Publications by authors named "Abhay Moghekar"

85 Publications

Cognitive and gait outcomes after primary endoscopic third ventriculostomy in adults with chronic obstructive hydrocephalus.

J Neurosurg 2021 Sep 17:1-8. Epub 2021 Sep 17.

12Department of Clinical Neurosciences, Division of Neurosurgery, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada.

Objective: The object of this study was to determine the short- and long-term efficacy of primary endoscopic third ventriculostomy (ETV) on cognition and gait in adults with chronic obstructive hydrocephalus.

Methods: Patients were prospectively accrued through the Adult Hydrocephalus Clinical Research Network patient registry. Patients with previously untreated congenital or acquired obstructive hydrocephalus were included in this study. Gait velocity was assessed using a 10-m walk test. Global cognition was assessed with the Montreal Cognitive Assessment (MoCA). Only patients with documented pre- and post-ETV gait analysis and/or pre- and post-ETV MoCA were included.

Results: A total of 74 patients had undergone primary ETV, 42 of whom were analyzed. The remaining 32 patients were excluded, as they could not complete both pre- and post-ETV assessments. The mean age of the 42 patients, 19 (45.2%) of whom were female, was 51.9 ± 17.1 years (range 19-79 years). Most patients were White (37 [88.1%]), and the remainder were Asian. Surgical complications were minor. Congenital etiologies occurred in 31 patients (73.8%), with aqueductal stenosis in 23 of those patients (54.8%). The remaining 11 patients (26.2%) had acquired cases. The gait short-term follow-up cohort (mean 4.7 ± 4.1 months, 35 patients) had a baseline median gait velocity of 0.9 m/sec (IQR 0.7-1.3 m/sec) and a post-ETV median velocity of 1.3 m/sec (IQR 1.1-1.4 m/sec). Gait velocity significantly improved post-ETV with a median within-patient change of 0.3 m/sec (IQR 0.0-0.6 m/sec, p < 0.001). Gait velocity improvements were sustained in the long term (mean 14 ± 2.8 months, 12 patients) with a baseline median velocity of 0.7 m/sec (IQR 0.6-1.3 m/sec), post-ETV median of 1.3 m/sec (IQR 1.1-1.7 m/sec), and median within-patient change of 0.4 m/sec (IQR 0.2-0.6 m/sec, p < 0.001). The cognitive short-term follow-up cohort (mean 4.6 ± 4.0 months, 38 patients) had a baseline median MoCA total score (MoCA TS) of 24/30 (IQR 23-27) that improved to 26/30 (IQR 24-28) post-ETV. The median within-patient change was +1 point (IQR 0-2 points, p < 0.001). However, this change is not clinically significant. The cognitive long-term follow-up cohort (mean 14 ± 3.1 months, 15 patients) had a baseline median MoCA TS of 23/30 (IQR 22-27), which improved to 26/30 (IQR 25-28) post-ETV. The median within-patient change was +2 points (IQR 1-3 points, p = 0.007), which is both statistically and clinically significant.

Conclusions: Primary ETV can safely improve symptoms of gait and cognitive dysfunction in adults with chronic obstructive hydrocephalus. Gait velocity and global cognition were significantly improved, and the worsening of either was rare following ETV.
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http://dx.doi.org/10.3171/2021.3.JNS203424DOI Listing
September 2021

Predictors of cognitive impairment in pseudotumor cerebri.

Neurol Neurochir Pol 2021 11;55(4):394-402. Epub 2021 Aug 11.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.

Aims Of The Study: We aimed to define the cognitive burden of the largest pseudotumor cerebri syndrome (PTCS) population to date, compare objective to subjective cognitive dysfunction, and determine clinical predictors of cognitive dysfunction amongst an array of previously unstudied factors.

Clinical Rationale: Patients with PTCS commonly report cognitive dysfunction, a factor associated with poor quality of life. It is not definitively known whether cognitive impairment is present in these patients, and what features of the syndrome predict impairment.

Materials And Methods: We administered a cognitive battery consisting of the National Adult Reading Test, Mini-Mental Status Exam, Digit Span, Boston Naming Test, Rey Auditory Verbal Learning Test, Clock Drawing, Trail Making Test, Controlled Oral Word Association, and Category Fluency. Cognitive impairment was defined as mild-single domain with one test score, and mild-multiple domain with two scores, more than two standard deviations below the mean for age-, gender-, and education-adjusted norms.

Results: One-hundred and one prospectively recruited PTCS patients were enrolled. The objective testing showed 30 patients had mild-single domain impairment, and 25 had mild-multi domain impairment. More patients without objective cognitive impairment had transverse venous sinus stenosis, but otherwise the groups did not differ. Two measures of headache severity, the Headache Impact Test and pain on the Numeric Rating Scale, were negatively associated with the composite cognitive score, as was ocular pain, vision-related disability, and mental health. Opening pressure and visual function were not associated with objective cognitive impairment. We found no association between subjective and objective cognitive impairment.

Conclusions And Clinical Implications: Patients with PTCS may be cognitively impaired, and this correlates with measures of headache burden. Studies evaluating cognitive impairment before and after remission of the headache disorder would have to be performed to investigate this relationship further. Patients with self-perception of cognitive burden are no more likely to be cognitively impaired.
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http://dx.doi.org/10.5603/PJNNS.a2021.0057DOI Listing
September 2021

Evaluation of the effect comorbid Parkinson syndrome on normal pressure hydrocephalus assessment.

Clin Neurol Neurosurg 2021 08 10;207:106810. Epub 2021 Jul 10.

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

Objective: The primary aim of the study was to assess the effect comorbid Parkinson syndromes have on results of CSF tap test (TT) and shunt outcomes for patients presenting with Normal Pressure Hydrocephalus (NPH). We hypothesized that patients with possible NPH and comorbid Parkinson syndromes with Positive DaT scans will not respond to CSF TT at the same rate as patients without comorbid Parkinson syndromes. Additionally, we followed a small number of patients with positive DaT scans who were shunted to assess long term outcome of comorbid Parkinson syndromes.

Methods: Medical records and neurological exams of 251 patients were reviewed. In our analysis 101 patients with no parkinsonian symptoms and no DaT scans were included as a control group, there were 52 patients with DaT scans, 31 patients were positive (DaT-P). Gait measures were assessed before and after CSF TT using the Wilcoxon matched-pairs signed-rank test or paired t-tests were used. To compare the effect of DaT-P and Control, we used an ANCOVA controlling for age, sex, assistive device used, and past medical history effecting gait.

Results: There was not a significant difference in response between Control and DaT-P group. The Control group improved on timed up and go (TUG) by 14.82%, DualTUG 16.35%, 10-meter Walk Test (10MWT) 18.13%, MiniBEST 15.91%, and 6-minute Walk Test (6MWT) 13.96%, while the DaT-P group improved on TUG by 14.93%, DualTUG 17.24%, 10MWT 22.68%, MiniBEST 18.07%, and 6MWT 16.06%.

Conclusion: Our findings suggest that patients with possible NPH and suspected comorbid movement disorder, showed similar improvement after diagnostic CSF TT compared to participants with no parkinsonian symptoms present on exam.

Data Availability Statement: Data relevant to the study will be made available from the corresponding author upon a reasonable request.
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http://dx.doi.org/10.1016/j.clineuro.2021.106810DOI Listing
August 2021

A proposed framework for cerebral venous congestion.

Neuroradiol J 2021 Jul 5:19714009211029261. Epub 2021 Jul 5.

Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, USA.

Background: While venous congestion in the peripheral vasculature has been described and accepted, intracranial venous congestion remains poorly understood. The characteristics, pathophysiology, and management of cerebral venous stasis, venous hypertension and venous congestion remain controversial, and a unifying conceptual schema is absent. The cerebral venous and lymphatic systems are part of a complex and dynamic interaction between the intracranial compartments, with interplay between the parenchyma, veins, arteries, cerebrospinal fluid, and recently characterized lymphatic-like systems in the brain. Each component contributes towards intracranial pressure, occupying space within the fixed calvarial volume. This article proposes a framework to consider conditions resulting in brain and neck venous congestion, and seeks to expedite further study of cerebral venous diagnoses, mechanisms, symptomatology, and treatments.

