Publications by authors named "Peter J Snyder"

181 Publications

The relationship between cerebral and retinal microbleeds in cerebral amyloid angiopathy (CAA): A pilot study.

J Neurol Sci 2021 04 1;423:117383. Epub 2021 Mar 1.

Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA; George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, USA; Department of Neurology, Alpert Medical School of Brown University, Providence, RI, USA; Department of Surgery (Ophthalmology), Alpert Medical School of Brown University, Providence, RI, USA.

Background: The standard in vivo diagnostic imaging technique for cerebral amyloid angiopathy (CAA) is costly and thereby of limited utility for point-of-care diagnosis and monitoring of treatment efficacy. Recent recognition that retinal changes may reflect cerebral changes in neurodegenerative disease provides an ideal opportunity for development of accessible and cost-effective biomarkers for point-of-care use in the detection and monitoring of CAA. In this pilot study, we examined structural and angiographic retinal changes in CAA patients relative to a control group, and compared retinal and cerebral pathology in a group of CAA patients.

Methods: We used spectral domain optical coherence tomography (SD-OCT) to image the retina and compared retinal microbleeds to both cerebral microbleeds and white matter hyperintensities (WMH) in CAA patients, as seen on MRI. We compared retinal angiographic changes, along with structural retinal neuronal layer changes in CAA patients and cognitively normal older adults, and examined the relationship between retinal and cerebral microbleeds and cognition in CAA patients.

Results: We found a trend level correlation between retinal and cerebral microbleeds in CAA patients. Moreover, we found a significant correlation between retinal microbleeds and episodic memory performance in CAA patients. There were no significant group differences between CAA patients and cognitively normal older adults on retinal angiographic or structural measurements.

Conclusion: Retinal microbleeds may reflect degree of cerebral microbleed burden in CAA. This picture was complicated by systolic hypertension in the CAA group, which is a confounding factor for the interpretation of these data. Our results stimulate motivation for pursuit of a more comprehensive prospective study to determine the feasibility of retinal biomarkers in CAA.
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http://dx.doi.org/10.1016/j.jns.2021.117383DOI Listing
April 2021

Effect of Low-Intensity Vibration on Bone Strength, Microstructure, and Adiposity in Pre-Osteoporotic Postmenopausal Women: A Randomized Placebo-Controlled Trial.

J Bone Miner Res 2020 Dec 13. Epub 2020 Dec 13.

Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.

There has been evidence that cyclical mechanical stimulation may be osteogenic, thus providing opportunities for nonpharmacological treatment of degenerative bone disease. Here, we applied this technology to a cohort of postmenopausal women with varying bone mineral density (BMD) T-scores at the total hip (-0.524 ± 0.843) and spine (-0.795 ± 1.03) to examine the response to intervention after 1 year of daily treatment with 10 minutes of vibration therapy in a randomized double-blinded trial. The device operates either in an active mode (30 Hz and 0.3 g) or placebo. Primary endpoints were changes in bone stiffness at the distal tibia and marrow adiposity of the vertebrae, based on 3 Tesla high-resolution MRI and spectroscopic imaging, respectively. Secondary outcome variables included distal tibial trabecular microstructural parameters and vertebral deformity determined by MRI, volumetric and areal bone densities derived using peripheral quantitative computed tomography (pQCT) of the tibia, and dual-energy X-ray absorptiometry (DXA)-based BMD of the hip and spine. Device adherence was 83% in the active group (n = 42) and 86% in the placebo group (n = 38) and did not differ between groups (p = .7). The mean 12-month changes in tibial stiffness in the treatment group and placebo group were +1.31 ± 6.05% and -2.55 ± 3.90%, respectively (group difference 3.86%, p = .0096). In the active group, marrow fat fraction significantly decreased after 12 months of intervention (p = .0003), whereas no significant change was observed in the placebo group (p = .7; group difference -1.59%, p = .029). Mean differences of the changes in trabecular bone volume fraction (p = .048) and erosion index (p = .044) were also significant, as was pQCT-derived trabecular volumetric BMD (vBMD; p = .016) at the tibia. The data are commensurate with the hypothesis that vibration therapy is protective against loss in mechanical strength and, further, that the intervention minimizes the shift from the osteoblastic to the adipocytic lineage of mesenchymal stem cells. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4229DOI Listing
December 2020

Alzheimer's team care approach-akin to diabetes-in the development, validation, and population assessment of retinal biomarkers for disease.

Alzheimers Dement 2021 01 23;17(1):112-114. Epub 2020 Nov 23.

Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

There exists a public health imperative to discover and to develop disease-modifying Alzheimer's disease (AD) therapeutics to protect the health of millions of individuals facing AD. Achievement of this goal will be dependent on developing the clinical tools to detect high risk, in the earliest phases of the disease, and at the population level. This article describes the study of retinal biomarkers for the identification of, and tracking of change over time for, individuals in the preclinical stage of AD and substantiates the need for a major cross-disciplinary effort for comparison across labs and clinical sites using diabetes risk monitoring as a perfect analogy. Proposed framework would: (1) support AD working groups across disciplines; (2) establish common imaging platforms to develop and test basic standards, and minimum datasets to embrace and test novel innovations as they emerge; and (3) accelerate AD prevention and quality improvement in real-world care.
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http://dx.doi.org/10.1002/alz.12234DOI Listing
January 2021

Clinically Important Differences for Mobility Measures Derived from the Testosterone Trials.

J Am Geriatr Soc 2021 Feb 18;69(2):517-523. Epub 2020 Nov 18.

Section of Geriatric Medicine, Yale School of Medicine, New Haven, Connecticut, USA.

Background/objectives: Accurate estimates of clinically important difference (CID) are required for interpreting the clinical importance of treatments to improve physical function, but CID estimates vary in different disease populations. We determined the CID for two common measures of walking ability in mobility-limited older men.

Design: Longitudinal, multisite placebo-controlled trial.

Setting/participants: Men enrolled in the Testosterone Trials who had self-reported mobility limitation and gait speed less than 1.2 m/second (n = 429). Testosterone- and placebo-allocated participants were combined for this study.

Results: Mean changes from baseline, adjusting for time-in-intervention and site, were 29.6, 13.2, 12.5, -2.4, and -32.6 m for 6MWD, and 15.4, 7.2, 2.1, -3.4, and -7.2 for PF10 in men who reported their mobility was "very/much better," "little better," "no change," "little worse," or "much worse," respectively. CID estimates using regression, ROC, and eCDF varied from 5.0-29.6 m for 6MWD, and 5.0-15.2 points for PF10.

