Publications by authors named "Ilya M Nasrallah"

37 Publications

Cholesterol, Atherosclerosis, and APOE in Vascular Contributions to Cognitive Impairment and Dementia (VCID): Potential Mechanisms and Therapy.

Front Aging Neurosci 2021 25;13:647990. Epub 2021 Mar 25.

Geisel School of Medicine, Dartmouth College, Hanover, NH, United States.

Vascular contributions to cognitive impairment and dementia (VCID) are a common cause of cognitive decline, yet limited therapies exist. This cerebrovascular disease results in neurodegeneration acute, chronic, local, and systemic mechanisms. The etiology of VCID is complex, with a significant impact from atherosclerosis. Risk factors including hypercholesterolemia and hypertension promote intracranial atherosclerotic disease and carotid artery stenosis (CAS), which disrupt cerebral blood flow and trigger ischemic strokes and VCID. Apolipoprotein E (APOE) is a cholesterol and phospholipid carrier present in plasma and various tissues. APOE is implicated in dyslipidemia and Alzheimer disease (AD); however, its connection with VCID is less understood. Few experimental models for VCID exist, so much of the present information has been drawn from clinical studies. Here, we review the literature with a focus on the clinical aspects of atherosclerotic cerebrovascular disease and build a working model for the pathogenesis of VCID. We describe potential intermediate steps in this model, linking cholesterol, atherosclerosis, and APOE with VCID. APOE4 is a minor isoform of APOE that promotes lipid dyshomeostasis in astrocytes and microglia, leading to chronic neuroinflammation. APOE4 disturbs lipid homeostasis in macrophages and smooth muscle cells, thus exacerbating systemic inflammation and promoting atherosclerotic plaque formation. Additionally, APOE4 may contribute to stromal activation of endothelial cells and pericytes that disturb the blood-brain barrier (BBB). These and other risk factors together lead to chronic inflammation, atherosclerosis, VCID, and neurodegeneration. Finally, we discuss potential cholesterol metabolism based approaches for future VCID treatment.
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http://dx.doi.org/10.3389/fnagi.2021.647990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026881PMC
March 2021

Association of Intensive vs Standard Blood Pressure Control With Magnetic Resonance Imaging Biomarkers of Alzheimer Disease: Secondary Analysis of the SPRINT MIND Randomized Trial.

JAMA Neurol 2021 Mar 8. Epub 2021 Mar 8.

Department of Diagnostic Medicine, Dell Medical School, University of Texas at Austin, Austin.

Importance: Meta-analyses of randomized clinical trials have indicated that improved hypertension control reduces the risk for cognitive impairment and dementia. However, it is unclear to what extent pathways reflective of Alzheimer disease (AD) pathology are affected by hypertension control.

Objective: To evaluate the association of intensive blood pressure control on AD-related brain biomarkers.

Design, Setting, And Participants: This is a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT MIND), a multicenter randomized clinical trial that compared the efficacy of 2 different blood pressure-lowering strategies. Potential participants (n = 1267) 50 years or older with hypertension and without a history of diabetes or stroke were approached for a brain magnetic resonance imaging (MRI) study. Of these, 205 participants were deemed ineligible and 269 did not agree to participate; 673 and 454 participants completed brain MRI at baseline and at 4-year follow-up, respectively; the final follow-up date was July 1, 2016. Analysis began September 2019 and ended November 2020.

Interventions: Participants were randomized to either a systolic blood pressure goal of less than 120 mm Hg (intensive treatment: n = 356) or less than 140 mm Hg (standard treatment: n = 317).

Main Outcomes And Measures: Changes in hippocampal volume, measures of AD regional atrophy, posterior cingulate cerebral blood flow, and mean fractional anisotropy in the cingulum bundle.