Methods: A multi-institution retrospective review was performed to identify unique patient cases, complemented with a published case series to assess a spectrum of disease states with components of venous congestion affecting the brain. These diseases were organized according to anatomical location and purported mechanisms. Outcomes of treatments were also analyzed. Illustrative cases were identified in the venous treatment databases of the authors.

Conclusion: This framework is the first clinically structured description of venous pathologies resulting in intracranial venous and cerebrospinal fluid hypertension. Our proposed system highlights unique clinical symptoms and features critical for appropriate diagnostic work-up and potential treatment. This novel schema allows clinicians effectively to approach cases of intracranial hypertension secondary to venous etiologies, and furthermore provides a framework by which researchers can better understand this developing area of cerebrovascular disease.
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http://dx.doi.org/10.1177/19714009211029261DOI Listing
July 2021

Intracranial Hypotension Related Skull Remodeling with Enophthalmos.

Orbit 2021 Oct 15;40(5):444-446. Epub 2021 Jun 15.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

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http://dx.doi.org/10.1080/01676830.2021.1939729DOI Listing
October 2021

Cerebrospinal fluid lipidomics for biomarkers of Alzheimer's disease.

Mol Omics 2021 06;17(3):454-463

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55902, USA.

Alzheimer's disease (AD) is the most common cause of dementia and is associated with serious neurologic sequelae resulting from neurodegenerative changes. Identification of markers of early-stage AD could be important for designing strategies to arrest the progression of the disease. The brain is rich in lipids because they are crucial for signal transduction and anchoring of membrane proteins. Cerebrospinal fluid (CSF) is an excellent specimen for studying the metabolism of lipids in AD because it can reflect changes occurring in the brain. We aimed to identify CSF lipidomic alterations associated with AD, using untargeted lipidomics, carried out in positive and negative ion modes. We found CSF lipids that were significantly altered in AD cases. In addition, comparison of CSF lipid profiles between persons with mild cognitive impairment (MCI) and AD showed a strong positive correlation between the lipidomes of the MCI and AD groups. The novel lipid biomarkers identified in this study are excellent candidates for validation in a larger set of patient samples and as predictive biomarkers of AD through future longitudinal studies. Once validated, the lipid biomarkers could lead to early detection, disease monitoring and the ability to measure the efficacy of potential therapeutic interventions in AD.
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http://dx.doi.org/10.1039/d0mo00186dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210464PMC
June 2021

Cerebrospinal fluid in COVID-19 neurological complications: Neuroaxonal damage, anti-SARS-Cov2 antibodies but no evidence of cytokine storm.

J Neurol Sci 2021 08 31;427:117517. Epub 2021 May 31.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America. Electronic address:

Objective: To study in cerebrospinal fluid (CSF) of COVID-19 subjects if a "cytokine storm" or neuroinflammation are implicated in pathogenesis of neurological complications.

Methods: Cross-sectional study of CSF neuroinflammatory profiles from 18 COVID-19 subjects with neurological complications categorized by diagnosis (stroke, encephalopathy, headache) and illness severity. COVID-19 CSF was compared with CSF from healthy, infectious and neuroinflammatory disorders and stroke controls (n = 82). Cytokines (IL-6, TNFα, IFNγ, IL-10, IL-12p70, IL-17A), inflammation and coagulation markers (high-sensitivity-C Reactive Protein [hsCRP], ferritin, fibrinogen, D-dimer, Factor VIII) and neurofilament light chain (NF-L), were quantified. SARS-CoV2 RNA and SARS-CoV2 IgG and IgA antibodies in CSF were tested with RT-PCR and ELISA.

Results: CSF from COVID-19 subjects showed absence of pleocytosis or specific increases in pro-inflammatory markers (IL-6, ferritin, or D-dimer). Although pro-inflammatory cytokines (IL-6, TNFα, IL-12p70) and IL-10 were increased in CSF of stroke COVID-19 subjects, a similar increase was observed in non-COVID-19 stroke subjects. Anti-SARS-CoV2 antibodies in CSF of COVID-19 subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. CSF-NF-L was elevated in subjects with stroke and critical COVID-19 as compared to controls and other COVID-19 severity categories. CSF-hsCRP was present in all subjects with critical stages of COVID-19 (7/18) but only in 1/82 controls.

Conclusion: The paucity of neuroinflammatory changes in CSF of COVID-19 subjects and lack of SARS-CoV2 RNA do not support the presumed neurovirulence of SARS-CoV2 or neuroinflammation in pathogenesis of neurological complications in COVID-19. The role of CSF SARS-CoV2 IgG antibodies and mechanisms of neuronal damage are still undetermined.
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http://dx.doi.org/10.1016/j.jns.2021.117517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166041PMC
August 2021

Blood-Brain Barrier Breakdown in Relationship to Alzheimer and Vascular Disease.

Ann Neurol 2021 Aug 5;90(2):227-238. Epub 2021 Jun 5.

Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD.

Objective: Blood-brain barrier (BBB) breakdown has been suggested to be an early biomarker in human cognitive impairment. However, the relationship between BBB breakdown and brain pathology, most commonly Alzheimer disease (AD) and vascular disease, is still poorly understood. The present study measured human BBB function in mild cognitive impairment (MCI) patients on 2 molecular scales, specifically BBB's permeability to water and albumin molecules.

Methods: Fifty-five elderly participants were enrolled, including 33 MCI patients and 22 controls. BBB permeability to water was measured with a new magnetic resonance imaging technique, water extraction with phase contrast arterial spin tagging. BBB permeability to albumin was determined using cerebrospinal fluid (CSF)/serum albumin ratio. Cognitive performance was assessed by domain-specific composite scores. AD pathology (including CSF Aβ and ptau) and vascular risk factors were examined.

Results: Compared to cognitively normal subjects, BBB in MCI patients manifested an increased permeability to small molecules such as water but was no more permeable to large molecules such as albumin. BBB permeability to water was found to be related to AD markers of CSF Aβ and ptau. On the other hand, BBB permeability to albumin was found to be related to vascular risk factors, especially hypercholesterolemia, but was not related to AD pathology. BBB permeability to small molecules, but not to large molecules, was found to be predictive of cognitive function.

Interpretation: These findings provide early evidence that BBB breakdown is related to both AD and vascular risks, but their effects can be differentiated by spatial scales. BBB permeability to small molecules has a greater impact on cognitive performance. ANN NEUROL 2021;90:227-238.
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http://dx.doi.org/10.1002/ana.26134DOI Listing
August 2021

Assessing the predictive value of common gait measure for predicting falls in patients presenting with suspected normal pressure hydrocephalus.

BMC Neurol 2021 Feb 8;21(1):60. Epub 2021 Feb 8.

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

Objective: To assess the predictive value of common measures validated to predict falls in other geriatric populations in patients presenting with suspected Normal Pressure Hydrocephalus (NPH).

Methods: One hundred ninety-five patients over the age of 60 who received the Fall Risk Questionnaire were retrospectively recruited from the CSF Disorders clinic within the departments of Neurosurgery and Neurology. Multiple logistic regression was used to create a model to predict falls for patients with suspected NPH using common measures: Timed Up & Go, Dual Timed Up & Go, 10 Meter Walk, MiniBESTest, 6-Minute Walk, Lower Extremity Function (Mobility), Fall Risk Questionnaire, and Functional Activities Questionnaire.

Results: The Fall Risk Questionnaire and age were shown to be the best predictors of falls. The model was 95.92% (Positive predictive value: 83.93%) sensitive and 47.92% specific (Negative predictive value: 77.78%).

Conclusion: Patients presenting with suspected NPH are at an increased fall risk, 75% of the total patients and 89% of patients who responded to a temporary drain of CSF had at least one fall in the past 6 months. The Fall Risk Questionnaire and age were shown to be predictive of falls for patients with suspected NPH. The preliminary evidence indicates measures that have been validated to assess fall risk in other populations may not be valid for patients presenting with suspected NPH.
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http://dx.doi.org/10.1186/s12883-021-02068-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869204PMC
February 2021

MarkVCID cerebral small vessel consortium: I. Enrollment, clinical, fluid protocols.