Conclusion: CID estimates vary by the population studied and by the method and precision of measurement. Increases of 16 to 30 m for 6MWD and 5 to 15 points for PF10 over 12 months appear to be clinically meaningful in mobility-limited, older hypogonadal men. These CID estimates may be useful in the design of efficacy trials of therapies to improve physical function.
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http://dx.doi.org/10.1111/jgs.16942DOI Listing
February 2021

A recommended "minimum data set" framework for SD-OCT retinal image acquisition and analysis from the Atlas of Retinal Imaging in Alzheimer's Study (ARIAS).

Alzheimers Dement (Amst) 2020 1;12(1):e12119. Epub 2020 Nov 1.

Department of Biomedical and Pharmaceutical Sciences University of Rhode Island Kingston Rhode Island USA.

Introduction: We propose a minimum data set framework for the acquisition and analysis of retinal images for the development of retinal Alzheimer's disease (AD) biomarkers. Our goal is to describe methodology that will increase concordance across laboratories, so that the broader research community is able to cross-validate findings in parallel, accumulate large databases with normative data across the cognitive aging spectrum, and progress the application of this technology from the discovery stage to the validation stage in the search for sensitive and specific retinal biomarkers in AD.

Methods: The proposed minimum data set framework is based on the Atlas of Retinal Imaging Study (ARIAS), an ongoing, longitudinal, multi-site observational cohort study. However, the ARIAS protocol has been edited and refined with the expertise of all co-authors, representing 16 institutions, and research groups from three countries, as a first step to address a pressing need identified by experts in neuroscience, neurology, optometry, and ophthalmology at the Retinal Imaging in Alzheimer's Disease (RIAD) conference, convened by the Alzheimer's Association and held in Washington, DC, in May 2019.

Results: Our framework delineates specific imaging protocols and methods of analysis for imaging structural changes in retinal neuronal layers, with optional add-on procedures of fundus autofluorescence to examine beta-amyloid accumulation and optical coherence tomography angiography to examine AD-related changes in the retinal vasculature.

Discussion: This minimum data set represents a first step toward the standardization of retinal imaging data acquisition and analysis in cognitive aging and AD. A standardized approach is essential to move from discovery to validation, and to examine which retinal AD biomarkers may be more sensitive and specific for the different stages of the disease severity spectrum. This approach has worked for other biomarkers in the AD field, such as magnetic resonance imaging; amyloid positron emission tomography; and, more recently, blood proteomics. Potential context of use for retinal AD biomarkers is discussed.
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http://dx.doi.org/10.1002/dad2.12119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604454PMC
November 2020

Prostate-Specific Antigen Concentrations in Response to Testosterone Treatment of Severely Hypogonadal Men.

J Endocr Soc 2020 Nov 25;4(11):bvaa141. Epub 2020 Sep 25.

Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Context: Clinical guidelines recommend measurement of the serum prostate-specific antigen (PSA) concentration during testosterone treatment of hypogonadal men to determine whether the increase is sufficiently high to warrant urologic referral. Prior studies of the effect of testosterone treatment on PSA concentrations have been conducted in men who were mildly to moderately hypogonadal.

Objective: The objective of this work is to determine the PSA response to testosterone treatment of men who are severely hypogonadal.

Design And Setting: This retrospective cohort study was conducted at a single academic medical center.

Participants: Eighty-five men participated who were severely hypogonadal as a result hypothalamic-pituitary or testicular disease.

Main Outcome Measure: Changes in serum PSA concentrations were measured during testosterone treatment for up to 18 months.

Results: Testosterone treatment increased the median serum testosterone concentration from 36 ng/dL (interquartile range [IQR], 20-91 ng/dL) at baseline to 395 ng/dL (IQR, 266-542 ng/dL) at 6 to 18 months. This treatment resulted in a median increment in PSA above baseline of 0.70 ng/mL (IQR, 0.10-1.85 ng/mL) at 6 to 18 months. Apropos current Endocrine Society clinical guidelines, 31% of the men experienced a PSA increase above baseline greater than 1.4 ng/mL, and 13% reached an absolute PSA concentration of greater than 4.0 ng/mL. Four men were diagnosed with prostate cancer.

Conclusions: The PSA response to testosterone replacement in men who are severely hypogonadal as a result of pituitary or testicular disease is greater than that previously reported in men with mild to moderate hypogonadism. These results suggest the magnitude of the PSA response to testosterone replacement is related to the degree of hypogonadism.
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http://dx.doi.org/10.1210/jendso/bvaa141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584115PMC
November 2020

Retinal imaging in Alzheimer's and neurodegenerative diseases.

Alzheimers Dement 2021 01 8;17(1):103-111. Epub 2020 Oct 8.

Medical & Scientific Relations, Alzheimer's Association, Chicago, Illinois.

In the last 20 years, research focused on developing retinal imaging as a source of potential biomarkers for Alzheimer's disease and other neurodegenerative diseases, has increased significantly. The Alzheimer's Association and the Alzheimer's & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Alzheimer's & Dementia) convened an interdisciplinary discussion in 2019 to identify a path to expedite the development of retinal biomarkers capable of identifying biological changes associated with AD, and for tracking progression of disease severity over time. As different retinal imaging modalities provide different types of structural and/or functional information, the discussion reflected on these modalities and their respective strengths and weaknesses. Discussion further focused on the importance of defining the context of use to help guide the development of retinal biomarkers. Moving from research to context of use, and ultimately to clinical evaluation, this article outlines ongoing retinal imaging research today in Alzheimer's and other brain diseases, including a discussion of future directions for this area of study.
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http://dx.doi.org/10.1002/alz.12179DOI Listing
January 2021

Markers of Iron Flux during Testosterone-Mediated Erythropoiesis in Older Men with Unexplained or Iron-Deficiency Anemia.

J Clin Endocrinol Metab 2020 11;105(11)

Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Context: Testosterone treatment of hypogonadal men improves their hemoglobin, but the mechanism is not understood.

Objective: To investigate possible mechanisms by which testosterone stimulates erythropoiesis in hypogonadal older men with unexplained or iron-deficiency anemia.

Design: The Anemia Trial of The Testosterone Trials, a placebo-controlled study in older, hypogonadal men.

Setting: Twelve academic medical centers.

