling (dashed lines) and Youden Index (solid lines) approaches produced disparate cutoffs, particularly for neurodegenerative markers (NfL/atrophy) indicating the challenges inherent to binarizing continuous variables (Figure 1). Kendall’s t provide an estimate of pairwise congruence between biomarkers in cognitively unimpaired (CN, CDR=0, upper left diagonal) and impaired individuals (CI, CDR 〉 0, lower right diagonal) (Figure 2). Measures of amyloid had generally high concordance (t ‐0.45 and ‐0.43 for CN and CI respectively ) than those of non‐specific neurodegeneration, which were quite low (t ‐0.16 and ‐0.23). Although ptau 181 and tau were moderately related (t 0.21 and 0.23), ptau 181 had higher Correspondence with both PET and CSF measures of amyloid. A sequential timing of biomarkers could be clearly seen when plotting z‐scored biomarkers as a function of amyloid PET (Figure 3). Conclusions Neuroimaging and CSF markers provide complimentary information and help to deeply phenotype the AD biological cascade. While measures of amyloid are highly congruent, non‐specific markers of neurodegeneration have poor agreement., CSF measures of phosphorylated tau likely index a response to amyloidosis rather than being a marker of tau aggregation.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S1
    DOI: 10.1002/alz.062634
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 10
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    Temporal Correlation of CSF and Neuroimaging in the Amyloid-Tau-Neurodegeneration Model of Alzheimer Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Neurology Vol. 97, No. 1 ( 2021-07-6), p. e76-e87
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 97, No. 1 ( 2021-07-6), p. e76-e87
    Abstract: To evaluate temporal correlations between CSF and neuroimaging (PET and MRI) measures of amyloid, tau, and neurodegeneration in relation to Alzheimer disease (AD) progression. Methods A total of 371 cognitively unimpaired and impaired participants enrolled in longitudinal studies of AD had both CSF (β-amyloid [Aβ] 42 , phosphorylated tau 181 , total tau, and neurofilament light chain) and neuroimaging (Pittsburgh compound B [PiB] PET, flortaucipir PET, and structural MRI) measures. The pairwise time interval between CSF and neuroimaging measures was binned into 2-year periods. Spearman correlations identified the time bin when CSF and neuroimaging measures most strongly correlated. CSF and neuroimaging measures were then binarized as biomarker-positive or biomarker-negative using Gaussian mixture modeling. Cohen kappa coefficient identified the time bin when CSF measures best agreed with corresponding neuroimaging measures when determining amyloid, tau, and neurodegeneration biomarker positivity. Results CSF Aβ 42 and PiB PET showed maximal correlation when collected within 6 years of each other ( R ≈ −0.5). CSF phosphorylated tau 181 and flortaucipir PET showed maximal correlation when CSF was collected 4 to 8 years prior to PET ( R ≈ 0.4). CSF neurofilament light chain and cortical thickness showed low correlation, regardless of time interval ( R avg ≈ −0.3). Similarly, CSF total tau and cortical thickness had low correlation, regardless of time interval ( R avg 〈 −0.2). Conclusions CSF Aβ 42 and PiB PET best agree when acquired in close temporal proximity, whereas CSF phosphorylated tau precedes flortaucipir PET by 4 to 8 years. CSF and neuroimaging measures of neurodegeneration have low correspondence and are not interchangeable at any time interval.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000012123
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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