Alzheimers Dement 2021 04 21;17(4):704-715. Epub 2021 Jan 21.

Alzheimer's Clinical and Translational Research Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

The concept of vascular contributions to cognitive impairment and dementia (VCID) derives from more than two decades of research indicating that (1) most older individuals with cognitive impairment have post mortem evidence of multiple contributing pathologies and (2) along with the preeminent role of Alzheimer's disease (AD) pathology, cerebrovascular disease accounts for a substantial proportion of this contribution. Contributing cerebrovascular processes include both overt strokes caused by etiologies such as large vessel occlusion, cardioembolism, and embolic infarcts of unknown source, and frequently asymptomatic brain injuries caused by diseases of the small cerebral vessels. Cerebral small vessel diseases such as arteriolosclerosis and cerebral amyloid angiopathy, when present at moderate or greater pathologic severity, are independently associated with worse cognitive performance and greater likelihood of dementia, particularly in combination with AD and other neurodegenerative pathologies. Based on this evidence, the US National Alzheimer's Project Act explicitly authorized accelerated research in vascular and mixed dementia along with frontotemporal and Lewy body dementia and AD itself. Biomarker development has been consistently identified as a key step toward translating scientific advances in VCID into effective prevention and treatment strategies. Validated biomarkers can serve a range of purposes in trials of candidate interventions, including (1) identifying individuals at increased VCID risk, (2) diagnosing the presence of cerebral small vessel disease or specific small vessel pathologies, (3) stratifying study participants according to their prognosis for VCID progression or treatment response, (4) demonstrating an intervention's target engagement or pharmacodynamic mechanism of action, and (5) monitoring disease progression during treatment. Effective biomarkers allow academic and industry investigators to advance promising interventions at early stages of development and discard interventions with low success likelihood. The MarkVCID consortium was formed in 2016 with the goal of developing and validating fluid- and imaging-based biomarkers for the cerebral small vessel diseases associated with VCID. MarkVCID consists of seven project sites and a central coordinating center, working with the National Institute of Neurologic Diseases and Stroke and National Institute on Aging under cooperative agreements. Through an internal selection process, MarkVCID has identified a panel of 11 candidate biomarker "kits" (consisting of the biomarker measure and the clinical and cognitive data used to validate it) and established a range of harmonized procedures and protocols for participant enrollment, clinical and cognitive evaluation, collection and handling of fluid samples, acquisition of neuroimaging studies, and biomarker validation. The overarching goal of these protocols is to generate rigorous validating data that could be used by investigators throughout the research community in selecting and applying biomarkers to multi-site VCID trials. Key features of MarkVCID participant enrollment, clinical/cognitive testing, and fluid biomarker procedures are summarized here, with full details in the following text, tables, and supplemental material, and a description of the MarkVCID imaging biomarker procedures in a companion paper, "MarkVCID Cerebral small vessel consortium: II. Neuroimaging protocols." The procedures described here address a range of challenges in MarkVCID's design, notably: (1) acquiring all data under informed consent and enrollment procedures that allow unlimited sharing and open-ended analyses without compromising participant privacy rights; (2) acquiring the data in a sufficiently wide range of study participants to allow assessment of candidate biomarkers across the various patient groups who might ultimately be targeted in VCID clinical trials; (3) defining a common dataset of clinical and cognitive elements that contains all the key outcome markers and covariates for VCID studies and is realistically obtainable during a practical study visit; (4) instituting best fluid-handling practices for minimizing avoidable sources of variability; and (5) establishing rigorous procedures for testing the reliability of candidate fluid-based biomarkers across replicates, assay runs, sites, and time intervals (collectively defined as the biomarker's instrumental validity). Participant Enrollment Project sites enroll diverse study cohorts using site-specific inclusion and exclusion criteria so as to provide generalizable validation data across a range of cognitive statuses, risk factor profiles, small vessel disease severities, and racial/ethnic characteristics representative of the diverse patient groups that might be enrolled in a future VCID trial. MarkVCID project sites include both prospectively enrolling centers and centers providing extant data and samples from preexisting community- and population-based studies. With approval of local institutional review boards, all sites incorporate MarkVCID consensus language into their study documents and informed consent agreements. The consensus language asks prospectively enrolled participants to consent to unrestricted access to their data and samples for research analysis within and outside MarkVCID. The data are transferred and stored as a de-identified dataset as defined by the Health Insurance Portability and Accountability Act Privacy Rule. Similar human subject protection and informed consent language serve as the basis for MarkVCID Research Agreements that act as contracts and data/biospecimen sharing agreements across the consortium. Clinical and Cognitive Data Clinical and cognitive data are collected across prospectively enrolling project sites using common MarkVCID instruments. The clinical data elements are modified from study protocols already in use such as the Alzheimer's Disease Center program Uniform Data Set Version 3 (UDS3), with additional focus on VCID-related items such as prior stroke and cardiovascular disease, vascular risk factors, focal neurologic findings, and blood testing for vascular risk markers and kidney function including hemoglobin A1c, cholesterol subtypes, triglycerides, and creatinine. Cognitive assessments and rating instruments include the Clinical Dementia Rating Scale, Geriatric Depression Scale, and most of the UDS3 neuropsychological battery. The cognitive testing requires ≈60 to 90 minutes. Study staff at the prospectively recruiting sites undergo formalized training in all measures and review of their first three UDS3 administrations by the coordinating center. Collection and Handling of Fluid Samples Fluid sample types collected for MarkVCID biomarker kits are serum, ethylenediaminetetraacetic acid-plasma, platelet-poor plasma, and cerebrospinal fluid (CSF) with additional collection of packed cells to allow future DNA extraction and analyses. MarkVCID fluid guidelines to minimize variability include fasting morning fluid collections, rapid processing, standardized handling and storage, and avoidance of CSF contact with polystyrene. Instrumental Validation for Fluid-Based Biomarkers Instrumental validation of MarkVCID fluid-based biomarkers is operationally defined as determination of intra-plate and inter-plate repeatability, inter-site reproducibility, and test-retest repeatability. MarkVCID study participants both with and without advanced small vessel disease are selected for these determinations to assess instrumental validity across the full biomarker assay range. Intra- and inter-plate repeatability is determined by repeat assays of single split fluid samples performed at individual sites. Inter-site reproducibility is determined by assays of split samples distributed to multiple sites. Test-retest repeatability is determined by assay of three samples acquired from the same individual, collected at least 5 days apart over a 30-day period and assayed on a single plate. The MarkVCID protocols are designed to allow direct translation of the biomarker validation results to multicenter trials. They also provide a template for outside groups to perform analyses using identical methods and therefore allow direct comparison of results across studies and centers. All MarkVCID protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the MarkVCID kits will undergo biological validation to determine whether the candidate biomarker measures important aspects of VCID such as cognitive function. Analytic methods and results of these validation studies for the 11 MarkVCID biomarker kits will be published separately. The results of this rigorous validation process will ultimately determine each kit's potential usefulness for multicenter interventional trials aimed at preventing or treating small vessel disease related VCID.
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http://dx.doi.org/10.1002/alz.12215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122220PMC
April 2021

Cerebrospinal fluid in COVID-19 neurological complications: no cytokine storm or neuroinflammation.

medRxiv 2021 Jan 12. Epub 2021 Jan 12.

Background: Neurological complications occur in COVID-19. We aimed to examine cerebrospinal fluid (CSF) of COVID-19 subjects with neurological complications and determine presence of neuroinflammatory changes implicated in pathogenesis.

Methods: Cross-sectional study of CSF neuroinflammatory profiles from 18 COVID-19 subjects with neurological complications categorized by diagnosis (stroke, encephalopathy, headache) and illness severity (critical, severe, moderate, mild). COVID-19 CSF was compared with CSF from healthy, infectious and neuroinflammatory disorders and stroke controls (n=82). Cytokines (IL-6, TNFα, IFNγ, IL-10, IL-12p70, IL-17A), inflammation and coagulation markers (high-sensitivity-C Reactive Protein [hsCRP], ferritin, fibrinogen, D-dimer, Factor VIII) and neurofilament light chain (NF-L), were quantified. SARS-CoV2 RNA and SARS-CoV2 IgG and IgA antibodies in CSF were tested with RT-PCR and ELISA.