Participants: A total of 95 hypogonadal men (testosterone < 275 ng/mL) ≥65 years with anemia (hemoglobin < 12.7 g/dL). They were classified as having unexplained (n = 58) or iron deficiency anemia (n = 37).

Intervention: Testosterone or placebo gel for 1 year.

Main Outcome Measures: Markers of iron metabolism during the first 3 months of treatment.

Results: Testosterone replacement significantly (P < 0.001) increased hemoglobin in the 58 men who had unexplained anemia (adjusted mean difference 0.58 g/dL; 95% confidence interval, 0.31-0.85). Testosterone replacement tended to increase hemoglobin in the 37 men who had iron deficiency (0.38 g/dL; -0.19, 0.95), but the response was more variable and not statistically significant (P = 0.19). In men with unexplained anemia, testosterone replacement suppressed hepcidin (-8.2 ng/mL; -13.7, -2.7; P = 0.004) and ferritin (-19.6 µg/L; -32.8, -6.3; P = 0.004), but in men with iron deficiency, testosterone replacement did not. The decrease in hepcidin was moderately correlated with the increase in hemoglobin in the men with unexplained anemia (correlation coefficient -0.35, P = 0.01) but not in those with iron deficiency anemia (correlation coefficient -0.07, P = 0.73).

Conclusions: Testosterone replacement of older hypogonadal men with unexplained anemia stimulates erythropoiesis associated with increased iron mobilization. This effect appears to be attenuated by iron deficiency.
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http://dx.doi.org/10.1210/clinem/dgaa521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500468PMC
November 2020

Ectopic Prolactin Secretion From a Uterine Leiomyoma.

J Endocr Soc 2020 Apr 16;4(4):bvaa035. Epub 2020 Mar 16.

Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Ectopic hormone production is well recognized, but ectopic production of prolactin has been reported infrequently. We report here the case of a 47-year-old woman who had hyperprolactinemia (213-224 ng/mL) causing galactorrhea and hypogonadism. Cabergoline treatment, 1.0 mg twice a week, did not lower the prolactin level at all, but excision of a large uterine leiomyoma corrected the hyperprolactinemia and the hypogonadism. The excised leiomyoma tissue exhibited immunostaining for prolactin, confirming by this method for the first time that a uterine leiomyoma was the cause of hyperprolactinemia. This case illustrates the need to consider an ectopic source of prolactin in a patient who has hyperprolactinemia that is not associated with a large sellar mass and is completely resistant to cabergoline.
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http://dx.doi.org/10.1210/jendso/bvaa035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145276PMC
April 2020

Disruption of cholinergic neurotransmission, within a cognitive challenge paradigm, is indicative of Aβ-related cognitive impairment in preclinical Alzheimer's disease after a 27-month delay interval.

Alzheimers Res Ther 2020 03 24;12(1):31. Epub 2020 Mar 24.

Department of Biological & Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 75 Lower College Road, 2nd Floor, Kingston, RI, USA.

Background: Abnormal beta-amyloid (Aβ) is associated with deleterious changes in central cholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist (J Prev Alzheimers Dis 1:1-4, 2017). Previously, we established the scopolamine challenge test (SCT) as a "cognitive stress test" screening measure to identify individuals at risk for AD (Alzheimer's & Dementia 10(2):262-7, 2014) (Neurobiol. Aging 36(10):2709-15, 2015). Here we aim to demonstrate the potential of the SCT as an indicator of cognitive change and neocortical amyloid aggregation after a 27-month follow-up interval.

Methods: Older adults (N = 63, aged 55-75 years) with self-reported memory difficulties and first-degree family history of AD completed the SCT and PET amyloid imaging at baseline and were then seen for cognitive testing at 9, 18, and 27 months post-baseline. Repeat PET amyloid imaging was completed at the time of the 27-month exam.

Results: Significant differences in both cognitive performance and in Aβ neocortical burden were observed between participants who either failed vs. passed the SCT at baseline, after a 27-month follow-up period.

Conclusions: Cognitive response to the SCT (Alzheimer's & Dementia 10(2):262-7, 2014) at baseline is related to cognitive change and PET amyloid imaging results, over the course of 27 months, in preclinical AD. The SCT may be a clinically useful screening tool to identify individuals who are more likely to both have positive evidence of amyloidosis on PET imaging and to show measurable cognitive decline over several years.
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http://dx.doi.org/10.1186/s13195-020-00599-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093953PMC
March 2020

Retinal imaging think tank convened by the Alzheimer's Association to examine its promise in the early detection of Alzheimer's.

Alzheimers Dement 2020 01;16(1):244

Independent Science Writer, Elverson, Pennsylvania, USA.

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http://dx.doi.org/10.1002/alz.12034DOI Listing
January 2020

Developing retinal biomarkers for the earliest stages of Alzheimer's disease: What we know, what we don't, and how to move forward.

Alzheimers Dement 2020 01;16(1):229-243

Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, USA.

The last decade has seen a substantial increase in research focused on the identification, development, and validation of diagnostic and prognostic retinal biomarkers for Alzheimer's disease (AD). Sensitive retinal biomarkers may be advantageous because they are cost and time efficient, non-invasive, and present a minimal degree of patient risk and a high degree of accessibility. Much of the work in this area thus far has focused on distinguishing between symptomatic AD and/or mild cognitive impairment (MCI) and cognitively normal older adults. Minimal work has been done on the detection of preclinical AD, the earliest stage of AD pathogenesis characterized by the accumulation of cerebral amyloid absent clinical symptoms of MCI or dementia. The following review examines retinal structural changes, proteinopathies, and vascular alterations that have been proposed as potential AD biomarkers, with a focus on studies examining the earliest stages of disease pathogenesis. In addition, we present recommendations for future research to move beyond the discovery phase and toward validation of AD risk biomarkers that could potentially be used as a first step in a multistep screening process for AD risk detection.
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http://dx.doi.org/10.1002/alz.12006DOI Listing
January 2020

Rates of age- and amyloid β-associated cortical atrophy in older adults with superior memory performance.

Alzheimers Dement (Amst) 2019 Dec 12;11:566-575. Epub 2019 Aug 12.

The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.

Introduction: Superior cognitive performance in older adults may reflect underlying resistance to age-associated neurodegeneration. While elevated amyloid β (Aβ) deposition (Aβ+) has been associated with increased cortical atrophy, it remains unknown whether "SuperAgers" may be protected from Aβ-associated neurodegeneration.

