Publications by authors named "Gwenn S Smith"

80 Publications

Mapping autonomic, mood, and cognitive effects of hypothalamic region deep brain stimulation.

Brain 2021 Apr 26. Epub 2021 Apr 26.

Division of Neurosurgery, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.

Due to its involvement in a wide variety of cardiovascular, metabolic, and behavioral functions, the hypothalamus constitutes a potential target for neuromodulation in a number of treatment-refractory conditions. The precise neural substrates and circuitry subserving these responses, however, are poorly characterized to date. We sought to retrospectively explore the acute sequalae of hypothalamic region deep brain stimulation and characterize their neuroanatomical correlates. To this end we studied at multiple international centers 58 patients (mean age: 68.5 ± 7.9 years, 26 females) suffering from mild Alzheimer's disease who underwent stimulation of the fornix region between 2007 and 2019. We catalogued the diverse spectrum of acutely induced clinical responses during electrical stimulation and interrogated their neural substrates using volume of tissue activated modelling, voxel-wise mapping, and supervised machine learning techniques. In total 627 acute clinical responses to stimulation - including tachycardia, hypertension, flushing, sweating, warmth, coldness, nausea, phosphenes, and fear - were recorded and catalogued across patients using standard descriptive methods. The most common manifestations during hypothalamic region stimulation were tachycardia (30.9%) and warmth (24.6%) followed by flushing (9.1%) and hypertension (6.9%). Voxel-wise mapping identified distinct, locally separable clusters for all sequelae that could be mapped to specific hypothalamic and extrahypothalamic gray- and white-matter structures. K-nearest neighbor classification further validated the clinico-anatomical correlates emphasizing the functional importance of identified neural substrates with area under the receiving operating characteristic curves (AUROC) between 0.67 - 0.91. Overall, we were able to localize acute effects of hypothalamic region stimulation to distinct tracts and nuclei within the hypothalamus and the wider diencephalon providing clinico-anatomical insights that may help to guide future neuromodulation work.
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http://dx.doi.org/10.1093/brain/awab170DOI Listing
April 2021

The treatment of cognitive impairment in late-life depression: neurobiological predictors of treatment response.

Authors:
Gwenn S Smith

Int Psychogeriatr 2021 Feb;33(2):113-114

Division of Geriatric Psychiatry and Neuopsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MarylandUSA21287.

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http://dx.doi.org/10.1017/S1041610220000484DOI Listing
February 2021

Molecular imaging of beta-amyloid deposition in late-life depression.

Neurobiol Aging 2021 May 15;101:85-93. Epub 2021 Jan 15.

Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Late-life depression (LLD) is associated with an increased risk of all-cause dementia and may involve Alzheimer's disease pathology. Twenty-one LLD patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for a current major depressive episode and 21 healthy controls underwent clinical and neuropsychological assessments, magnetic resonance imaging to measure gray matter volumes, and high-resolution positron emission tomography to measure beta-amyloid (Aβ) deposition. Clinical and neuropsychological assessments were repeated after 10-12 weeks of Citalopram or Sertraline treatment (LLD patients only). LLD patients did not differ from healthy controls in baseline neuropsychological function, although patients improved in both depressive symptoms and visual-spatial memory during treatment. Greater Aβ in the left parietal cortex was observed in LLD patients compared with controls. Greater Aβ was correlated with greater depressive symptoms and poorer visual-spatial memory, but not with improvement with treatment. The study of LLD patients with prospective measurements of mood and cognitive responses to antidepressant treatment is an opportunity to understand early neurobiological mechanisms underlying the association between depression and subsequent cognitive decline.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.01.002DOI Listing
May 2021

Brain structures and networks responsible for stimulation-induced memory flashbacks during forniceal deep brain stimulation for Alzheimer's disease.

Alzheimers Dement 2021 May 21;17(5):777-787. Epub 2021 Jan 21.

Division of Neurosurgery, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Canada.

Introduction: Fornix deep brain stimulation (fx-DBS) is under investigation for treatment of Alzheimer's disease (AD). We investigated the anatomic correlates of flashback phenomena that were reported previously during acute diencephalic stimulation.

Methods: Thirty-nine patients with mild AD who took part in a prior fx-DBS trial (NCT01608061) were studied. After localizing patients' implanted electrodes and modeling the volume of tissue activated (VTA) by DBS during systematic stimulation testing, we performed (1) voxel-wise VTA mapping to identify flashback-associated zones; (2) machine learning-based prediction of flashback occurrence given VTA overlap with specific structures; (3) normative functional connectomics to define flashback-associated brain-wide networks.

Results: A distinct diencephalic region was associated with greater flashback likelihood. Fornix, bed nucleus of stria terminalis, and anterior commissure involvement predicted memory events with 72% accuracy. Flashback-inducing stimulation exhibited greater functional connectivity to a network of memory-evoking and autobiographical memory-related sites.

Discussion: These results clarify the neuroanatomical substrates of stimulation-evoked flashbacks.
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http://dx.doi.org/10.1002/alz.12238DOI Listing
May 2021

Molecular Imaging of the Serotonin Transporter Availability and Occupancy by Antidepressant Treatment in Late-Life Depression.

Neuropharmacology 2021 Jan 12:108447. Epub 2021 Jan 12.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.