Results: CSF from COVID-19 subjects showed a paucity of neuroinflammatory changes, absence of pleocytosis or specific increases in pro-inflammatory markers or cytokines (IL-6, ferritin, or D-dimer). Anti-SARS-CoV2 antibodies in CSF of COVID-19 subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. A similar increase of pro-inflammatory cytokines (IL-6, TNFα, IL-12p70) and IL-10 in CSF of COVID-19 and non-COVID-19 stroke subjects was observed compared to controls. CSF-NF-L was elevated in subjects with stroke and critical COVID-19. CSF-hsCRP was present almost exclusively in COVID-19 cases.

Conclusion: The paucity of neuroinflammatory changes in CSF of COVID-19 subjects and lack of SARS-CoV2 RNA do not support the presumed neurovirulence of SARS-CoV2 or neuroinflammation in pathogenesis of neurological complications in COVID-19. Elevated CSF-NF-L indicates neuroaxonal injury in COVID-19 cases. The role of CSF SARS-CoV2 IgG antibodies is still undetermined.

Funding: This work was supported by NIH R01-NS110122 and The Bart McLean Fund for Neuroimmunology Research.
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http://dx.doi.org/10.1101/2021.01.10.20249014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814842PMC
January 2021

Systematic volumetric analysis predicts response to CSF drainage and outcome to shunt surgery in idiopathic normal pressure hydrocephalus.

Eur Radiol 2021 Jul 3;31(7):4972-4980. Epub 2021 Jan 3.

Department of Radiology, University Hospitals, Case Western Reserve University, Cleveland, OH, 44106, USA.

Objectives: Idiopathic normal pressure hydrocephalus (INPH) is a neurodegenerative disorder characterized by excess cerebrospinal fluid (CSF) in the ventricles, which can be diagnosed by invasive CSF drainage test and treated by shunt placement. Here, we aim to investigate the diagnostic and prognostic power of systematic volumetric analysis based on brain structural MRI for INPH.

Methods: We performed a retrospective study with a cohort of 104 probable INPH patients who underwent CSF drainage tests and another cohort of 41 INPH patients who had shunt placement. High-resolution T1-weighted images of the patients were segmented using an automated pipeline into 283 structures that are grouped into different granularity levels for volumetric analysis. Volumes at multi-granularity levels were used in a recursive feature elimination model to classify CSF drainage responders and non-responders. We then used pre-surgical brain volumes to predict Tinetti and MMSE scores after shunting, based on the least absolute shrinkage and selection operator.

Results: The classification accuracy of differentiating the CSF drainage responders and non-responders increased as the granularity increased. The highest diagnostic accuracy was achieved at the finest segmentation with a sensitivity/specificity/precision/accuracy of 0.89/0.91/0.84/0.90 and an area under the curve of 0.94. The predicted post-surgical neurological scores showed high correlations with the ground truth, with r = 0.80 for Tinetti and r = 0.88 for MMSE. The anatomical features that played important roles in the diagnostic and prognostic tasks were also illustrated.

Conclusions: We demonstrated that volumetric analysis with fine segmentation could reliably differentiate CSF drainage responders from other INPH-like patients, and it could accurately predict the neurological outcomes after shunting.

Key Points: • We performed a fully automated segmentation of brain MRI at multiple granularity levels for systematic volumetric analysis of idiopathic normal pressure hydrocephalus (INPH) patients. • We were able to differentiate patients that responded to CSF drainage test with an accuracy of 0.90 and area under the curve of 0.94 in a cohort of 104 probable INPH patients, as well as to predict the post-shunt gait and cognitive scores with a coefficient of 0.80 for Tinetti and 0.88 for MMSE. • Feature analysis showed the inferior lateral ventricle, bilateral hippocampus, and orbital cortex are positive indicators of CSF drainage responders, whereas the posterior deep white matter and parietal subcortical white matter were negative predictors.
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http://dx.doi.org/10.1007/s00330-020-07531-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213563PMC
July 2021

Effect of Patient-Specific Preanalytic Variables on CSF Aβ1-42 Concentrations Measured on an Automated Chemiluminescent Platform.

J Appl Lab Med 2021 03;6(2):397-408

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD.

Background: Cerebrospinal fluid (CSF) biomarkers are increasingly used to confirm the accuracy of a clinical diagnosis of mild cognitive impairment or dementia due to Alzheimer disease (AD). Recent evidence suggests that fully automated assays reduce the impact of some preanalytical factors on the variability of these measures. This study evaluated the effect of several preanalytical variables common in clinical settings on the variability of CSF β-amyloid 1-42 (Aβ1-42) concentrations.

Methods: Aβ1-42 concentrations were measured using the LUMIPULSE G1200 from both freshly collected and frozen CSF samples. Preanalytic variables examined were: (1) patient fasting prior to CSF collection, (2) blood contamination of specimens, and (3) aliquoting specimens sequentially over the course of collection (i.e., CSF gradients).

Results: Patient fasting did not significantly affect CSF Aβ1-42 levels. While assessing gradient effects, Aβ1-42 concentrations remained stable within the first 5 1-mL aliquots. However, there is evidence of a gradient effect toward higher concentrations over successive aliquots. Aβ1-42 levels were stable when fresh CSF samples were spiked with up to 2.5% of blood. However, in frozen CSF samples, even 0.25% blood contamination significantly decreased Aβ1-42 concentrations.

Conclusions: The preanalytical variables examined here do not have significant effects on Aβ1-42 concentrations if fresh samples are processed within 2 h. However, a gradient effect can be observed on Aβ1-42 concentrations after the first 5 mL of collection and blood contamination has a significant impact on Aβ1-42 concentrations once specimens have been frozen.
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http://dx.doi.org/10.1093/jalm/jfaa145DOI Listing
March 2021

Association of midlife vascular risk and AD biomarkers with subsequent cognitive decline.

Neurology 2020 12 28;95(23):e3093-e3103. Epub 2020 Sep 28.

From the Department of Neurology (C.P., A.S., K.A., A.M., R.F.G., M.A.), The Johns Hopkins University School of Medicine; and Department of Biostatistics (J.W., M.-C.W.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Objective: To determine whether vascular risk and Alzheimer disease (AD) biomarkers have independent or synergistic effects on cognitive decline and whether vascular risk is associated with the accumulation of AD pathology as measured by change in biomarkers over time.

Methods: At baseline, participants (n = 168) were cognitively normal and primarily middle-aged (mean 56.4 years, SD 10.9 years) and had both vascular risk factor status and proximal CSF biomarkers available. Baseline vascular risk was quantified with a composite vascular risk score reflecting the presence or absence of hypertension, hypercholesterolemia, diabetes, current smoking, and obesity. CSF biomarkers of β-amyloid (Aβ), total tau (t-tau), and phosphorylated tau (p-tau) were used to create dichotomous high and low AD biomarker groups (based on Aβ and tau). Linear mixed-effects models were used to examine change in a cognitive composite score (mean follow-up 13.9 years) and change in CSF biomarkers (mean follow-up 4.2 years).

Results: There was no evidence of a synergistic relationship between the vascular risk score and CSF AD biomarkers and cognitive decline. Instead, the vascular risk score (estimate -0.022, 95% confidence interval [CI] -0.043 to -0.002, = 0.03) and AD biomarkers (estimate -0.060, 95% CI -0.096 to -0.024, = 0.001) were independently and additively associated with cognitive decline. In addition, the vascular risk score was unrelated to levels of or rate of change in CSF Aβ, t-tau, or p-tau.

Conclusions: The results of this observational cohort study suggest that vascular risk and biomarkers of AD pathology, when measured in midlife, act along independent pathways and underscore the importance of accounting for multiple risk factors for identifying cognitively normal individuals at the greatest risk of cognitive decline.
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http://dx.doi.org/10.1212/WNL.0000000000010946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734925PMC
December 2020

Association of cerebrovascular reactivity and Alzheimer pathologic markers with cognitive performance.