Methods: Neuropsychologically defined SuperAgers (n = 172) and cognitively normal for age (n = 172) older adults from the Australian Imaging, Biomarkers and Lifestyle study were case matched. Rates of cortical atrophy over 8 years were examined by SuperAger classification and Aβ status.

Results: Of the case-matched SuperAgers and cognitively normal for age older adults, 40.7% and 40.1%, respectively, were Aβ+. Rates of age- and Aβ-associated atrophy did not differ between the groups on any measure. Aβ- individuals displayed the slowest rates of atrophy.

Discussion: Maintenance of superior memory in late life does not reflect resistance to age- or Aβ-associated atrophy. However, those individuals who reached old age without cognitive impairment nor elevated Aβ deposition (i.e. Aβ-) displayed reduced rates of cortical atrophy.
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http://dx.doi.org/10.1016/j.dadm.2019.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939054PMC
December 2019

Biomarkers and Noncalcified Coronary Artery Plaque Progression in Older Men Treated With Testosterone.

J Clin Endocrinol Metab 2020 07;105(7)

Division of Cardiology, Lundquist Institute of Biomedical Innovation, Harbor-University of California at Los Angeles Medical Center, Torrance, California.

Objective: Recent results from the Cardiovascular Trial of the Testosterone Trials showed that testosterone treatment of older men with low testosterone was associated with greater progression of noncalcified plaque (NCP). We evaluated the effect of anthropometric measures and cardiovascular biomarkers on plaque progression in individuals in the Testosterone Trial.

Methods: The Cardiovascular part of the trial included 170 men aged 65 years or older with low testosterone. Participants received testosterone gel or placebo gel for 12 months. The primary outcome was change in NCP volume from baseline to 12 months, as determined by coronary computed tomography angiography (CCTA). We assayed several markers of cardiovascular risk and analyzed each marker individually in a model as predictive variables and change in NCP as the dependent variable.

Results: Of 170 enrollees, 138 (73 testosterone, 65 placebo) completed the study and were available for the primary analysis. Of 10 markers evaluated, none showed a significant association with the change in NCP volume, but a significant interaction between treatment assignment and waist-hip ratio (WHR) (P = 0.0014) indicated that this variable impacted the testosterone effect on NCP volume. The statistical model indicated that for every 0.1 change in the WHR, the testosterone-induced 12-month change in NCP volume increased by 26.96 mm3 (95% confidence interval, 7.72-46.20).

Conclusion: Among older men with low testosterone treated for 1 year, greater WHR was associated with greater NCP progression, as measured by CCTA. Other biomarkers and anthropometric measures did not show statistically significant association with plaque progression.
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http://dx.doi.org/10.1210/clinem/dgz242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209773PMC
July 2020

Blood-based biomarkers for Alzheimer's disease and related dementias: Keys to success and things to consider.

Alzheimers Dement (Amst) 2019 Dec 14;11:784-786. Epub 2019 Nov 14.

Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, USA.

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http://dx.doi.org/10.1016/j.dadm.2019.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872805PMC
December 2019

A Potential Association Between Retinal Changes, Subjective Memory Impairment, and Anxiety in Older Adults at Risk for Alzheimer's Disease: A 27-Month Pilot Study.

Front Aging Neurosci 2019 29;11:288. Epub 2019 Oct 29.

Department of Neurology, Alpert Medical School, Brown University, Providence, RI, United States.

Introduction: The utility of subjective memory impairment (SMI) as a risk marker for preclinical Alzheimer's disease (AD) remains unclear; however, recent studies have identified a correlation between retinal biomarkers and onset of preclinical disease. This study examines the relationship between retinal biomarkers that have been associated with cerebral amyloid, an early hallmark of AD, and SMI scores in patients at risk for developing AD.

Methods: Forty-nine cognitively normal subjects were followed over 27 months and evaluated using a combination of neuropsychological, psychological, and retinal imaging instruments. Subjective memory testing was conducted using the memory assessment clinic questionnaire (MACQ) and Depression, Anxiety, and Stress Scales (DASS). Multivariate linear analysis was conducted using STATA software.

Results: Positive correlations were found between retinal nerve fiber layer (RNFL) volume and scores obtained from the MAC-Q at 27 months (MAC-Q_27), the DASS questionnaire for anxiety at 27 months (DASS-A_27), and the change in DASS-A over 27 months (dDASSA). There was also a significant positive correlation between these variables and the change in RNFL thickness over 27 months (dRNFL). MACQ_27, DASSA_27, and dDASS-A accounted for 35.7% of RFNL variance at 27 months and 21.5% of dRFNL variance.

Discussion: These findings suggest that worse subjective memory complaints and anxiety scores may be associated with one of the most commonly used structural anatomical retinal markers of early disease burden in AD. If so, these results lend support to SMI as a valid risk marker for later cognitive decline.
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http://dx.doi.org/10.3389/fnagi.2019.00288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830450PMC
October 2019

Prostate-Specific Antigen Levels During Testosterone Treatment of Hypogonadal Older Men: Data from a Controlled Trial.

J Clin Endocrinol Metab 2019 12;104(12):6238-6246

Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Context: Prostate-specific antigen (PSA) changes during testosterone treatment of older hypogonadal men have not been rigorously evaluated.

Design: Double-blinded, placebo-controlled trial.

Setting: Twelve US academic medical centers.

Participants: Seven hundred ninety hypogonadal men ≥65 years of age with average testosterone levels ≤275 ng/dL. Men at high risk for prostate cancer were excluded.

Interventions: Testosterone or placebo gel for 12 months.

Main Outcomes: Percentile changes in PSA during testosterone treatment of 12 months.

Results: Testosterone treatment that increased testosterone levels from 232 ± 63 ng/dL to midnormal was associated with a small but substantially greater increase (P < 0.001) in PSA levels than placebo treatment. Serum PSA levels increased from 1.14 ± 0.86 ng/mL (mean ± SD) at baseline by 0.47 ± 1.1 ng/mL at 12 months in the testosterone group and from 1.25 ± 0.86 ng/mL by 0.06 ± 0.72 ng/mL in the placebo group. Five percent of men treated with testosterone had an increase ≥1.7 ng/mL and 2.5% of men had an increase of ≥3.4 ng/mL. A confirmed absolute PSA >4.0 ng/mL at 12 months was observed in 1.9% of men in the testosterone group and 0.3% in the placebo group. Four men were diagnosed with prostate cancer; two were Gleason 8.