Patients with late-life depression (LLD) have a more variable response to pharmacotherapy relative to patients with mid-life depression. Degeneration of the serotonergic system and lower occupancy of the initial target for antidepressant medications, the serotonin transporter (5-HTT) may contribute to variability in treatment response. The focus of this study was to test the hypotheses that lower cortical and limbic 5-HTT availability in LLD patients relative to controls and less 5-HTT occupancy by antidepressant medications would be associated with less improvement in mood and cognition with treatment in the LLD patients. Twenty LLD patients meeting DSM-IV criteria for a current major depressive episode and 20 non-depressed controls underwent clinical and neuropsychological assessments, magnetic resonance imaging to measure grey matter volumes and high-resolution positron emission tomography (PET) scanning to measure 5-HTT before and after 10-12 weeks of treatment with citalopram or sertraline (patients only). Prior to treatment, 5-HTT was lower in LLD patients relative to controls in cortical and limbic (amygdala) regions. Grey matter volumes were not significantly different between groups. 5-HTT occupancy was detected throughout cortical, striatal, thalamic and limbic (amygdala, hippocampus) regions. The magnitude of 5-HTT occupancy by antidepressants was 70% or greater across cortical and sub-cortical regions, consistent with the magnitude of 5-HTT occupancy observed in mid-life depressed patients. Greater regional 5-HTT occupancy correlated with greater improvement in depressive symptoms and visual-spatial memory performance. These data support the hypothesis that serotonin degeneration and variability in 5-HTT occupancy may contribute to heterogeneity in treatment response in LLD patients.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108447DOI Listing
January 2021

Neurotransmitters and Neurometabolites in Late-Life Depression: A Preliminary Magnetic Resonance Spectroscopy Study at 7T.

J Affect Disord 2021 01 7;279:417-425. Epub 2020 Oct 7.

Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Background: Magnetic resonance spectroscopy (MRS) methods have quantified changes in levels of neurotransmitters and neurometabolites in patients with major depression across the lifespan. The application of 7T field strengths and greater have not been a major focus of study in patients with late-life depression (LLD).

Methods: Nine LLD patients who met DSM-IV criteria for a current major depressive episode and nine non-depressed, healthy, age-matched controls underwent clinical and neuropsychological assessment and single-voxel 7T H-MRS at baseline and after 10-12 weeks of antidepressant treatment (Citalopram; patients only). Spectra were acquired from two brain regions implicated in both depressive symptoms and neuropsychological deficits in LLD, the anterior (ACC) and posterior cingulate (PCC). Levels of γ-aminobutyric acid (GABA), glutamate (Glu), glutathione (GSH), N-acetylaspartylglutamate (NAAG), N-acetylaspartate (NAA), and myo-inositol (mI) were quantified relative to total creatine (tCr) using linear-combination modeling.

Results: Baseline Glu/tCr levels were not significantly different between groups. Decreased Glu/tCr levels after Citalopram treatment were observed in a subset of LLD patients. Exploratory analyses showed that LLD patients had lower NAA levels in the PCC relative to controls. Higher levels of ml in the LLD patients relative to the controls and decreases after Citalopram treatment had large effect sizes but were not statistically significant. Further, decreases in PCC Glu/tCr and increases in ACC GSH/tCr were associated with improvement in depressive symptoms.

Limitations: Sample size.

Conclusions: These preliminary results suggest a role of neurochemicals and neurometabolites in the neurobiology of LLD and antidepressant treatment response.
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http://dx.doi.org/10.1016/j.jad.2020.10.011DOI Listing
January 2021

Trajectories of neuropsychiatric symptoms over time in healthy volunteers and risk of MCI and dementia.

Int J Geriatr Psychiatry 2019 12 2;34(12):1865-1873. Epub 2019 Sep 2.

Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD.

Objectives: To identify subtypes of neuropsychiatric symptom (NPS) course among cognitively normal individuals and to assess the association between these subtypes and hazard of later mild cognitive impairment (MCI) or dementia diagnosis.

Methods: We modeled neuropsychiatric inventory questionnaire (NPI-Q) scores from 4184 volunteers over approximately 4 years using growth mixture models, generating latent classes of trajectory. We then fit Cox proportional hazard models to determine if membership in trajectory classes was associated with increased hazard of diagnosis of MCI or dementia.

Results: We identified four trajectory classes: the majority of the sample (65%) would be expected to belong to a class with consistently low or zero NPS. The next most prevalent class, (16%) showed a decrease over time in NPI-Q total score but, compared with the majority class had an almost threefold increase in hazard of MCI or dementia (HR: 2.92; 95% CI: 1.82-4.68). Another class (14%) showed an increase in NPS over time and was also associated with greater hazard of MCI or dementia (HR: 3.96; CI: 2.61-6.03). The smallest class (5%) had high and fluctuating NPI-Q total scores and had the greatest hazard (HR: 4.57; CI: 2.72-7.63).

Conclusion: We have demonstrated that it is possible to identify meaningful groups of NPS trajectories and that trajectory of NPS can convey information beyond a single cross-sectional measure. While even those whose NPS improved were at increased hazard of MCI or dementia, hazard increased as a function of the severity of the NPS trajectory.
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http://dx.doi.org/10.1002/gps.5203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854285PMC
December 2019

High Availability of the α7-Nicotinic Acetylcholine Receptor in Brains of Individuals with Mild Cognitive Impairment: A Pilot Study Using F-ASEM PET.