Results: Among 673 recruited patients who had baseline MRI (mean [SD] age, 67.3 [8.2] years; 271 women [40.3%]), 454 completed the follow-up MRI at a median (interquartile range) of 3.98 (3.7-4.1) years after randomization. In the intensive treatment group, mean hippocampal volume decreased from 7.45 cm3 to 7.39 cm3 (difference, -0.06 cm3; 95% CI, -0.08 to -0.04) vs a decrease from 7.48 cm3 to 7.46 cm3 (difference, -0.02 cm3; 95% CI, -0.05 to -0.003) in the standard treatment group (between-group difference in change, -0.033 cm3; 95% CI, -0.062 to -0.003; P = .03). There were no significant treatment group differences for measures of AD regional atrophy, cerebral blood flow, or mean fractional anisotropy.

Conclusions And Relevance: Intensive treatment was associated with a small but statistically significant greater decrease in hippocampal volume compared with standard treatment, consistent with the observation that intensive treatment is associated with greater decreases in total brain volume. However, intensive treatment was not associated with changes in any of the other MRI biomarkers of AD compared with standard treatment.

Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.
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http://dx.doi.org/10.1001/jamaneurol.2021.0178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941253PMC
March 2021

Changes in brain functional connectivity and cognition related to white matter lesion burden in hypertensive patients from SPRINT.

Neuroradiology 2021 Jan 6. Epub 2021 Jan 6.

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

Purpose: Hypertension is a risk factor for cognitive impairment; however, the mechanisms leading to cognitive changes remain unclear. In this cross-sectional study, we evaluate the impact of white matter lesion (WML) burden on brain functional connectivity (FC) and cognition in a large cohort of hypertensive patients from the Systolic Blood Pressure Intervention Trial (SPRINT) at baseline.

Methods: Functional networks were identified from baseline resting state functional MRI scans of 660 SPRINT participants using independent component analysis. WML volumes were calculated from structural MRI. Correlation analyses were carried out between mean FC of each functional network and global WML as well as WML within atlas-defined white matter regions. For networks of interest, voxel-wise-adjusted correlation analyses between FC and regional WML volume were performed. Multiple variable linear regression models were built for cognitive test performance as a function of network FC, followed by mediation analysis.

Results: Mean FC of the default mode network (DMN) was negatively correlated with global WML volume, and regional WML volume within the precuneus. Voxel-wise correlation analyses revealed that regional WML was negatively correlated with FC of the DMN's left lateral temporal region. FC in this region of the DMN was positively correlated to performance on the Montreal Cognitive Assessment and demonstrated significant mediation effects. Additional networks also demonstrated global and regional WML correlations; however, they did not demonstrate an association with cognition.

Conclusion: In hypertensive patients, greater WML volume is associated with lower FC of the DMN, which in turn is related to poorer cognitive test performance.

Trial Registration: NCT01206062.
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http://dx.doi.org/10.1007/s00234-020-02614-6DOI Listing
January 2021

Cognitive processing speed is strongly related to driving skills, financial abilities, and other instrumental activities of daily living in persons with MCI and mild dementia.

J Gerontol A Biol Sci Med Sci 2020 Dec 12. Epub 2020 Dec 12.

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.

Background: Cognitive processing speed is important for performing everyday activities in persons with Mild Cognitive Impairment (MCI). However, its role in daily function has not been examined while simultaneously accounting for contributions of Alzheimer's disease (AD) risk biomarkers. We examine the relationships of processing speed and genetic and neuroimaging biomarkers to composites of daily function, mobility, and driving.

Methods: We used baseline data from 103 participants on the MCI/mild dementia spectrum from the Applying Programs to Preserve Skills trial. Linear regression models examined relationships of processing speed, structural MRI, and genetic risk alleles for AD to composites of performance-based instrumental activities of daily living (IADLs), community mobility, and on-road driving evaluations.

Results: In multivariable models, processing speed and the brain MRI neurodegeneration biomarker Spatial Pattern of Abnormality for Recognition of Early Alzheimer's disease (SPARE-AD) were significantly associated with functional and mobility composite performance. Better processing speed and younger age were associated with on-road driving ratings. Genetic risk markers, left hippocampal atrophy, and white matter lesion volumes were not significant correlates of these abilities. Processing speed had a strong positive association with IADL function (p < .001), mobility (p < .001), and driving (p = .002).