Conclusions: When hypogonadal older men with normal baseline PSA are treated with testosterone, 5% had an increase in PSA ≥1.7 ng/mL, and 2.5% had an increase ≥3.4 ng/mL.
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http://dx.doi.org/10.1210/jc.2019-00806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823728PMC
December 2019

Clinically Meaningful Change in Sexual Desire in the Psychosexual Daily Questionnaire in Older Men from the TTrials.

J Sex Med 2019 07 14;16(7):951-953. Epub 2019 May 14.

Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA.

Background: A recent study of older men participating in the Testosterone Trials (TTrials) defined a clinically meaningful change in the Psychosexual Daily Questionnaire (PDQ) question 4 in hypogonadal men age ≥65 years. This study defines clinically meaningful change in the same population for sexual desire assessed by PDQ question 1.

Aim: To determine a clinically meaningful change in the answers to question 1 of the PDQ in hypogonadal older men.

Methods: Participants in the Sexual Function Trial of the TTrials were randomly divided into a training and test set. Anchor-based methods, including regression analysis, receiver operating characteristic curves, and empirical cumulative distribution functions, were used to determine a clinically meaningful change on question 1 in the training set, and the selected threshold was evaluated in the test set for an effect of testosterone treatment.

Results: A clinically meaningful increase in question 1 of the PDQ was determined to be ≥0.7 points.

Clinical Implications: Question 1 of the PDQ can be used to assess sexual desire in response to testosterone treatment.

Strengths & Limitations: Data were obtained from a single large study of older hypogonadal men.

Conclusion: Clinically meaningful improvement of sexual desire is a change of ≥0.7 in the score of question 1 of the PDQ. Stephens-Shields AJ, Wang C, Preston P, et al. Clinically Meaningful Change in Sexual Desire in the Psychosexual Daily Questionnaire in Older Men from the TTrials. J Sex Med 2019;16:951-953.
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http://dx.doi.org/10.1016/j.jsxm.2019.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359814PMC
July 2019

Sensitivity of a Preclinical Alzheimer's Cognitive Composite (PACC) to amyloid β load in preclinical Alzheimer's disease.

J Clin Exp Neuropsychol 2019 08 29;41(6):591-600. Epub 2019 Mar 29.

a The Florey Institute of Neuroscience and Mental Health , The University of Melbourne , Melbourne , VIC , Australia.

: Preclinical Alzheimer's disease (AD) is characterized by amyloid-related cognitive decline. Reduction in this decline is used to determine the efficacy of drug therapies designed to forestall the disease in preclinical AD clinical trials, measured by a Preclinical Alzheimer's Cognitive Composite (PACC). Most studies estimate rates of cognitive change by comparing cognitively normal (CN) older adults with abnormally high beta-amyloid (Aβ+) to those with low levels (Aβ-). However, participants of preclinical AD clinical trials must be Aβ+ for entry. Therefore, we estimated the effect of very high amyloid (Aβ++) and Aβ+ on cognitive change over three years measured by different versions of the PACC in individuals with preclinical AD. : CN older adults underwent Aβ neuroimaging and neuropsychological assessments over three years as part of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Three cognitive composite scores were computed: the Alzheimer's Disease Cooperative Study (ADCS)-PACC, the ADCS-PACC with no Mini-Mental State Examination (MMSE), and the -scores of Attention, Verbal Fluency and Episodic Memory for Nondemented Older Adults (ZAVEN) composite. : Compared to the Aβ++ group, the Aβ+ group showed a slower rate of cognitive decline with the largest magnitude of difference reflected by the ADCS-PACC ( = 0.85). The ADCS-PACC excluding the MMSE and the ZAVEN also reflected a moderate to large magnitude of difference between groups ( = 0.62, = 0.72, respectively). : When all individuals have abnormal Aβ, the level of Aβ at baseline is associated with the rate of subsequent decline. The ADCS-PACC was the most sensitive composite score in showing that lower Aβ is associated with a slower rate of cognitive decline; however, there are limitations to the use of the MMSE. These results provide a benchmark of comparison for preclinical AD clinical trials aiming to slow cognitive deterioration.
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http://dx.doi.org/10.1080/13803395.2019.1593949DOI Listing
August 2019

Effect of testosterone replacement on measures of mobility in older men with mobility limitation and low testosterone concentrations: secondary analyses of the Testosterone Trials.

Lancet Diabetes Endocrinol 2018 11;6(11):879-890

Section of Geriatric Medicine, Yale School of Medicine, New Haven, CT, USA.

Background: The Physical Function Trial (PFT) was one of seven Testosterone Trials (TTrials), the aim of which was to assess the effect of testosterone on mobility, self-reported physical function, falls, and patient global impression-of-change (PGIC) in older men with low testosterone concentrations, self-reported mobility limitation, and walking speed of less than 1·2 m/s. Using data from the PFT and the overall TTrials study population, we also aimed to identify whether the effect of testosterone on mobility differed according to baseline walking speed, mobility limitation, or other participant-level factors.

Methods: The TTrials included 790 men aged 65 years or older and with an average of two total testosterone concentrations below 275 ng/dL (9·5 nmol/L), of whom 390 had mobility limitation and a walking speed below 1·2 m/s and were enrolled in the PFT. Participants were assigned (by minimisation method) to 1% testosterone gel or placebo gel daily for 12 months, with participants and study staff masked to intervention allocation. The primary outcome of the PFT was an increase in 6 min walk test (6MWT) distance of 50 m or more. Here we report data for absolute change in 6MWT distance and physical component of Short Form-36 (PF10), and for PGIC and falls. Data are reported for men enrolled in the PFT and those who were not, and for all men in TTrials; data are also reported according to baseline walking speed and mobility limitation. Analyses were done in a modified intention-to-treat population in all patients who were allocated to treatment, had a baseline assessment, and at least one post-intervention assessment. The TTrials are registered with ClinicalTrials.gov, number NCT00799617.