J Nucl Med 2020 03 16;61(3):423-426. Epub 2019 Aug 16.

Department of Psychiatry, Johns Hopkins Medical Institutions, Baltimore, Maryland.

Emerging evidence supports a hypothesized role for the α7-nicotinic acetylcholine receptor (α7-nAChR) in the pathophysiology of Alzheimer's disease. F-ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-F-fluorodibenzo[b,d]thiophene 5,5-dioxide) is a radioligand for estimating the availability of α7-nAChR in the brain in vivo with PET. In this cross-sectional study, 14 patients with mild cognitive impairment (MCI), a prodromal stage to dementia, and 17 cognitively intact, elderly controls completed F-ASEM PET. For each participant, binding in each region of interest was estimated using Logan graphical analysis with a metabolite-corrected arterial input function. Higher F-ASEM binding was observed in MCI patients than in controls across all regions, supporting higher availability of α7-nAChR in MCI. F-ASEM binding was not associated with verbal memory in this small MCI sample. These data support use of F-ASEM PET to examine further the relationship between α7-nAChR availability and MCI.
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http://dx.doi.org/10.2967/jnumed.119.230979DOI Listing
March 2020

Effect of STN DBS on vesicular monoamine transporter 2 and glucose metabolism in Parkinson's disease.

Parkinsonism Relat Disord 2019 07 16;64:235-241. Epub 2019 Apr 16.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.

Introduction: Deep brain stimulation (DBS) is an established treatment for Parkinson's Disease (PD). Despite the improvement of motor symptoms in most patients by sub-thalamic nucleus (STN) DBS and its widespread use, the neurobiological mechanisms are not completely understood. The objective of the present study was to elucidate the effects of subthalamic nucleus (STN) DBS in PD on the dopamine system and neural circuitry, employing high-resolution positron emission tomography (PET) imaging. The hypotheses tested were that STN DBS would decrease the striatal vesicular monoamine transporter (VMAT2), secondary to an increase in dopamine concentrations, and would decrease striatal cerebral metabolism and increase cortical cerebral metabolism.

Methods: PET imaging of the vesicular monoamine transporter (VMAT2) and cerebral glucose metabolism was performed prior to DBS surgery and after 4-6 months of STN stimulation in seven PD patients (mean age 67 ± 7).

Results: The patients demonstrated significant improvement in motor and neuropsychiatric symptoms after STN DBS. Decreased VMAT2 was observed in the caudate, putamen and associative striatum and in extra-striatal, cortical and limbic regions. Cerebral glucose metabolism was decreased in striatal sub-regions and increased in temporal and parietal cortices and the cerebellum. Decreased striatal VMAT2 was correlated with decreased striatal and increased cortical and limbic metabolism. Improvement of depressive symptoms was correlated with decreased VMAT2 in striatal and extra-striatal regions and with striatal decreases and cortical increases in metabolism.

Conclusions: The present results support further investigation of the role of VMAT2, and associated changes in neural circuitry in the improvement of motor and non-motor symptoms with STN DBS in PD.
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http://dx.doi.org/10.1016/j.parkreldis.2019.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304230PMC
July 2019

Reproducibility of brain MRS in older healthy adults at 7T.

NMR Biomed 2019 02 29;32(2):e4040. Epub 2018 Nov 29.

Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

To date, the majority of MRS reproducibility studies have been conducted in healthy younger adults, with only a few conducted in older adults at 3 T. With the growing interest in applying MRS methods to study the longitudinal course and effects of treatments in neurodegenerative disease, it is important to establish reproducibility in age-matched controls, especially in older individuals. In this study, spectroscopic data were acquired using a stimulated echo acquisition mode (STEAM) localization technique in two regions (anterior and posterior cingulate cortices-ACC, PCC, respectively) in 10 healthy, cognitively normal older adults (64 ± 8.1 years). Reproducibility was assessed via mean coefficients of variation (CVs) and relative differences (RDs) calculated across two visits performed 2-3 months apart. Metabolites with high signal-to-noise ratio (SNR) such as NAA, tCho, and Glu had mean CVs of 10% or less and mean RDs of 15% or less across both regions. Metabolites with lower SNR such as GABA and Gln had slightly higher mean CVs of 22% or less and mean RDs of 27% or less across both regions. These results demonstrate the feasibility of acquiring MRS data at 7 T in older subjects, and establish that the spectroscopic data are reproducible in both the ACC and PCC in older, healthy subjects to the same extent as in previous studies in young subjects.
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http://dx.doi.org/10.1002/nbm.4040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324949PMC
February 2019

Advanced Research Institute (ARI): An Effective Model for Career Development and Transition to Independence.

Am J Geriatr Psychiatry 2019 07 29;27(7):660-663. Epub 2018 Oct 29.