Conclusions: Cognitive processing speed is strongly and consistently associated with critical daily functions in persons with MCI in models including genetic and neuroimaging biomarkers of AD risk. SPARE-AD scores also significantly correlate with IADL performance and mobility. Results highlight the central role of processing speed in everyday task performance among persons with MCI/mild dementia.
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http://dx.doi.org/10.1093/gerona/glaa312DOI Listing
December 2020

Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.

Science 2020 11 1;370(6519). Epub 2020 Oct 1.

Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, PA, USA.

Neurodegeneration in Alzheimer's disease (AD) is closely associated with the accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in (valosin-containing protein) was associated with dementia characterized neuropathologically by neuronal vacuoles and neurofibrillary tangles. Moreover, VCP appeared to exhibit tau disaggregase activity in vitro, which was impaired by the p.Asp395Gly mutation. Additionally, intracerebral microinjection of pathologic tau led to increased tau aggregates in mice in which p.Asp395Gly mice was knocked in, as compared with injected wild-type mice. These findings suggest that p.Asp395Gly is an autosomal-dominant genetic mutation associated with neurofibrillary degeneration in part owing to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD.
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http://dx.doi.org/10.1126/science.aay8826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818661PMC
November 2020

Multimodal in vivo and postmortem assessments of tau in Lewy body disorders.

Neurobiol Aging 2020 12 21;96:137-147. Epub 2020 Aug 21.

Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Frontotemporal Degeneration Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

We compared regional retention of F-flortaucipir between 20 patients with Lewy body disorders (LBD), 12 Alzheimer's disease patients with positive amyloid positron emission tomography (PET) scans (AD+Aβ) and 15 healthy controls with negative amyloid PET scans (HC-Aβ). In LBD subjects, we compared the relationship between F-flortaucipir retention and cerebrospinal fluid (CSF) tau, cognitive performance, and neuropathological tau at autopsy. The LBD cohort was stratified using an Aβ42 cut-off of 192 pg/mL to enrich for groups likely harboring tau pathology (LBD+Aβ = 11, LBD-Aβ = 9). F-flortaucipir retention was higher in LBD+AB than HC-Aβ in five, largely temporal-parietal regions with sparing of medial temporal regions. Higher retention was associated with higher CSF total-tau levels (p = 0.04), poorer domain-specific cognitive performance (p = 0.02-0.04), and greater severity of neuropathological tau in corresponding regions. While F-flortaucipir retention in LBD is intermediate between healthy controls and AD, retention relates to cognitive impairment, CSF total-tau, and neuropathological tau. Future work in larger autopsy-validated cohorts is needed to define LBD-specific tau biomarker profiles.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819484PMC
December 2020

Flare Phenomenon in -(2-[F]-Fluoroethyl)-L-Tyrosine PET After Resection of Gliomas: Potential Contribution from Postoperative Ischemia.

J Nucl Med 2020 12 9;61(12):1851-1852. Epub 2020 Jul 9.

Perelman School of Medicine of the University of Pennsylvania 3400 Spruce St. Philadelphia, PA 19104 E-mail:

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http://dx.doi.org/10.2967/jnumed.120.251116DOI Listing
December 2020

Artificial Intelligence System Approaching Neuroradiologist-level Differential Diagnosis Accuracy at Brain MRI.

Radiology 2020 06 7;295(3):626-637. Epub 2020 Apr 7.

From the Department of Radiology & Biomedical Imaging, University of California, San Francisco, 513 Parnassus Ave, Room S-261, Box 0628, San Francisco, CA 94143-0628 (A.M.R.); Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104 (A.M.R., J.D.R., L.X., J.W., M.T.D., A.M.K., J.E., T.C.C., I.M.N., S.M., J.C.G.); Mecklenburg Radiology Associates, Charlotte, NC (E.J.B.); and Department of Radiology, University of Texas at Austin, Austin, TX (R.N.B.).