Findings: The TTrials took place between April 28, 2011 and June 16, 2014. Of 790 TTrials participants, 395 were allocated to testosterone and 395 to placebo; of the 390 participants enrolled in the PFT, 193 were allocated to testosterone and 197 to placebo. As reported previously, 6MWT distance improved significantly more in the testosterone than in the placebo group among all men in the TTrials, but not in those who were enrolled in the PFT; among TTrials participants not enrolled in the PFT, 6MWT distance improved with a treatment effect of 8·9 m (95% CI 2·2-15·6; p=0·010). As reported previously, PF10 improved more in the testosterone group than in the placebo group in all men in TTrials and in men enrolled in the PFT; among those not enrolled in the PFT, PF10 improved with an effect size of 4·0 (1·5-6·5; p=0·0019). Testosterone-treated men with baseline walking speed of 1·2 m/s or higher had significantly greater improvements in 6MWT distance (treatment effect 14·2 m, 6·5-21·9; p=0·0004) and PF10 (4·9, 2·2-7·7; p=0·0005) than placebo-treated men. Testosterone-treated men reporting mobility limitation showed significantly more improvement in 6MWT distance (7·6 m, 1·0-14·1; p=0·0237) and PF10 (3·6, 1·3-5·9; p=0·0018) than placebo-treated men. Men in the testosterone group were more likely to perceive improvement in their walking ability (PGIC) than men in the placebo group, both for men enrolled in the PFT (effect size 2·21, 1·35-3·63; p=0·0018) and those not enrolled in the PFT (3·01, 1·61-5·63; p=0·0006). Changes in 6MWT distance were significantly associated with changes in testosterone, free testosterone, dihydrotestosterone, and haemoglobin concentrations. Fall frequency during the intervention period was identical in the two treatment groups of the TTrials (103 [27%] of 380 analysed in both groups had at least one fall).

Interpretation: Testosterone therapy consistently improved self-reported walking ability, modestly improved 6MWT distance (across all TTtrials participants), but did not affect falls. The effect of testosterone on mobility measures were related to baseline gait speed and self-reported mobility limitation, and changes in testosterone and haemoglobin concentrations.

Funding: US National Institute on Aging and AbbVie.
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http://dx.doi.org/10.1016/S2213-8587(18)30171-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816466PMC
November 2018

Episodic Memory and Learning Dysfunction Over an 18-Month Period in Preclinical and Prodromal Alzheimer's Disease.

J Alzheimers Dis 2018 ;65(3):977-988

The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.

Recent meta-analyses suggest that episodic memory impairment associated with preclinical Alzheimer's disease (AD) equates to 0.15-0.24 standard deviations below that of cognitively healthy older adults. The current study aimed to characterize impairments in verbal acquisition and recall detectable at a single assessment, and investigate how verbal learning and episodic memory deteriorates in preclinical AD. A verbal list-learning task, the International Shopping List Test (ISLT), was administered multiple times over an 18-month period, to three groups of participants: amyloid-beta negative healthy older adults (Aβ- CN; n = 50); Aβ+ positive healthy older adults (preclinical AD; n = 25); and Aβ+ positive individuals diagnosed with mild cognitive impairment (prodromal AD; n = 22). At baseline, there was no significant difference between the preclinical AD and control groups rate of acquisition, or total and delayed recall, however all indices were impaired in prodromal AD. Performance on ISLT total score improved in the control group over the 18-month period, but showed a moderate magnitude decline in the preclinical AD group (Cohen's d = - 0.63, [- 1.12, - 0.14]) and the prodromal AD group (Cohen's d = - 0.36, [- 0.94, 0.22]). No significant impairment in acquisition associated with preclinical AD was seen at baseline. Individuals with preclinical AD showed a significantly different performance on the ISLT total score over an 18-month period, compared to those without abnormal Aβ. Individuals with prodromal AD showed substantial impairment on the ISLT at baseline and declined to a greater extent over time.
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http://dx.doi.org/10.3233/JAD-180344DOI Listing
August 2019

Validity and Clinically Meaningful Changes in the Psychosexual Daily Questionnaire and Derogatis Interview for Sexual Function Assessment: Results From the Testosterone Trials.

J Sex Med 2018 07;15(7):997-1009

HealthCore/New England Research Institutes Inc, Watertown, MA, USA.

Background: Limited information is available on the performance characteristics of 2 questionnaires commonly used in clinical research, the Psychosexual Daily Questionnaire (PDQ) and the Derogatis Interview for Sexual Function (DISF)-II Assessment, especially in older men with low testosterone (T) and impaired sexual function.

Aim: To determine reliability of PDQ and DISF-II by assessing the correlation within and between domains in the questionnaires and to define clinically meaningful changes in sexual activity (PDQ question 4 [Q4]) and desire (DISF-II sexual desire domain [SDD]) domains.

Methods: Data from 470 men participating in the T Trials were used to calculate Spearman correlation coefficients of individual items and total score among questionnaires to determine convergent and construct validity. Clinically meaningful changes for sexual desire and activity were determined by randomly dividing the sample into training and validation sets. Anchor- and distribution-based clinically meaningful change criteria were defined in the training set, and selected changes were evaluated in the validation set.

Outcomes: Validity of the PDQ and DISF-II and clinically meaningful changes in sexual desire and activity were determined in older men in T Trials.

Results: Moderate to strong correlations were shown within and between domains from different questionnaires. Using Patient Global Impression of Change as an anchor, clinically meaningful change in PDQ sexual activity was ≥0.6, and in DISF-SDD was ≥5.0. Applying these change cut-points to the validation set, a greater proportion of T-treated men achieved clinically meaningful improvement in their sexual desire and activity compared to placebo-treated men.

Clinical Implications: The PDQ-Q4 and DISF-II-SDD can be used to reliably assess clinically meaningful changes in sexual activity and sexual desire in hypogonadal men treated with T.

Strengths & Limitations: Strengths of this study include a large sample size, long trial duration, and inclusion of men with low libido and unequivocally low T levels. Limitations include using data from a single study that enrolled only older hypogonadal men, and only 1 anchor for both sexual desire and activity.

Conclusion: Moderate to strong correlations were demonstrated within and between different sexual domains of the PDQ and DISF-II confirming construct and convergent validity. Clinically meaningful improvement in elderly hypogonadal men was change of ≥0.6 score in the PDQ-Q4 and ≥5.0 in the DISF-SDD. Improvements in sexual activity and desire in the T Trials were modest but clinically meaningful. Wang C, Stephens-Shields AJ, DeRogatis LR, et al. Validity and Clinically Meaningful Changes in the Psychosexual Daily Questionnaire and Derogatis Interview for Sexual Function Assessment: Results From the Testosterone Trials. J Sex Med 2018;15:997-1009.
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http://dx.doi.org/10.1016/j.jsxm.2018.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435333PMC
July 2018

Discontinuation and nonpublication of interventional clinical trials conducted in patients with mild cognitive impairment and Alzheimer's disease.