Geisel School of Medicine at Dartmouth, University of Rochester School of Medicine & Dentistry, University of Pennsylvania School of Medicine, Weill Cornell Medical College, Johns Hopkins School of Medicine. Electronic address:

The vitality of geriatric mental health research requires an ongoing infusion of new investigators into the career pipeline. This report examines outcomes of the NIMH-funded, Advanced Research Institute (ARI) in Geriatric Mental Health, a national mentoring program supporting the transition of early career researchers to independent investigators. Outcome data for 119 ARI Scholars were obtained from the NIH Reporter database, CVs, and PubMed: 95.0% continue in research, 80.7% had obtained federal grants, and 45.4% had achieved an NIH R01. Among all NIMH mentored K awardees initially funded 2002-2014 (n=901), 60.4% (32/53) of ARI participants vs. 42.0% (356/848) of nonparticipants obtained an R01. Controlling for funding year, ARI participants were 1.9 times more likely to achieve R01 funding than nonparticipants. These data suggest that ARI has helped new generations of researchers to achieve independent funding, become scientific leaders, and conduct high impact research contributing to public health and patient care.
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http://dx.doi.org/10.1016/j.jagp.2018.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488458PMC
July 2019

Neurometabolites and associations with cognitive deficits in mild cognitive impairment: a magnetic resonance spectroscopy study at 7 Tesla.

Neurobiol Aging 2019 01 27;73:211-218. Epub 2018 Sep 27.

Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, United States. Electronic address:

The levels of several brain metabolites were investigated in the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) in 13 healthy controls (HC) and 13 patients with mild cognitive impairment (MCI) using single-voxel magnetic resonance spectroscopy at 7T. Levels of γ-aminobutyric acid (GABA), glutamate (Glu), glutathione (GSH), N-acetylaspartylglutamate (NAAG), N-acetylaspartate (NAA), and myo-inositol (mI) were quantified relative to total creatine (tCr). The effect of diagnosis on metabolite levels, and relationships between metabolite levels and memory and executive function, correcting for age, were investigated. MCI patients showed significantly decreased GABA/tCr (ACC, PCC), Glu/tCr (PCC), and NAA/tCr (PCC), and significantly increased mI/tCr (ACC). In the combined group, worse episodic verbal memory performance was correlated with lower Glu/tCr (PCC), lower NAA/tCr (PCC), and higher mI/tCr (ACC, PCC). Worse verbal fluency performance was correlated with lower GSH/tCr (PCC). In summary, MCI is associated with decreased GABA and Glu, most consistently in the PCC. Further studies in larger patient samples should be undertaken to determine the utility of 7T magnetic resonance spectroscopy in detecting MCI-related neurochemical changes.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294473PMC
January 2019

Blood-brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound.

Nat Commun 2018 07 25;9(1):2336. Epub 2018 Jul 25.

Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, M4N 3M5, Canada.

Magnetic resonance-guided focused ultrasound in combination with intravenously injected microbubbles has been shown to transiently open the blood-brain barrier, and reduce beta-amyloid and tau pathology in animal models of Alzheimer's disease. Here, we used focused ultrasound to open the blood-brain barrier in five patients with early to moderate Alzheimer's disease in a phase I safety trial. In all patients, the blood-brain barrier within the target volume was safely, reversibly, and repeatedly opened. Opening the blood-brain barrier did not result in serious clinical or radiographic adverse events, as well as no clinically significant worsening on cognitive scores at three months compared to baseline. Beta-amyloid levels were measured before treatment using [F]-florbetaben PET to confirm amyloid deposition at the target site. Exploratory analysis suggested no group-wise changes in amyloid post-sonication. The results of this safety and feasibility study support the continued investigation of focused ultrasound as a potential novel treatment and delivery strategy for patients with Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-018-04529-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060168PMC
July 2018

Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation.

J Alzheimers Dis 2018 ;64(2):597-606

Department of Psychiatry and Behavioral Sciences, Memory and Alzheimer's Treatment Center andAlzheimer's Disease Research Center, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years.

Objective: To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f treatment of mild AD after two years.

Methods: 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial.

Results: DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants.

Conclusion: DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65.
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http://dx.doi.org/10.3233/JAD-180121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518401PMC
July 2019

F-XTRA PET for Enhanced Imaging of the Extrathalamic α4β2 Nicotinic Acetylcholine Receptor.

J Nucl Med 2018 10 1;59(10):1603-1608. Epub 2018 Mar 1.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland

Reduced density of the α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) in the cortex and hippocampus of the human brain has been reported in aging and patients with neurodegenerative disease. This study assessed the pharmacokinetic behavior of F-(-)-JHU86428 (F-XTRA), a new radiotracer for in vivo PET imaging of the α4β2-nAChR, particularly in extrathalamic regions of interest in which the α4β2-nAChR is less densely expressed than in thalamus. F-XTRA was also used to evaluate the α4β2-nAChR in the hippocampus in human aging. Seventeen healthy nonsmoker adults (11 men, 6 women; age, 30-82 y) underwent PET neuroimaging over 90 or 180 min in a high-resolution research tomograph after bolus injection of F-XTRA. Methods to quantify binding of F-XTRA to the α4β2-nAChR in the human brain were compared, and the relationship between age and binding in the hippocampus was tested. F-XTRA rapidly entered the brain, and time-activity curves peaked within 10 min after injection for extrathalamic regions and at approximately 70 min in the thalamus. The 2-tissue-compartment model (2TCM) predicted the regional time-activity curves better than the 1-tissue-compartment model, and total distribution volume (V) was well identified by the 2TCM in all ROIs. V values estimated using Logan analysis with metabolite-corrected arterial input were highly correlated with those from the 2TCM in all regions, and values from 90-min scan duration were on average within 5% of those values from 180 min of data. Parametric images of V were consistent with the known distribution of the α4β2-nAChR across the brain. Finally, an inverse correlation between V in the hippocampus and age was observed. Our results extend support for use of F-XTRA with 90 min of emission scanning in quantitative human neuroimaging of the extrathalamic α4β2-nAChR, including in studies of aging.
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http://dx.doi.org/10.2967/jnumed.117.205492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167533PMC
October 2018

Molecular imaging in neuropsychiatry.