Background Although artificial intelligence (AI) shows promise across many aspects of radiology, the use of AI to create differential diagnoses for rare and common diseases at brain MRI has not been demonstrated. Purpose To evaluate an AI system for generation of differential diagnoses at brain MRI compared with radiologists. Materials and Methods This retrospective study tested performance of an AI system for probabilistic diagnosis in patients with 19 common and rare diagnoses at brain MRI acquired between January 2008 and January 2018. The AI system combines data-driven and domain-expertise methodologies, including deep learning and Bayesian networks. First, lesions were detected by using deep learning. Then, 18 quantitative imaging features were extracted by using atlas-based coregistration and segmentation. Third, these image features were combined with five clinical features by using Bayesian inference to develop probability-ranked differential diagnoses. Quantitative feature extraction algorithms and conditional probabilities were fine-tuned on a training set of 86 patients (mean age, 49 years ± 16 [standard deviation]; 53 women). Accuracy was compared with radiology residents, general radiologists, neuroradiology fellows, and academic neuroradiologists by using accuracy of top one, top two, and top three differential diagnoses in 92 independent test set patients (mean age, 47 years ± 18; 52 women). Results For accuracy of top three differential diagnoses, the AI system (91% correct) performed similarly to academic neuroradiologists (86% correct; = .20), and better than radiology residents (56%; < .001), general radiologists (57%; < .001), and neuroradiology fellows (77%; = .003). The performance of the AI system was not affected by disease prevalence (93% accuracy for common vs 85% for rare diseases; = .26). Radiologists were more accurate at diagnosing common versus rare diagnoses (78% vs 47% across all radiologists; < .001). Conclusion An artificial intelligence system for brain MRI approached overall top one, top two, and top three differential diagnoses accuracy of neuroradiologists and exceeded that of less-specialized radiologists. © RSNA, 2020 See also the editorial by Zaharchuk in this issue.
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http://dx.doi.org/10.1148/radiol.2020190283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263320PMC
June 2020

Arterial spin labeling versus F-FDG-PET to identify mild cognitive impairment.

Neuroimage Clin 2020 23;25:102146. Epub 2019 Dec 23.

Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Neurodegenerative biomarkers support diagnosis and measurement of disease progression in the Alzheimer's disease (AD) continuum. F-Fluorodeoxyglucose Positron Emission Tomography (F-FDG-PET), which measures glucose metabolism, is one of the most commonly used biomarkers of neurodegeneration, but is expensive and requires exposure to ionizing radiation. Arterial Spin Labeled (ASL) perfusion Magnetic Resonance Imaging (MRI) provides non invasive quantification of cerebral blood flow (CBF), which is believed to be tightly coupled to glucose metabolism. Here we aimed to compare the performances of ASL derived CBF and F-FDG-PET derived standardized uptake value ratio (SUVR) in discriminating patients with mild cognitive impairment (MCI) from older Controls. 2D pseudo continuous ASL and F-FDG-PET data with adequate scan quality from 50 MCI study participants (age=73.0 ± 7.0 years, 16 female) and 35 older controls (age=70.2 ± 6.9 years, 20 female), acquired in close temporal proximity, usually on the same day, were considered for this study. We assessed Control-patient group differences both at voxel level and within a priori regions of interest (ROIs). We also compared their area under receiver operating characteristic curves (AUC) with mean CBF or SUVR in a priori selected posterior cingulate cortex (PCC). CBF and F-FDG-PET showed abnormalities in similar areas, particularly in medial temporoparietal regions, consistent with the typically observed pattern of prodromal AD. The hypoperfusion pattern with relative CBF (obtained by normalizing voxel CBF values with mean CBF in putamen) was more localized than with absolute CBF. Pearson's correlation coefficients between the T-scores corresponding to the group-differences obtained with F-FDG-PET SUVR and absolute and relative ASL CBF were 0.46 and 0.43 (p<0.001), respectively. ROI analyses were also consistent, with the strongest differences observed in PCC (p<0.01). F-FDG-PET SUVR, absolute and relative CBF in the PCC ROI demonstrated moderate and similar discriminatory power in predicting MCI status with AUC of 0.71 ± 0.12, 0.77 ± 0.12 and 0.74 ± 0.13, respectively. In conclusion, ASL CBF may be a reasonable, less expensive and safer substitute for F-FDG-PET in clinical research.
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http://dx.doi.org/10.1016/j.nicl.2019.102146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957781PMC
December 2020

Harmonization of large MRI datasets for the analysis of brain imaging patterns throughout the lifespan.