Neurology 2020 08 13;95(8):e962-e972. Epub 2020 Jul 13.

From the Departments of Radiology (S.S., Z.L., Y.L., X.H., K.H., G.P., C.X., P.v.Z., J.P., P.L., H.L.), Biomedical Engineering (Z.L., X.H., H.L.), Medicine (S.Y., R.K.), Psychiatry and Behavioral Sciences (P.R.), Neurology (A.M., M.A.), and Neurosurgery (J.P.), Johns Hopkins University, School of Medicine; and F.M. Kirby Research Center (P.v.Z., H.L.), Kennedy Krieger Institute, Baltimore, MD.

Objective: To determine whether MRI-based cerebrovascular reactivity (CVR) can predict cognitive performance independently of Alzheimer pathologic markers, we studied the relationship between cognition, CVR, and CSF-derived β-amyloid (Aβ) and tau in a group of elderly individuals with mixed Alzheimer and vascular cognitive impairment and dementia.

Methods: This was a cross-sectional study of 72 participants 69 ± 8 years of age consisting of individuals with normal cognition (n = 28) and cognitive impairment (n = 44) (including 36 with mild cognitive impairment [MCI] and 8 with mild dementia). CVR was measured with hypercapnia-MRI. Whole-brain CVR (percent blood oxygen level-dependent per 1 mm Hg Etco) was used to estimate vasodilatory capacity. Montreal Cognitive Assessment (MoCA) scores, cognitive domains scores, and a global composite cognitive score were obtained. AD biomarkers included CSF assays of Aβ and tau.

Results: Whole-brain CVR was lower in the impaired (mean ± SE, 0.132 ± 0.006%/mm Hg) compared to the normal (0.151 ± 0.007%/mm Hg) group (β = -0.02%/mm Hg; 95% confidence interval [CI] -0.038 to -0.001). After adjustment for CSF Aβ and tau, higher whole-brain CVR was associated with better performance on the MoCA (β = 29.64, 95% CI 9.94-49.34) and with a global composite cognitive score (β = 4.32, 95% CI 0.05-8.58). When the CVR marker was compared with the Fazekas score based on white matter hyperintensities and vascular risk-score in a single regression model predicting the MoCA score, only CVR revealed a significant effect (β = 28.09, 95% CI 6.14-50.04), while the other 2 measures were not significant.

Conclusions: CVR was significantly associated with cognitive performance independently of AD pathology. Whole-brain CVR may be a useful biomarker for evaluating cognitive impairment related to vascular disease in older individuals.

Classification Of Evidence: This study provides Class II evidence that CVR was significantly associated with cognitive performance independent of AD pathology.
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http://dx.doi.org/10.1212/WNL.0000000000010133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668551PMC
August 2020

Quantitative proteomic analysis of the frontal cortex in Alzheimer's disease.

J Neurochem 2021 03 22;156(6):988-1002. Epub 2020 Jul 22.

Department of Neurology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by intracellular formation of neurofibrillary tangles and extracellular deposition of β-amyloid protein (Aβ) in the extracellular matrix. The pathogenesis of AD has not yet been fully elucidated and little is known about global alterations in the brain proteome that are related to AD. To identify and quantify such AD-related changes in the brain, we employed a tandem mass tags approach coupled to high-resolution mass spectrometry. We compared the proteomes of frontal cortex from AD patients with corresponding age-matched brain samples. Liquid chromatography-mass spectrometry/MS analysis carried out on an Orbitrap Fusion Lumos Tribrid mass spectrometer led to identification of 8,066 proteins. Of these, 432 proteins were observed to be significantly altered (>1.5 fold) in their expression in AD brains. Proteins whose abundance was previously known to be altered in AD were identified including secreted phosphoprotein 1 (SPP1), somatostatin (SST), SPARC-related modular calcium binding 1 (SMOC1), dual specificity phosphatase 26 (DUSP26), and neuronal pentraxin 2 (NPTX2). In addition, we identified several novel candidates whose association with AD has not been previously described. Of the novel molecules, we validated chromogranin A (CHGA), inner membrane mitochondrial protein (IMMT) and RAS like proto-oncogene A (RALA) in an additional set of 20 independent brain samples using targeted parallel reaction monitoring mass spectrometry assays. The differentially expressed proteins discovered in our study, once validated in larger cohorts, should help discern the pathogenesis of AD.
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http://dx.doi.org/10.1111/jnc.15116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775912PMC
March 2021

Brain Oxygen Extraction Is Differentially Altered by Alzheimer's and Vascular Diseases.

J Magn Reson Imaging 2020 12 21;52(6):1829-1837. Epub 2020 Jun 21.

The Russell H. Morgan Department of Radiology & Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: Alzheimer's disease and vascular cognitive impairment (VCI), as well as their concurrence, represent the most common types of cognitive dysfunction. Treatment strategies for these two conditions are quite different; however, there exists a considerable overlap in their clinical manifestations, and most biomarkers reveal similar abnormalities between these two conditions.

Purpose: To evaluate the potential of cerebral oxygen extraction fraction (OEF) as a biomarker for differential diagnosis of Alzheimer's disease and VCI. We hypothesized that in Alzheimer's disease OEF will be reduced (decreased oxygen consumption due to decreased neural activity), while in vascular diseases OEF will be elevated (increased oxygen extraction due to abnormally decreased blood flow).

Study Type: Prospective cross-sectional.

Population: Sixty-five subjects aged 52-89 years, including 33 mild cognitive impairment (MCI), 7 dementia, and 25 cognitively normal subjects.

Field Strength/sequence: 3T T -relaxation-under-spin-tagging (TRUST) and fluid-attenuated inversion recovery imaging (FLAIR).

Assessment: OEF, consensus diagnoses of cognitive impairment, vascular risk factors (such as hypertension, hypercholesterolemia, diabetes, smoking, and obesity), cognitive assessments, and cerebrospinal fluid concentration of amyloid and tau were assessed.

Statistical Tests: Multiple linear regression analyses of OEF with diagnostic category (normal, MCI, or dementia), vascular risks, cognitive performance, amyloid and tau pathology.

Results: When evaluating the entire group, OEF was found to be lower with more severe cognitive impairment (β = -2.70 ± 1.15, T = -2.34, P = 0.02), but was higher with greater vascular risk factors (β = 1.36 ± 0.55, T = 2.48, P = 0.02). Further investigation of the subgroup of participants with low vascular risks (N = 44) revealed that lower OEF was associated with worse cognitive performance (β = 0.04 ± 0.01, T = 3.27, P = 0.002) and greater amyloid burden (β = 92.12 ± 41.23, T = 2.23, P = 0.03). Among cognitively impaired individuals (N = 40), higher OEF was associated with greater vascular risk factors (β = 2.19 ± 0.71, T = 3.08, P = 0.004).

Data Conclusion: These findings suggest that OEF is differentially affected by Alzheimer's disease and VCI pathology and may be useful in etiology-based diagnosis of cognitive impairment.

Level Of Evidence: 1 TECHNICAL EFFICACY: Stage 3 J. MAGN. RESON. IMAGING 2020;52:1829-1837.
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http://dx.doi.org/10.1002/jmri.27264DOI Listing
December 2020

Mid-term assessment of transverse sinus stent patency in 104 patients treated for intracranial hypertension secondary to dural sinus stenosis.

J Neurointerv Surg 2021 Feb 10;13(2):182-186. Epub 2020 Jun 10.

Division of Interventional Neuroradiology, Johns Hopkins Hospital, Baltimore, Maryland, USA

Background: Transverse sinus (TS) stenting is a valid treatment alternative for patients with intracranial hypertension caused by underlying bilateral TS stenoses. Its mid-term patency has, however, not been well documented.

Objective: To assess the 6-month patency of TS stenting using subtracted CT venography (CTV).

Methods: A retrospective analysis of a prospectively collected database of patients undergoing TS stenting was performed. The cohort was a single-center, single-operator series of 125 consecutive patients treated between 2008 and 2018. Mid-term follow-up 320-row detector CTV was available for review in 104 patients.