Int Rev Psychiatry 2017 12 12;29(6):527-529. Epub 2017 Dec 12.

a Department of Psychiatry and Behavioral Sciences , Johns Hopkins University School of Medicine , Baltimore , MD , USA.

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http://dx.doi.org/10.1080/09540261.2017.1403201DOI Listing
December 2017

The distribution of the alpha7 nicotinic acetylcholine receptor in healthy aging: An in vivo positron emission tomography study with [F]ASEM.

Neuroimage 2018 01 7;165:118-124. Epub 2017 Oct 7.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA. Electronic address:

Altered function of the alpha7 nicotinic acetylcholine receptor (α7-nAChR) is implicated in several neuropsychiatric diseases. Nevertheless, studies of the human cerebral α7-nAChR even in healthy aging are limited in number and to postmortem tissue.

Methods: The distribution of the cerebral α7-nAChR was estimated in nine brain regions in 25 healthy volunteers (ages 21-86 years; median 57 years, interquartile range 52 years) using [F]ASEM with positron emission tomography (PET) imaging. Regional total distribution volume (V) measurements were calculated using the Logan method from each subject's 90 min dynamic PET data and their metabolite-corrected plasma input function. Spearman's rank or Pearson's correlation analysis was used depending on the normality of the data. Correlation between age and regional 1) volume relative to intracranial volume (volume ratio) and 2) [F]ASEM V was tested. Correlation between regional volume ratio and [F]ASEM V was also evaluated. Finally, the relationship between [F]ASEM V and neuropsychological measures was investigated in a subpopulation of 15 elderly healthy participants (those 50 years of age and older). Bonferroni correction for multiple comparisons was applied to statistical analyses.

Results: A negative correlation between tissue volume ratio and age was observed in six of the nine brain regions including striatum and five cortical (temporal, occipital, cingulate, frontal, or parietal) regions. A positive correlation between [F]ASEM V and age was observed in all nine brain regions of interest (ROIs). There was no correlation between [F]ASEM V and volume ratio in any ROI after controlling for age. Regional [F]ASEM V and neuropsychological performance on each of eight representative subtests were not correlated among the well-performing subpopulation of elderly healthy participants.

Conclusions: Our results suggest an increase in cerebral α7-nAChR distribution over the course of healthy aging that should be tested in future longitudinal studies. The preservation of the α7-nAChR in the aging human brain supports the development of therapeutic agents that target this receptor for use in the elderly. Further study of the relationship between α7-nAChR availability and cognitive impairment over aging is needed.
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http://dx.doi.org/10.1016/j.neuroimage.2017.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738927PMC
January 2018

Molecular imaging of serotonin degeneration in mild cognitive impairment.

Neurobiol Dis 2017 Sep 13;105:33-41. Epub 2017 May 13.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Neuropathological and neuroimaging studies have consistently demonstrated degeneration of monoamine systems, especially the serotonin system, in normal aging and Alzheimer's disease. The evidence for degeneration of the serotonin system in mild cognitive impairment is limited. Thus, the goal of the present study was to measure the serotonin transporter in vivo in mild cognitive impairment and healthy controls. The serotonin transporter is a selective marker of serotonin terminals and of the integrity of serotonin projections to cortical, subcortical and limbic regions and is found in high concentrations in the serotonergic cell bodies of origin of these projections (raphe nuclei). Twenty-eight participants with mild cognitive impairment (age 66.6±6.9, 16 males) and 28 healthy, cognitively normal, demographically matched controls (age 66.2±7.1, 15 males) underwent magnetic resonance imaging for measurement of grey matter volumes and high-resolution positron emission tomography with well-established radiotracers for the serotonin transporter and regional cerebral blood flow. Beta-amyloid imaging was performed to evaluate, in combination with the neuropsychological testing, the likelihood of subsequent cognitive decline in the participants with mild cognitive impairment. The following hypotheses were tested: 1) the serotonin transporter would be lower in mild cognitive impairment compared to controls in cortical and limbic regions, 2) in mild cognitive impairment relative to controls, the serotonin transporter would be lower to a greater extent and observed in a more widespread pattern than lower grey matter volumes or lower regional cerebral blood flow and 3) lower cortical and limbic serotonin transporters would be correlated with greater deficits in auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls. Reduced serotonin transporter availability was observed in mild cognitive impairment compared to controls in cortical and limbic areas typically affected by Alzheimer's disease pathology, as well as in sensory and motor areas, striatum and thalamus that are relatively spared in Alzheimer's disease. The reduction of the serotonin transporter in mild cognitive impairment was greater than grey matter atrophy or reductions in regional cerebral blood flow compared to controls. Lower cortical serotonin transporters were associated with worse performance on tests of auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls. The serotonin system may represent an important target for prevention and treatment of MCI, particularly the post-synaptic receptors (5-HT4 and 5-HT6), which may not be as severely affected as presynaptic aspects of the serotonin system, as indicated by the observation of lower serotonin transporters in MCI relative to healthy controls.
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http://dx.doi.org/10.1016/j.nbd.2017.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663212PMC
September 2017

Association between serotonin denervation and resting-state functional connectivity in mild cognitive impairment.