Alzheimers Dement (N Y) 2018 25;4:161-164. Epub 2018 Apr 25.

Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI, USA.

Introduction: Discontinuation and nonpublication of interventional clinical trials represents a waste of already scarce resources. We sought to identify the prevalence of discontinuation and nonpublication of interventional clinical trials conducted in patients afflicted by mild cognitive impairment and Alzheimer's disease.

Methods: We conducted a retrospective, cross-sectional study on mild cognitive impairment and Alzheimer's disease-based interventional clinical trials in ClinicalTrials.gov dating back to 1995. The analyzed data included trial phase, intervention type, enrollment, and funding sources. Fisher's exact and χ tests were used to determine any potential associations between trial characteristics and completion.

Results: A total of 744 studies were identified, of which 502 (67%) were industry-sponsored ones. A total of 127 (17%) were discontinued prematurely. Of the 617 completed trials, 450 (73%) were not published, representing approximately 66,655 participants who incurred the risks of trial participation without subsequently contributing to the medical literature. Similarly, there were 18,246 patients from unpublished, discontinued trials. Of the 744 trials examined, 247 publications from 167 trials could be identified via PubMed/MEDLINE and EMBASE searches. Most notably, the odds of nonpublication among industry-sponsored trials were more than 75% higher than those in studies funded by academia (odds ratio = 1.78; 95% confidence interval, 1.14-2.78;  = .01). Furthermore, industry-sponsored trials had a 50% greater odds of study discontinuation compared with trials funded by academia (odds ratio = 1.50; 95% confidence interval, 1.04-2.16;  = .03).

Discussion: The nonpublication of many trials and preliminary results of trials that are discontinued early dilutes the quality and decreases the comprehensive nature of the medical literature. This occurs in both industry and academia. Publication of inconclusive or negative results ensures that all research activities, regardless of outcome, contribute to global medical knowledge.
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http://dx.doi.org/10.1016/j.trci.2018.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021544PMC
April 2018

The cholinergic system in the pathophysiology and treatment of Alzheimer's disease.

Brain 2018 07;141(7):1917-1933

The Campaign to Prevent Alzheimer's Disease by 2020 (PAD2020), Potomac, MD, USA.

Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.
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http://dx.doi.org/10.1093/brain/awy132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022632PMC
July 2018

Change in retinal structural anatomy during the preclinical stage of Alzheimer's disease.

Alzheimers Dement (Amst) 2018 7;10:196-209. Epub 2018 Feb 7.

Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI, USA.

Introduction: We conducted a 27-month longitudinal study of mid-life adults with preclinical Alzheimer's disease (AD), using spectral domain optical coherence tomography to compare changes in volume and thickness in all retinal neuronal layers to those of age-matched healthy control subjects.

Methods: Fifty-six older adults (mean age = 65.36 years) with multiple risk factors for AD completed spectral domain optical coherence tomography retinal imaging and cognitive testing at baseline. Twenty-seven months later, they completed the same examinations and an F-florbetapir positron emission tomography imaging study.

Results: Compared to healthy control subjects, those in the preclinical stage of AD showed a significant decrease in macular retinal nerve fiber layer (mRNFL) volume, over a 27-month follow-up interval period, as well as a decrease in outer nuclear layer and inner plexiform layer volumes and thickness in the inferior quadrant. However, only the mRNFL volume was linearly related to neocortical positron emission tomography amyloid standardized uptake value ratio after controlling for any main effects of age ( = 0.103; ρ = 0.017). Furthermore, the magnitude of mRNFL volume reduction was significantly correlated with performance on a task of participants' abilities to efficiently integrate visual and auditory speech information (McGurk effect).

Discussion: We observed a decrease in mRNFL, outer nuclear layer, and inner plexiform layer volumes, in preclinical AD relative to controls. Moreover, the largely myelinated axonal loss in the RNFL is related to increased neocortical amyloid-β accumulation after controlling for age. Volume loss in the RNFL, during the preclinical stage, is not related to performance on measures of episodic memory or problem solving. However, this retinal change does appear to be modestly related to relative decrements in performance on a measure of audiovisual integration efficiency that has been recently advanced as a possible early cognitive marker of mild cognitive impairment.
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http://dx.doi.org/10.1016/j.dadm.2018.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956814PMC
February 2018

Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline.

J Clin Endocrinol Metab 2018 05;103(5):1715-1744

Brigham and Women's Hospital, Boston, Massachusetts.

Objective: To update the "Testosterone Therapy in Men With Androgen Deficiency Syndromes" guideline published in 2010.

Participants: The participants include an Endocrine Society-appointed task force of 10 medical content experts and a clinical practice guideline methodologist.

Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies.

Consensus Process: One group meeting, several conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees and members and the cosponsoring organization were invited to review and comment on preliminary drafts of the guideline.

Conclusions: We recommend making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone (T) deficiency and unequivocally and consistently low serum T concentrations. We recommend measuring fasting morning total T concentrations using an accurate and reliable assay as the initial diagnostic test. We recommend confirming the diagnosis by repeating the measurement of morning fasting total T concentrations. In men whose total T is near the lower limit of normal or who have a condition that alters sex hormone-binding globulin, we recommend obtaining a free T concentration using either equilibrium dialysis or estimating it using an accurate formula. In men determined to have androgen deficiency, we recommend additional diagnostic evaluation to ascertain the cause of androgen deficiency. We recommend T therapy for men with symptomatic T deficiency to induce and maintain secondary sex characteristics and correct symptoms of hypogonadism after discussing the potential benefits and risks of therapy and of monitoring therapy and involving the patient in decision making. We recommend against starting T therapy in patients who are planning fertility in the near term or have any of the following conditions: breast or prostate cancer, a palpable prostate nodule or induration, prostate-specific antigen level > 4 ng/mL, prostate-specific antigen > 3 ng/mL in men at increased risk of prostate cancer (e.g., African Americans and men with a first-degree relative with diagnosed prostate cancer) without further urological evaluation, elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia. We suggest that when clinicians institute T therapy, they aim at achieving T concentrations in the mid-normal range during treatment with any of the approved formulations, taking into consideration patient preference, pharmacokinetics, formulation-specific adverse effects, treatment burden, and cost. Clinicians should monitor men receiving T therapy using a standardized plan that includes: evaluating symptoms, adverse effects, and compliance; measuring serum T and hematocrit concentrations; and evaluating prostate cancer risk during the first year after initiating T therapy.
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http://dx.doi.org/10.1210/jc.2018-00229DOI Listing
May 2018

Use of Eflornithine (DFMO) in the Treatment of Early Alzheimer's Disease: A Compassionate Use, Single-Case Study.