Results: Follow-up CTV was obtained on average 6 months after stenting. Stents in all patients (100%) were patent. Subtracted reconstructions showed no intraluminal thrombus or neointimal hyperplasia. Native reconstructions confirmed the structural integrity of the stents. De novo stenosis proximal to the stent was noted in 10 cases (10%). A total of 10 patients (10%) received additional treatment due to recurrent symptoms. In univariate analysis, both high body mass index and stent size (>6 mm) were associated with development of de novo stenoses: OR 1.12 (95% CI 1.01 to 1.25, p=0.037) and OR 5.63 (95% CI 1.16 to 27.22, p=0.032), respectively. In multivariate analysis, only stent size (>6 mm) remained significant: OR 7.19 (95% CI 1.03 to 50.01, p=0.046).

Conclusion: TS stenting is an effective treatment for intracranial hypertension secondary to dural sinus stenosis in an appropriately selected patient population. A 320-row dynamic CTV is a high-quality non-invasive imaging method that can assess both the physical integrity of the stent and its patency. At mid-term follow-up, all imaged stents were patent. The occurrence of de novo stenoses proximal to the stent (10%) correlated with stent size (>6 mm).
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http://dx.doi.org/10.1136/neurintsurg-2020-015949DOI Listing
February 2021

Development of a novel method for the quantification of tyrosine 39 phosphorylated α- and β-synuclein in human cerebrospinal fluid.

Clin Proteomics 2020 4;17:13. Epub 2020 May 4.

Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130 USA.

Background: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. Biomarkers that can help monitor the progression of PD or response to disease-modifying agents will be invaluable in making appropriate therapeutic decisions. Further, biomarkers that could be used to distinguish PD from other related disorders with PD-like symptoms will be useful for accurate diagnosis and treatment. C-Abl tyrosine kinase is activated in PD resulting in increased phosphorylation of the tyrosine residue at position 39 (Y39) of α-synuclein (α-syn) (pY39 α-syn), which contributes to the death of dopaminergic neurons. Because pY39 α-syn may be pathogenic, monitoring pY39 α-syn could allow us to diagnose presymptomatic PD and help monitor disease progression and response to treatment. We sought to investigate if increased phosphorylation of pY39 α-syn can be detected in the cerebrospinal fluid (CSF) of PD patients by targeted mass spectrometry.

Methods: Here, we report a two-step enrichment method in which phosphotyrosine peptides were first enriched with an anti-phosphotyrosine antibody followed by a second round of enrichment by titanium dioxide (TiO) beads to detect EGVLpYVGSK sequence derived from tyrosine 39 region of α- and β-synuclein (αβ-syn). Accurate quantification was achieved by adding a synthetic heavy version of pY39 αβ-syn peptide before enzymatic digestion.

Results: Using the developed enrichment methods and optimized parallel reaction monitoring (PRM) assays, we detected pY39 αβ-syn peptide in human CSF and demonstrated that the ratio of pY39 αβ-syn to Y39 αβ-syn was significantly increased in the CSF of patients with PD.

Conclusions: We anticipate that this optimized two-step enrichment-based PRM detection method will help monitor c-Abl activation in PD patients and can also be used to quantify other phosphotyrosine peptides of low abundance in biological samples.
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http://dx.doi.org/10.1186/s12014-020-09277-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197159PMC
May 2020

Standardized regression-based clinical change score cutoffs for normal pressure hydrocephalus.

BMC Neurol 2020 Apr 16;20(1):140. Epub 2020 Apr 16.

Department of Neurology, Johns Hopkins University School of Medicine, 5200 Eastern Ave CTR STE 5100, Baltimore, MD, 21224, USA.

Background: Presently, for patients presenting with suspected Normal Pressure Hydrocephalus (NPH) who undergo temporary drainage of cerebrospinal fluid (CSF) there is no defined model to differentiate chance improvement form clinical significance change at the individual patient level. To address this lack of information we computed standard regression based clinical change models for the 10 Meter Walk Test, Timed Up & Go, Dual Timed Up & Go, 6-Minute Walk Test, Mini-Balance Evaluation Systems Test, Montreal Cognitive Assessment, and Symbol Digit Modalities using data from patients with suspected NPH that underwent temporary drainage of CSF. These clinically significant change modes can classify clinically significant improvement following temporary drainage of CSF at the individual patient level. This allows for physicians to differentiate a clinically significant improvement in symptoms from chance improvement.

Methods: Data was collected from 323 patients, over the age of 60, with suspected NPH that underwent temporary drainage of CSF with corresponding gait and cognitive testing. McSweeney Standardized Regression Based Clinical Change Models were computed for standard gait and cognitive measures: Timed Up & Go, Dual Timed Up & Go, 10 Meter Walk Test, MiniBESTest, 6-Minute Walk Test, Montreal Cognitive Assessment, and Symbol Digit Modalities Test. To assess the discriminate validity of the measures we used correlations, Chi, and regression analyses.

Results: The clinical change models explained 69-91.8% of the variability in post-drain performance (p <  0.001). As patient scores became more impaired, the percent change required for improvement to be clinically significant increased for all measures. We found that the measures were not discriminate, the Timed Up & Go was highly related to the 10 Meter Walk Test (r = 0.85, R = 0.769-0.738, p <  0.001), MiniBESTest (r = - 0.67, R = 0.589-0.734, p <  0.001), and 6 Minute Walk Test (r = - 0.77, R = 0.71-0.734, p <  0.001).

Conclusion: Standardized Regression Based Clinically Significant Change Models allow for physicians to use an evidence-based approach to differentiate clinically significant change from chance improvement at the individual patient level. The Timed Up & Go was shown to be predictive of detailed measures of gait velocity, balance, and endurance.
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http://dx.doi.org/10.1186/s12883-020-01719-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164303PMC
April 2020

General Anesthesia Alters Intracranial Venous Pressures During Transverse Sinus Stenting.

World Neurosurg 2020 06 16;138:e712-e717. Epub 2020 Mar 16.

Department of Radiology, The Johns Hopkins Hospital, Baltimore, Maryland, USA. Electronic address:

Introduction: Pressure gradients across venous stenosis are used as a marker for physiologically significant narrowing in idiopathic intracranial hypertension. Performing such measurements under conscious sedation (CS) more likely reflects physiologic conditions, but can be uncomfortable, leading some operators to perform measurement under general anesthesia (GA), though this may not be equivalent.

Methods: We performed a retrospective analysis of patients who received endovascular transverse sinus stenting due to idiopathic intracranial hypertension between August 2013 and May 2017. Patients' demographics and anesthetic parameters were collected along with venous pressure measurements.

Results: We identified 15 patients (14 women). The mean (SD) age was 30.5 (9.0) years and the mean body mass index (SD) was 39.5 (9.6) kg/m. After measurements during CS, GA was induced with propofol and maintained with a volatile anesthetic. The median [IQR; range] transverse sinus pressure gradient under CS was 18 [12, 25; 6-38] mmHg compared with 14 [8, 21; 3-26] mm Hg under GA. The median [IQR; range] pressure gradient change after initiation of GA was -3 [-12, 0; -22 to 9] mm Hg (P = 0.014). After correction for increases in internal jugular vein pressures associated with assumption of GA, the median [IQR; range] gradient change was -11 [-12.5, -5; -22 to 0] mm Hg (P < 0.001).

Conclusions: The transition from CS to GA results in clinically meaningful reductions in transverse sinus gradients in idiopathic intracranial hypertension. Correction for increases in the internal jugular vein pressures reveals even more dramatic reductions in transverse sinus gradients.
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http://dx.doi.org/10.1016/j.wneu.2020.03.050DOI Listing
June 2020

Multiplexed Phosphoproteomic Study of Brain in Patients with Alzheimer's Disease and Age-Matched Cognitively Healthy Controls.

OMICS 2020 04 17;24(4):216-227. Epub 2020 Mar 17.

Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.