Hum Brain Mapp 2017 Jul 5;38(7):3391-3401. Epub 2017 Apr 5.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Resting-state functional connectivity alterations have been demonstrated in Alzheimer's disease (AD) and mild cognitive impairment (MCI) before the observation of AD neuropathology, but mechanisms driving these changes are not well understood. Serotonin neurodegeneration has been observed in MCI and AD and is associated with cognitive deficits and neuropsychiatric symptoms, but the role of the serotonin system in relation to brain network dysfunction has not been a major focus of investigation. The current study investigated the relationship between serotonin transporter availability (SERT; measured using positron emission tomography) and brain network functional connectivity (measured using resting-state functional MRI) in 20 participants with MCI and 21 healthy controls. Two SERT regions of interest were selected for the analysis: the Dorsal Raphe Nuclei (DRN) and the precuneus which represent the cell bodies of origin and a cortical target of projections of the serotonin system, respectively. Both regions show decreased SERT in MCI compared to controls and are the site of early AD pathology. Average resting-state functional connectivity did not differ between MCI and controls. Decreased SERT in DRN was associated with lower hippocampal resting-state connectivity in MCI participants compared to controls. Decreased SERT in the right precuneus was also associated with lower resting-state connectivity of the retrosplenial cortex to the dorsal lateral prefrontal cortex and higher resting-state connectivity of the retrosplenial cortex to the posterior cingulate and in patients with MCI but not in controls. These results suggest that a serotonergic mechanism may underlie changes in brain functional connectivity in MCI. Hum Brain Mapp 38:3391-3401, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hbm.23595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628094PMC
July 2017

Deep brain stimulation of the subcallosal cingulate for treatment-refractory anorexia nervosa: 1 year follow-up of an open-label trial.

Lancet Psychiatry 2017 04 24;4(4):285-294. Epub 2017 Feb 24.

Division of Neurosurgery, Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada. Electronic address:

Background: Anorexia nervosa is a life-threatening illness. Brain circuits believed to drive anorexia nervosa symptoms can be accessed with surgical techniques such as deep brain stimulation (DBS). Initial results suggest that DBS of the subcallosal cingulate is safe and associated with improvements in mood and anxiety. Here, we investigated the safety, clinical, and neuroimaging outcomes of DBS of the subcallosal cingulate in a group of patients during 12 months of active stimulation.

Methods: We did this prospective open-label trial at the Department of Surgery of the University of Toronto (Toronto, ON, Canada). Patients were eligible to participate if they were aged 20-60 years and had a diagnosis of anorexia nervosa (restricting or binge-purging subtype) and a demonstrated history of chronicity or treatment resistance. Following a period of medical stabilisation, patients underwent surgery for DBS and received open-label continuous stimulation for the entire 1 year study duration. The primary outcome was safety and acceptability of the procedure. The secondary outcomes were body-mass index (BMI), mood, anxiety, affective regulation, and anorexia nervosa-specific behaviours at 12 months after surgery, as well as changes in neural circuitry (measured with PET imaging of cerebral glucose metabolism at baseline and at 6 and 12 months after surgery). This trial was registered with ClinicalTrials.gov, number NCT01476540.

Findings: 16 patients with treatment-refractory anorexia nervosa were enrolled between September, 2011, and January, 2014, and underwent DBS of the subcallosal cingulate between November, 2011, and April, 2014. Patients had a mean age of 34 years (SD 8) and average illness duration of 18 years (SD 6). Two patients requested that their devices be removed or deactivated during the study, although their reasons for doing so were poorly defined. The most common adverse event was pain related to surgical incision or positioning that required oral analgesics for longer than 3-4 days after surgery (five [31%] of 16 patients). Seven (44%) of 16 patients had serious adverse events, most of which were related to the underlying illness, including electrolyte disturbances. Average BMI at surgery was 13·83 (SD 1·49) and 14 (88%) of the 16 patients had comorbid mood disorders, anxiety disorders, or both. Mean BMI after 12 months of stimulation was 17·34 (SD 3·40; p=0·0009 vs baseline). DBS was associated with significant improvements in measures of depression (mean Hamilton Depression Rating Scale scores 19·40 [SD 6·76] at baseline vs 8·79 [7·64] at 12 months; p=0·00015), anxiety (mean Beck Anxiety Inventory score 38·00 [15·55] vs 27·14 [18·39]; p=0·035), and affective regulation (mean Dysfunction in Emotional Regulation Scale score 131·80 [22·04] vs 104·36 [31·27]; p=0·019). We detected significant changes in cerebral glucose metabolism in key anorexia nervosa-related structures at both 6 months and 12 months of ongoing brain stimulation.

Interpretation: In patients with chronic treatment-refractory anorexia nervosa, DBS is well tolerated and is associated with significant and sustained improvements in affective symptoms, BMI, and changes in neural circuitry at 12 months after surgery.