Front Aging Neurosci 2018 6;10:60. Epub 2018 Mar 6.

Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, United States.

Recent genome-wide association screening (GWAS) studies have linked Alzheimer's disease (AD) neuropathology to gene networks that regulate immune function. Kan et al. recently reported that (an anti-inflammatory gene that codes for arginase-1) is expressed in parts of the brain associated with amyloidosis prior to the onset of neuronal loss, suggesting that chronic brain arginine deprivation promotes AD-related neuropathology. They blocked arginine catabolism in their mouse AD model by administration of eflornithine (DFMO) to juvenile animals, effectively blocking the expression of AD-related amyloid pathology as the mice aged. We report results from a single-case study in which DFMO was administered, for the first time, in an attempt to slow progression of AD in a single woman with multi-domain, amnestic MCI who was unable to tolerate an acetylcholinesterase inhibitor. Patient C.S. is a 74-year old female with a 5-year history of cognitive decline who was placed on DFMO (500 mg b.i.d.) for 12 months, with amyloid PET scans (baseline and 12-months), APOE genotyping and neuropsychological exams at baseline, 3, 9, and 12 months. C.S. suffered continued cognitive decline over 12 months, including progressive worsening of orientation, social functions and ability to engage in IADL's. She also showed progressive decline on measures of episodic memory and executive function. Florbetapir PET imaging yielded elevated total neocortical SUVr scores at both baseline (SUVr = 1.55) and at 12 months (SUVr = 1.69). We report a first attempt at using DFMO to slow AD progression. This 12-month single-case trial did not halt continued amyloidosis nor cognitive decline. Although this trial was predicated on data reported by Kan et al. (2015) showing that DFMO administered to AD-prone mice led to diminished amyloid aggregation, this attempt to treat an older mild AD patient may not be a fair test of Kan et al.'s model and results. A future trial might seek to block amyloidosis in young adults who are autosomal gene carriers for early onset AD, or perhaps in adults who are very clearly in the pre-clinical disease stage. This trial was registered as a Compassionate Use IND #128888 with the United States Food and Drug Administration (FDA).
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http://dx.doi.org/10.3389/fnagi.2018.00060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845715PMC
March 2018

Lessons From the Testosterone Trials.

Endocr Rev 2018 06;39(3):369-386

Department of Biostatistics, Epidemiology and Bioinformatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

The Testosterone Trials (TTrials) were a coordinated set of seven placebo-controlled, double-blind trials in 788 men with a mean age of 72 years to determine the efficacy of increasing the testosterone levels of older men with low testosterone. Testosterone treatment increased the median testosterone level from unequivocally low at baseline to midnormal for young men after 3 months and maintained that level until month 12. In the Sexual Function Trial, testosterone increased sexual activity, sexual desire, and erectile function. In the Physical Function Trial, testosterone did not increase the distance walked in 6 minutes in men whose walk speed was slow; however, in all TTrial participants, testosterone did increase the distance walked. In the Vitality Trial, testosterone did not increase energy but slightly improved mood and depressive symptoms. In the Cognitive Function Trial, testosterone did not improve cognitive function. In the Anemia Trial, testosterone increased hemoglobin in both men who had anemia of a known cause and in men with unexplained anemia. In the Bone Trial, testosterone increased volumetric bone mineral density and the estimated strength of the spine and hip. In the Cardiovascular Trial, testosterone increased the coronary artery noncalcified plaque volume as assessed using computed tomographic angiography. Although testosterone was not associated with more cardiovascular or prostate adverse events than placebo, a trial of a much larger number of men for a much longer period would be necessary to determine whether testosterone increases cardiovascular or prostate risk.
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http://dx.doi.org/10.1210/er.2017-00234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287281PMC
June 2018

The Effect of Testosterone on Cardiovascular Biomarkers in the Testosterone Trials.

J Clin Endocrinol Metab 2018 02;103(2):681-688

Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Context: Studies of the possible cardiovascular risk of testosterone treatment are inconclusive.

Objective: To determine the effect of testosterone treatment on cardiovascular biomarkers in older men with low testosterone.

Design: Double-blind, placebo-controlled trial.

Setting: Twelve academic medical centers in the United States.

Participants: In all, 788 men ≥65 years old with an average of two serum testosterone levels <275 ng/dL who were enrolled in The Testosterone Trials.

Intervention: Testosterone gel, the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months.

Main Outcome Measures: Serum markers of cardiovascular risk, including lipids and markers of glucose metabolism, fibrinolysis, inflammation, and myocardial damage.

Results: Compared with placebo, testosterone treatment significantly decreased total cholesterol (adjusted mean difference, -6.1 mg/dL; P < 0.001), high-density lipoprotein cholesterol (adjusted mean difference, -2.0 mg/dL; P < 0.001), and low-density lipoprotein cholesterol (adjusted mean difference, -2.3 mg/dL; P = 0.051) from baseline to month 12. Testosterone also slightly but significantly decreased fasting insulin (adjusted mean difference, -1.7 µIU/mL; P = 0.02) and homeostatic model assessment‒insulin resistance (adjusted mean difference, -0.6; P = 0.03). Testosterone did not change triglycerides, d-dimer, C-reactive protein, interleukin 6, troponin, glucose, or hemoglobin A1c levels more than placebo.

Conclusions And Relevance: Testosterone treatment of 1 year in older men with low testosterone was associated with small reductions in cholesterol and insulin but not with other glucose markers, markers of inflammation or fibrinolysis, or troponin. The clinical importance of these findings is unclear and requires a larger trial of clinical outcomes.
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http://dx.doi.org/10.1210/jc.2017-02243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800829PMC
February 2018

WITHDRAWN: Revisiting the cholinergic hypothesis in Alzheimer's disease: Emerging evidence from translational and clinical research.

Alzheimers Dement 2017 Oct 10. Epub 2017 Oct 10.

The Campaign to Prevent Alzheimer's Disease by 2020 (PAD2020), Potomac, MD, USA.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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http://dx.doi.org/10.1016/j.jalz.2017.08.016DOI Listing
October 2017