Alzheimer's disease (AD) is the most common neurodegenerative disorder caused by neuronal loss that results in cognitive and functional impairment. Formation of neurofibrillary tangles composed of abnormal hyperphosphorylation of tau protein is one of the major pathological hallmarks of AD. Importantly, several neurodegenerative disorders, including AD, are associated with abnormal protein phosphorylation events. However, little is known thus far on global protein phosphorylation changes in AD. We report a phosphoproteomics study examining the frontal gyrus of people with AD and age-matched cognitively normal subjects, using tandem mass tag (TMT) multiplexing technology along with immobilized metal affinity chromatography to enrich phosphopeptides. We identified 4631 phosphopeptides corresponding to 1821 proteins with liquid chromatography-mass spectrometry (MS)/MS analysis on an Orbitrap Fusion Lumos Tribrid mass spectrometer. Of these, 504 phosphopeptides corresponding to 350 proteins were significantly altered in the AD brain: 389 phosphopeptides increased whereas 115 phosphopeptides decreased phosphorylation. We observed significant changes in phosphorylation of known as well as novel molecules. Using targeted parallel reaction monitoring experiments, we validated the phosphorylation of microtubule-associated protein tau and myristoylated alanine-rich protein kinase C substrate (MARCKS) in control and AD (Control = 6, AD = 11) brain samples. In conclusion, our study provides new evidence on alteration of RNA processing and splicing, neurogenesis and neuronal development, and metabotropic glutamate receptor 5 (GRM5) calcium signaling pathways in the AD brain, and it thus offers new insights to accelerate diagnostics and therapeutics innovation in AD.
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http://dx.doi.org/10.1089/omi.2019.0191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366319PMC
April 2020

Association of peripheral inflammatory markers with connectivity in large-scale functional brain networks of non-demented older adults.

Brain Behav Immun 2020 07 11;87:388-396. Epub 2020 Jan 11.

Division of Geriatric Medicine and Gerontology, Center on Aging and Health, Johns Hopkins University School of Medicine, Baltimore, United States. Electronic address:

Background: Systemic inflammation has emerged as a risk factor for cognitive decline and Alzheimer's disease, but inflammation's effect on distributed brain networks is unclear. We examined the relationship between peripheral inflammatory markers and subsequent functional connectivity within five large-scale cognitive networks and evaluated the modifying role of cortical amyloid and APOE ε4 status.

Methods: Blood levels of soluble tumor necrosis factor-alpha receptor-1 and interleukin 6 were assessed in 176 participants (at baseline mean age: 65 (SD 9) years; 63% women; 85% cognitively normal, 15% mild cognitive impairment (MCI)) and were combined to derive an Inflammatory Index. Approximately six years later, participants underwent resting-state functional magnetic resonance imaging to quantify functional connectivity; a subset of 137 participants also underwent C Pittsburgh compound-B (PiB) PET imaging to assess cortical amyloid burden.

Results: Using linear regression models adjusted for demographic characteristics and cardiovascular risk factors, a higher Inflammatory Index was associated with lower connectivity within the Default Mode (β = -0.013; 95% CI: -0.023, -0.003) and the Dorsal Attention Networks (β = -0.017; 95% CI: -0.028, -0.006). The strength of these associations did not vary by amyloid status (positive/negative). However, there was a significant interaction between Inflammatory Index and APOE ε4 status, whereby ε4-positive participants with a higher Inflammatory Index demonstrated lower connectivity. Inflammatory Index was unrelated to connectivity within other large-scale cognitive networks (Control, Limbic, and Salience/Ventral Attention networks).

Conclusion: Peripheral pro-inflammatory signaling in older adults without dementia, especially among APOE ε4-positive individuals, is associated with altered connectivity within two large-scale cognitive networks.
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http://dx.doi.org/10.1016/j.bbi.2020.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316598PMC
July 2020

Cognitive reserve and rate of change in Alzheimer's and cerebrovascular disease biomarkers among cognitively normal individuals.

Neurobiol Aging 2020 04 17;88:33-41. Epub 2019 Dec 17.

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

We examined whether cognitive reserve (CR) impacts level of, or rate of change in, biomarkers of Alzheimer's disease (AD) and small-vessel cerebrovascular disease in >250 individuals who were cognitively normal and middle-aged and older at the baseline. The four primary biomarker categories commonly examined in studies of AD were measured longitudinally: cerebrospinal fluid measures of amyloid (A) and tau (T); cerebrospinal fluid and neuroimaging measures of neuronal injury (N); and neuroimaging measures of white matter hyperintensities (WMHs) to assess cerebrovascular pathology (V). CR was indexed by a composite score including years of education, reading, and vocabulary test performance. Higher CR was associated with lower levels of WMHs, particularly among those who subsequently progressed from normal cognition to MCI. CR was not associated with WMH trajectories. In addition, CR was not associated with either levels of, or rate of change in, A/T/N biomarkers. This may suggest that higher CR is associated with lifestyle factors that reduce levels of cerebrovascular disease, allowing individuals with higher CR to better tolerate other types of pathology.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160864PMC
April 2020

White matter hyperintensities and CSF Alzheimer disease biomarkers in preclinical Alzheimer disease.

Neurology 2020 03 30;94(9):e950-e960. Epub 2019 Dec 30.

From the Department of Neurology (A.S., C.P., A.M., R.F.G., M.A.), The Johns Hopkins University School of Medicine; Department of Biostatistics (Y.Z., M.-C.W.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; and Department of Neurology (B.S., O.M., E.F., C.D.), School of Medicine, University of California, Davis.

Objective: Recent studies suggest that white matter hyperintensities (WMH) on MRI, which primarily reflect small vessel cerebrovascular disease, may play a role in the evolution of Alzheimer disease (AD). In a longitudinal study, we investigated whether WMH promote the progression of AD pathology, or alter the association between AD pathology and risk of progression from normal cognition to mild cognitive impairment (MCI).

Methods: Two sets of analyses were conducted. The relationship between whole brain WMH load, based on fluid-attenuated inversion recovery MRI, obtained in initially cognitively normal participants (n = 274) and time to onset of symptoms of MCI (n = 60) was examined using Cox regression models. In a subset of the participants with both MRI and CSF data (n = 204), the interaction of WMH load and CSF AD biomarkers was also evaluated.

Results: Baseline WMH load interacted with CSF total tau (t-tau) with respect to symptom onset, but not with CSF β-amyloid 1-42 or phosphorylated tau (p-tau) 181. WMH volume was associated with time to symptom onset of MCI among individuals with low t-tau (hazard ratio [HR] 1.35, confidence interval [CI] 1.06-1.73, = 0.013), but not those with high t-tau (HR 0.86, CI 0.56-1.32, = 0.47). The rate of change in the CSF biomarkers over time was not associated with the rate of change in WMH volumes.

Conclusion: These results suggest that WMH primarily affect the risk of progression when CSF measures of neurodegeneration or neuronal injury (as reflected by t-tau) are low. However, CSF biomarkers of amyloid and p-tau and WMH appear to have largely independent and nonsynergistic effects on the risk of progression to MCI.
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http://dx.doi.org/10.1212/WNL.0000000000008864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238945PMC
March 2020

Medial temporal lobe white matter pathway variability is associated with individual differences in episodic memory in cognitively normal older adults.

Neurobiol Aging 2020 03 21;87:78-88. Epub 2019 Nov 21.

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

Significant evidence demonstrates that aging is associated with variability in cognitive performance, even among individuals who are cognitively normal. In this study, we examined measures from magnetic resonance imaging and cerebrospinal fluid (CSF) to investigate which measures, alone or in combination, were associated with individual differences in episodic memory performance. Using hierarchical linear regressions, we compared the ability of diffusion tensor imaging (DTI) metrics, CSF measures of amyloid and tau, and gray matter volumes to explain variability in memory performance in a cohort of cognitively normal older adults. Measures of DTI microstructure were significantly associated with variance in memory performance, even after accounting for the contribution of the CSF and magnetic resonance imaging gray matter volume measures. Significant associations were found between DTI measures of the hippocampal cingulum and fornix with individual differences in memory. No such relationships were found between memory performance and CSF markers or gray matter volumes. These findings suggest that DTI metrics may be useful in identifying changes associated with aging or age-related diseases.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064393PMC
March 2020

Plasma Markers of Inflammation Linked to Clinical Progression and Decline During Preclinical AD.

Front Aging Neurosci 2019 6;11:229. Epub 2019 Sep 6.