Funding: Klarman Family Foundation Grants Program in Eating Disorders Research and Canadian Institutes of Health Research.
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http://dx.doi.org/10.1016/S2215-0366(17)30076-7DOI Listing
April 2017

Molecular Imaging of the Nicotinic Cholinergic Receptor in Alzheimer Disease.

Authors:
Gwenn S Smith

Am J Geriatr Psychiatry 2017 04 5;25(4):354-356. Epub 2017 Jan 5.

Department of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD; Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD. Electronic address:

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http://dx.doi.org/10.1016/j.jagp.2017.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646276PMC
April 2017

The Mild Behavioral Impairment Checklist (MBI-C): A Rating Scale for Neuropsychiatric Symptoms in Pre-Dementia Populations.

J Alzheimers Dis 2017 ;56(3):929-938

Memory and Alzheimer's Treatment Center and Alzheimer's Disease Research Center, Department of Psychiatry and Behavioral Sciences, Johns Hopkins Bayview and Johns Hopkins Medicine, Baltimore, MD, USA.

Background: Mild behavioral impairment (MBI) is a construct that describes the emergence at ≥50 years of age of sustained and impactful neuropsychiatric symptoms (NPS), as a precursor to cognitive decline and dementia. MBI describes NPS of any severity, which are not captured by traditional psychiatric nosology, persist for at least 6 months, and occur in advance of or in concert with mild cognitive impairment. While the detection and description of MBI has been operationalized in the International Society to Advance Alzheimer's Research and Treatment - Alzheimer's Association (ISTAART-AA) research diagnostic criteria, there is no instrument that accurately reflects MBI as described.

Objective: To develop an instrument based on ISTAART-AA MBI criteria.

Methods: Eighteen subject matter experts participated in development using a modified Delphi process. An iterative process ensured items reflected the five MBI domains of 1) decreased motivation; 2) emotional dysregulation; 3) impulse dyscontrol; 4) social inappropriateness; and 5) abnormal perception or thought content. Instrument language was developed a priori to pertain to non-demented functionally independent older adults.

Results: We present the Mild Behavioral Impairment Checklist (MBI-C), a 34-item instrument, which can easily be completed by a patient, close informant, or clinician.

Conclusion: The MBI-C provides the first measure specifically developed to assess the MBI construct as explicitly described in the criteria. Its utility lies in MBI case detection, and monitoring the emergence of MBI symptoms and domains over time. Studies are required to determine the prognostic value of MBI for dementia development, and for predicting different dementia subtypes.
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http://dx.doi.org/10.3233/JAD-160979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652315PMC
February 2018

Application of texture analysis to DAT SPECT imaging: Relationship to clinical assessments.

Neuroimage Clin 2016 23;12:e1-e9. Epub 2016 Feb 23.

Department of Physics & Astronomy, University of British Columbia, Vancouver, Canada.

Dopamine transporter (DAT) SPECT imaging is increasingly utilized for diagnostic purposes in suspected Parkinsonian syndromes. We performed a cross-sectional study to investigate whether assessment of texture in DAT SPECT radiotracer uptake enables enhanced correlations with severity of motor and cognitive symptoms in Parkinson's disease (PD), with the long-term goal of enabling clinical utility of DAT SPECT imaging, beyond standard diagnostic tasks, to tracking of progression in PD. Quantitative analysis in routine DAT SPECT imaging, if performed at all, has been restricted to assessment of mean regional uptake. We applied a framework wherein textural features were extracted from the images. Notably, the framework did not require registration to a common template, and worked in the subject-native space. Image analysis included registration of SPECT images onto corresponding MRI images, automatic region-of-interest (ROI) extraction on the MRI images, followed by computation of Haralick texture features. We analyzed 141 subjects from the Parkinson's Progressive Marker Initiative (PPMI) database, including 85 PD and 56 healthy controls (HC) (baseline scans with accompanying 3 T MRI images). We performed univariate and multivariate regression analyses between the quantitative metrics and different clinical measures, namely (i) the UPDRS (part III - motor) score, disease duration as measured from (ii) time of diagnosis (DD-diag.) and (iii) time of appearance of symptoms (DD-sympt.), as well as (iv) the Montreal Cognitive Assessment (MoCA) score. For conventional mean uptake analysis in the putamen, we showed significant correlations with clinical measures only when both HC and PD were included (Pearson correlation  = - 0.74, p-value < 0.001). However, this was not significant when applied to PD subjects only ( = - 0.19, p-value = 0.084), and no such correlations were observed in the caudate. By contrast, for the PD subjects, significant correlations were observed in the caudate when including texture metrics, with (i) UPDRS (p-values < 0.01), (ii) DD-diag. (p-values < 0.001), (iii) DD-sympt (p-values < 0.05), and (iv) MoCA (p-values < 0.01), while no correlations were observed for conventional analysis (p-values = 0.94, 0.34, 0.88 and 0.96, respectively). Our results demonstrated the ability to capture valuable information using advanced texture metrics from striatal DAT SPECT, enabling significant correlations of striatal DAT binding with clinical, motor and cognitive outcomes, and suggesting that textural features hold potential as biomarkers of PD severity and progression.
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http://dx.doi.org/10.1016/j.nicl.2016.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153560PMC
November 2017

Proceedings of the Fourth Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies.

Front Integr Neurosci 2016 22;10:38. Epub 2016 Nov 22.