Division of Geriatric Medicine and Gerontology, Johns Hopkins School of Medicine, Baltimore, MD, United States.

Objective: To examine the prospective association between blood biomarkers of immune functioning (i.e., innate immune activation, adaptive immunity, and inflammation) and subsequent cognitive decline and clinical progression to mild cognitive impairment (MCI) in cognitively normal individuals.

Methods: The BIOCARD study is an observational cohort study of = 191 initially cognitively healthy participants (mean age 65.2 years). Blood plasma samples were assayed for markers of chronic inflammation (TNFR1, IL-6), adaptive immunity (CD25), and innate immune activation (CD14 and CD163). Participants were followed annually for ongoing clinical assessment and cognitive testing for up to 7.3 years. Primary study outcomes were progression to MCI and cognitive change over time, as measured by a global factor score encompassing multiple cognitive domains.

Results: Higher levels of plasma TNFR1 were associated with greater risk of progression from normal cognition to MCI (HR: 3.27; 95% confidence interval, CI: 1.27, 8.40). Elevated levels of TNFR1 were also associated with steeper rate of cognitive decline on follow-up but not with baseline cognitive performance. Baseline IL-6 levels and markers of innate and adaptive immune activation showed no relationship with MCI risk or cognitive decline.

Conclusion: Inflammation, mediated by TNF signaling, may play a selective role in the early phase of AD. Accordingly, plasma TNFR1 may facilitate improved prediction of disease progression for individuals in the preclinical stage of AD.
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http://dx.doi.org/10.3389/fnagi.2019.00229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742958PMC
September 2019

Tau pathology in cognitively normal older adults.

Alzheimers Dement (Amst) 2019 Dec 6;11:637-645. Epub 2019 Sep 6.

Brain Aging and Behavior Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA.

Introduction: Tau pathology, a hallmark of Alzheimer's disease, is observed in the brains of virtually all individuals over 70 years.

Methods: Using F-AV-1451 (F-flortaucipir) positron emission tomography, we evaluated tau pathology in 54 cognitively normal participants (mean age: 77.5 years, SD: 8.9) from the Baltimore Longitudinal Study of Aging. We assessed associations between positron emission tomography signal and age, sex, race, and amyloid positivity. We investigated relationships between regional signal and retrospective rates of change in regional volumes and cognitive function adjusting for age, sex, and amyloid status.

Results: Greater age, male sex, black race, and amyloid positivity were associated with higher F-AV-1451 retention in distinct brain regions. Retention in the entorhinal cortex was associated with lower entorhinal volume ( = -1.124, SE = 0.485, = .025) and a steeper decline in memory performance ( = -0.086, SE = 0.039, = .029).

Discussion: Assessment of medial temporal tau pathology will provide insights into early structural brain changes associated with later cognitive impairment and Alzheimer's disease.
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http://dx.doi.org/10.1016/j.dadm.2019.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732758PMC
December 2019

Resting-State Functional Connectivity Is Associated With Cerebrospinal Fluid Levels of the Synaptic Protein NPTX2 in Non-demented Older Adults.

Front Aging Neurosci 2019 7;11:132. Epub 2019 Jun 7.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Intrinsic functional connectivity of large-scale brain networks has been shown to change with aging and Alzheimer's disease (AD). These alterations are thought to reflect changes in synaptic function, but the underlying biological mechanisms are poorly understood. This study examined whether Neuronal Pentraxin 2 (NPTX2), a synaptic protein that mediates homeostatic strengthening of inhibitory circuits to control cortical excitability, is associated with functional connectivity as measured by resting-state functional magnetic resonance imaging (rsfMRI) in five large-scale cognitive brain networks. In this cross-sectional study, rsfMRI scans were obtained from 130 older individuals (mean age = 69 years) with normal cognition ( = 113) and Mild Cognitive Impairment ( = 17); NPTX2 was measured in the same individuals in cerebrospinal fluid (CSF). Higher levels of NPTX2 in CSF were associated with greater functional connectivity in the salience/ventral attention network, based on linear regression analysis. Moreover, this association was stronger among individuals with lower levels of cognitive reserve, as measured by a composite score (comprised of years of education, reading, and vocabulary measures). Additionally, higher connectivity in the salience/ventral attention network was related to better performance on a composite measure of executive function. Levels of NPTX2 were not associated with connectivity in other networks (executive control, limbic, dorsal attention, and default-mode). Findings also confirmed prior reports that individuals with MCI have lower levels of NPTX2 compared to those with normal cognition. Taken together, the results suggest that NPTX2 mechanisms may play a central role among older individuals in connectivity within the salience/ventral attention network and for cognitive tasks that require modulation of attention and response selection.
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http://dx.doi.org/10.3389/fnagi.2019.00132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6568192PMC
June 2019

The clinical spectrum of hydrocephalus in adults: report of the first 517 patients of the Adult Hydrocephalus Clinical Research Network registry.

J Neurosurg 2019 May 24;132(6):1773-1784. Epub 2019 May 24.

13Department of Clinical Neurosciences, Division of Neurosurgery, University of Calgary School of Medicine, Calgary, Alberta, Canada.

Objective: The authors describe the demographics and clinical characteristics of the first 517 patients enrolled in the Adult Hydrocephalus Clinical Research Network (AHCRN) during its first 2 years.

Methods: Adults ≥ 18 years were nonconsecutively enrolled in a registry at 6 centers. Four categories of adult hydrocephalus were defined: transition (treated before age 18 years), unrecognized congenital (congenital pattern, not treated before age 18 years), acquired (secondary to known risk factors, treated or untreated), and suspected idiopathic normal pressure hydrocephalus (iNPH) (≥ age 65 years, not previously treated). Data include etiology, symptoms, examination findings, neuropsychology screening, comorbidities, treatment, complications, and outcomes. Standard evaluations were administered to all patients by trained examiners, including the Montreal Cognitive Assessment, the Symbol Digit Modalities Test, the Beck Depression Inventory-II, the Overactive Bladder Questionnaire Short Form symptom bother, the 10-Meter Walk Test, the Boon iNPH gait scale, the Lawton Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL) questionnaire, the iNPH grading scale, and the modified Rankin Scale.

Results: Overall, 517 individuals were enrolled. Age ranged from 18.1 to 90.7 years, with patients in the transition group (32.7 ± 10.0 years) being the youngest and those in the suspected iNPH group (76.5 ± 5.2 years) being the oldest. The proportion of patients in each group was as follows: 16.6% transition, 26.5% unrecognized congenital, 18.2% acquired, and 38.7% suspected iNPH. Excluding the 86 patients in the transition group, who all had received treatment, 79.4% of adults in the remaining 3 groups had not been treated at the time of enrollment. Patients in the suspected iNPH group had the poorest performance in cognitive evaluations, and those in the unrecognized congenital group had the best performance. The same pattern was seen in the Lawton ADL/IADL scores. Gait velocity was lowest in patients in the suspected iNPH group. Categories that had the most comorbidities (suspected iNPH) or etiologies of hydrocephalus that directly cause neurological injury (transition, acquired) had greater degrees of impairment compared to unrecognized congenital, which had the fewest comorbidities or etiologies associated with neurological injury.

Conclusions: The clinical spectrum of hydrocephalus in adults comprises more than iNPH or acquired hydrocephalus. Only 39% of patients had suspected iNPH, whereas 43% had childhood onset (i.e., those in the transition and unrecognized congenital groups). The severity of symptoms and impairment was worsened when the etiology of the hydrocephalus or complications of treatment caused additional neurological injury or when multiple comorbidities were present. However, more than half of patients in the transition, unrecognized congenital, and acquired hydrocephalus groups had minimal or no impairment. Excluding the transition group, nearly 80% of patients in the AHCRN registry were untreated at the time of enrollment. A future goal for the AHCRN is to determine whether patients with unrecognized congenital and acquired hydrocephalus need treatment and which patients in the suspected iNPH cohort actually have possible hydrocephalus and should undergo further diagnostic testing. Future prospective research is needed in the diagnosis, treatment, outcomes, quality of life, and macroeconomics of all categories of adult hydrocephalus.
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http://dx.doi.org/10.3171/2019.2.JNS183538DOI Listing
May 2019
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