Psychiatry and Behavioral Sciences, Johns Hopkins Bayview Medical Center, Johns Hopkins School of Medicine Baltimore, MD, USA.

This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinson's disease, essential tremor, Alzheimer's disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this year's international Think Tank, with a view toward current and near future advancement of the field.
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http://dx.doi.org/10.3389/fnint.2016.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119052PMC
November 2016

A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease.

J Alzheimers Dis 2016 09;54(2):777-87

Memory and Alzheimer's Treatment Center & Alzheimer's Disease Research Center, Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown.

Objective: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer's disease (AD).

Methods: We evaluated active "on" versus sham "off" bilateral DBS directed at the fornix-a major fiber bundle in the brain's memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation.

Results: Surgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the "on" versus "off" stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients <65 years old (n = 12) whose results trended toward being worse with DBS ON versus OFF, in patients≥65 (n = 30) DBS-f ON treatment was associated with a trend toward both benefit on clinical outcomes and a greater increase in cerebral glucose metabolism.

Conclusion: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation.
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http://dx.doi.org/10.3233/JAD-160017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026133PMC
September 2016

In vivo imaging of neurodegeneration in dementia with Lewy bodies (DLB).

Int Psychogeriatr 2016 Apr;28(4):527-8

Department of Psychiatry and Behavioral Sciences,Johns Hopkins University School of Medicine,Baltimore,Maryland,USA.

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http://dx.doi.org/10.1017/S1041610216000156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646266PMC
April 2016

Bilateral deep brain stimulation of the fornix for Alzheimer's disease: surgical safety in the ADvance trial.

J Neurosurg 2016 07 18;125(1):75-84. Epub 2015 Dec 18.

Division of Neurosurgery, University of Toronto, Ontario, Canada.

OBJECT This report describes the stereotactic technique, hospitalization, and 90-day perioperative safety of bilateral deep brain stimulation (DBS) of the fornix in patients who underwent DBS for the treatment of mild, probable Alzheimer's disease (AD). METHODS The ADvance Trial is a multicenter, 12-month, double-blind, randomized, controlled feasibility study being conducted to evaluate the safety, efficacy, and tolerability of DBS of the fornix in patients with mild, probable AD. Intraoperative and perioperative data were collected prospectively. All patients underwent postoperative MRI. Stereotactic analyses were performed in a blinded fashion by a single surgeon. Adverse events (AEs) were reported to an independent clinical events committee and adjudicated to determine the relationship between the AE and the study procedure. RESULTS Between June 6, 2012, and April 28, 2014, a total of 42 patients with mild, probable AD were treated with bilateral fornix DBS (mean age 68.2 ± 7.8 years; range 48.0-79.7 years; 23 men and 19 women). The mean planned target coordinates were x = 5.2 ± 1.0 mm (range 3.0-7.9 mm), y = 9.6 ± 0.9 mm (range 8.0-11.6 mm), z = -7.5 ± 1.2 mm (range -5.4 to -10.0 mm), and the mean postoperative stereotactic radial error on MRI was 1.5 ± 1.0 mm (range 0.2-4.0 mm). The mean length of hospitalization was 1.4 ± 0.8 days. Twenty-six (61.9%) patients experienced 64 AEs related to the study procedure, of which 7 were serious AEs experienced by 5 patients (11.9%). Four (9.5%) patients required return to surgery: 2 patients for explantation due to infection, 1 patient for lead repositioning, and 1 patient for chronic subdural hematoma. No patients experienced neurological deficits as a result of the study, and no deaths were reported. CONCLUSIONS Accurate targeting of DBS to the fornix without direct injury to it is feasible across surgeons and treatment centers. At 90 days after surgery, bilateral fornix DBS was well tolerated by patients with mild, probable AD. Clinical trial registration no.: NCT01608061 ( clinicaltrials.gov ).
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http://dx.doi.org/10.3171/2015.6.JNS15716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912949PMC
July 2016

Oral glucose tolerance testing to modulate plasma amyloid levels: A novel biomarker.

Alzheimers Dement (Amst) 2015 Sep;1(3):311-315

Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Introduction: Plasma levels of amyloid-beta (Aβ) do not correlate well with different stages of Alzheimer's disease (AD) in cross-sectional studies. Measuring the changes in Aβ plasma levels with an acute intervention may be more sensitive to distinguishing individuals in earlier stages of AD (mild cognitive impairment; MCI) from normal controls.

Methods: 57 participants (18 with AD/MCI and 39 cognitively normal controls) underwent oral glucose tolerance testing (OGTT). Blood samples were obtained over a 2 hour time period. Changes in plasma Aβ40 and42 levels were measured from either baseline or 5 minutes to the 10 minute time point.

Results: Compared to normal controls, subjects with AD/MCI had significantly less change (Δ) in plasma levels for both Aβ40(-3.13(40.93)pg/ml vs. 41.34(57.16)pg/ml;p=0.002) and Aβ42(-0.15(3.77)pg/ml vs. 5.64(10.65)pg/ml; p=0.004).

Discussion: OGTT combined with measures of plasma Aβ40 and 42 is potentially useful in distinguishing aging individuals who are in different stages of AD.
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http://dx.doi.org/10.1016/j.dadm.2015.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578701PMC
September 2015