Neuroimage 2020 03 9;208:116450. Epub 2019 Dec 9.

Center for Biomedical Image Computing and Analytics, Department of Radiology, University of Pennsylvania, USA. Electronic address:

As medical imaging enters its information era and presents rapidly increasing needs for big data analytics, robust pooling and harmonization of imaging data across diverse cohorts with varying acquisition protocols have become critical. We describe a comprehensive effort that merges and harmonizes a large-scale dataset of 10,477 structural brain MRI scans from participants without a known neurological or psychiatric disorder from 18 different studies that represent geographic diversity. We use this dataset and multi-atlas-based image processing methods to obtain a hierarchical partition of the brain from larger anatomical regions to individual cortical and deep structures and derive age trends of brain structure through the lifespan (3-96 years old). Critically, we present and validate a methodology for harmonizing this pooled dataset in the presence of nonlinear age trends. We provide a web-based visualization interface to generate and present the resulting age trends, enabling future studies of brain structure to compare their data with this reference of brain development and aging, and to examine deviations from ranges, potentially related to disease.
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http://dx.doi.org/10.1016/j.neuroimage.2019.116450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980790PMC
March 2020

Association of Intensive vs Standard Blood Pressure Control With Cerebral White Matter Lesions.

JAMA 2019 08;322(6):524-534

Department of Radiology, University of Pennsylvania, Philadelphia.

Importance: The effect of intensive blood pressure lowering on brain health remains uncertain.

Objective: To evaluate the association of intensive blood pressure treatment with cerebral white matter lesion and brain volumes.

Design, Setting, And Participants: A substudy of a multicenter randomized clinical trial of hypertensive adults 50 years or older without a history of diabetes or stroke at 27 sites in the United States. Randomization began on November 8, 2010. The overall trial was stopped early because of benefit for its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. Brain magnetic resonance imaging (MRI) was performed on a subset of participants at baseline (n = 670) and at 4 years of follow-up (n = 449); final follow-up date was July 1, 2016.

Interventions: Participants were randomized to a systolic blood pressure (SBP) goal of either less than 120 mm Hg (intensive treatment, n = 355) or less than 140 mm Hg (standard treatment, n = 315).

Main Outcomes And Measures: The primary outcome was change in total white matter lesion volume from baseline. Change in total brain volume was a secondary outcome.

Results: Among 670 recruited patients who had baseline MRI (mean age, 67.3 [SD, 8.2] years; 40.4% women), 449 (67.0%) completed the follow-up MRI at a median of 3.97 years after randomization, after a median intervention period of 3.40 years. In the intensive treatment group, based on a robust linear mixed model, mean white matter lesion volume increased from 4.57 to 5.49 cm3 (difference, 0.92 cm3 [95% CI, 0.69 to 1.14]) vs an increase from 4.40 to 5.85 cm3 (difference, 1.45 cm3 [95% CI, 1.21 to 1.70]) in the standard treatment group (between-group difference in change, -0.54 cm3 [95% CI, -0.87 to -0.20]). Mean total brain volume decreased from 1134.5 to 1104.0 cm3 (difference, -30.6 cm3 [95% CI, -32.3 to -28.8]) in the intensive treatment group vs a decrease from 1134.0 to 1107.1 cm3 (difference, -26.9 cm3 [95% CI, 24.8 to 28.8]) in the standard treatment group (between-group difference in change, -3.7 cm3 [95% CI, -6.3 to -1.1]).

Conclusions And Relevance: Among hypertensive adults, targeting an SBP of less than 120 mm Hg, compared with less than 140 mm Hg, was significantly associated with a smaller increase in cerebral white matter lesion volume and a greater decrease in total brain volume, although the differences were small.

Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.
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http://dx.doi.org/10.1001/jama.2019.10551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692679PMC
August 2019

Characterizing a perfusion-based periventricular small vessel region of interest.

Neuroimage Clin 2019 12;23:101897. Epub 2019 Jun 12.

Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA; Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

The periventricular white matter (PVWM) is supplied by terminal distributions of small vessels and is particularly susceptible to developing white matter lesions (WML) associated with cerebral small vessel disease (CSVD). We obtained group-averaged cerebral blood flow (CBF) maps from Arterial Spin Labeled (ASL) perfusion MRI data obtained in 436 middle-aged (50.4 ± 3.5 years) subjects in the NHLBI CARDIA study and in 61 elderly (73.3 ± 6.9 years) cognitively normal subjects recruited from the Penn Alzheimer's Disease Center (ADC) and found that the lowest perfused brain voxels are located within the PVWM. We constructed a white matter periventricular small vessel (PSV) region of interest (ROI) by empirically thresholding the group averaged CARDIA CBF map at CBF < 15 ml/100 g/min. Thereafter we compared CBF in the PSV ROI and in the remaining white matter (RWM) with the location and volume of WML measured with Fluid Attenuated Inversion Recovery (FLAIR) MRI. WM CBF was lower within WML than outside WML voxels (p < <0.0001) in both the PSV and RWM ROIs, however this difference was much smaller (p < <0.0001) in the PSV ROI than in the RWM suggesting a more homogenous reduction of CBF in the PSV region. Normalized WML volumes were significantly higher in the PSV ROI than in the RWM and in the elderly cohort as compared to the middle-aged cohort (p < <0.0001). Additionally, the PSV ROI showed a significantly (p = .001) greater increase in lesion volume than the RWM in the elderly ADC cohort than the younger CARDIA cohort. Considerable intersubject variability in PSV CBF observed in both study cohorts likely represents biological variability that may be predictive of future WML and/or cognitive decline. In conclusion, a data-driven PSV ROI defined by voxels with low perfusion in middle age defines a region with homogeneously reduced CBF that is particularly susceptible to progressive ischemic injury in elderly controls. PSV CBF may provide a mechanistically specific biomarker of CSVD.
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http://dx.doi.org/10.1016/j.nicl.2019.101897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595083PMC
June 2020

Poor awareness of IADL deficits is associated with reduced regional brain volume in older adults with cognitive impairment.

Neuropsychologia 2019 06 4;129:372-378. Epub 2019 May 4.

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Performance of instrumental activities of daily living (IADLs) can become compromised in older adults with mild cognitive impairment (MCI). Patients' level of insight into their everyday functioning varies both amongst individuals and across domains assessed, with some individuals exhibiting complete unawareness of deficits. The current cross-sectional study examined the neuroanatomical substrates of self-awareness in order to help explain the variability in this phenomenon in older adults across a continuum of cognitive impairment. Eighty-five participants (ages 54-88, mean age = 73 years, 57% female, 89% Caucasian) diagnosed with MCI or mild probable dementia underwent structural magnetic resonance imaging. Level of self-awareness was assessed by calculating the discrepancy between objective and subjective performance across six IADLs (Financial Management, Driving, Grocery Shopping, Nutrition Evaluation, Medication Management, and Telephone Use). Over-estimation of current abilities occurred in 13-31% of the sample depending on which IADL was evaluated. Poor awareness was significantly related to reduced volume in the bilateral medial prefrontal cortex, middle and posterior cingulate cortex, right insular cortex, and cerebellum. No associations were found with total white matter lesion load. These findings were broadly consistent across all functional domains assessed, supporting the theory that cortical midline and cerebellar structures are involved in self-referential processing across a variety of different cognitive and behavioral skills. Longitudinal studies are needed to confirm this association.
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http://dx.doi.org/10.1016/j.neuropsychologia.2019.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571164PMC
June 2019

Histologic, immunohistochemical, and molecular features of pituicytomas and atypical pituicytomas.

Acta Neuropathol Commun 2019 05 2;7(1):69. Epub 2019 May 2.

Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Pituicytoma is a rare, poorly characterized tumor of the sellar region that is thought to be derived from neurohypophyseal pituicytes. Resection of pituicytomas is often associated with significant morbidity including diabetes insipidus and panhypopituitarism. Most of the literature on this tumor exists as small case series or case reports. Here we describe a cohort of fourteen pituicytoma resections from eleven patients. The average follow-up on these cases is 3.7 years with some patients having over 10 years of follow-up data available in the electronic medical record. Pituicytomas were frequently misdiagnosed on pre-operative imaging, and surgical resection was associated with persistent endocrine abnormalities. Histologically, the tumors showed a range of morphologies from epithelioid to spindled. All tumors were positive for TTF-1 with variable immunostaining for other markers including GFAP, EMA, S100, SSTR2A, and synaptophysin. Within this cohort are two patients with atypical pituicytomas which showed increased cellularity, pleomorphism, mitoses and elevated Ki-67 proliferation indexes when compared to non-atypical pituicytomas. Next generation sequencing performed on three tumors revealed alterations in genes involved in the MAPK pathway. Additionally, immunohistochemical staining for phosphorylated-ERK was positive in the majority of tumors. Increased awareness of the neoplastic entity and identification of targetable mutations have the potential to decrease the morbidity associated with resection of pituicytomas.
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http://dx.doi.org/10.1186/s40478-019-0722-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498683PMC
May 2019

Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial.

JAMA 2019 02;321(6):553-561

National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.

Importance: There are currently no proven treatments to reduce the risk of mild cognitive impairment and dementia.

Objective: To evaluate the effect of intensive blood pressure control on risk of dementia.

Design, Setting, And Participants: Randomized clinical trial conducted at 102 sites in the United States and Puerto Rico among adults aged 50 years or older with hypertension but without diabetes or history of stroke. Randomization began on November 8, 2010. The trial was stopped early for benefit on its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. The final date for follow-up of cognitive outcomes was July 22, 2018.

Interventions: Participants were randomized to a systolic blood pressure goal of either less than 120 mm Hg (intensive treatment group; n = 4678) or less than 140 mm Hg (standard treatment group; n = 4683).

Main Outcomes And Measures: The primary cognitive outcome was occurrence of adjudicated probable dementia. Secondary cognitive outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia.

Results: Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 8563 (91.5%) completed at least 1 follow-up cognitive assessment. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% CI, 0.67-1.04). Intensive BP control significantly reduced the risk of mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95) and the combined rate of mild cognitive impairment or probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97).

Conclusions And Relevance: Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of less than 140 mm Hg did not result in a significant reduction in the risk of probable dementia. Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point.

Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.
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http://dx.doi.org/10.1001/jama.2018.21442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439590PMC
February 2019

Hypoglossal nerve palsy due to carotid artery dissection: an uncommon presentation of a common problem.

Neuroradiol J 2019 Apr 16;32(2):123-126. Epub 2019 Jan 16.

2 Department of Radiology, University of Pennsylvania Health System, USA.

Spontaneous internal carotid artery dissection occurs in patients of all ages, rarely presenting with hypoglossal nerve palsy. The characteristic imaging findings of internal carotid artery dissection and tongue denervation are reviewed in four patients. Recognition of internal carotid artery dissection is critical for appropriate treatment and to minimise the risk of thromboembolic-ischaemic complications. Radiologists must be aware of the radiological appearance of hypoglossal nerve palsy and maintain a high index of suspicion for internal carotid artery dissection when this finding is present.
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http://dx.doi.org/10.1177/1971400918825485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410449PMC
April 2019

Tau PET imaging predicts cognition in atypical variants of Alzheimer's disease.

Hum Brain Mapp 2018 02 6;39(2):691-708. Epub 2017 Nov 6.

Penn Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, 19104.

Accumulation of paired helical filament tau contributes to neurodegeneration in Alzheimer's disease (AD). F-flortaucipir is a positron emission tomography (PET) radioligand sensitive to tau in AD, but its clinical utility will depend in part on its ability to predict cognitive symptoms in diverse dementia phenotypes associated with selective, regional uptake. We examined associations between F-flortaucipir and cognition in 14 mildly-impaired patients (12 with cerebrospinal fluid analytes consistent with AD pathology) who had amnestic (n = 5) and non-amnestic AD syndromes, including posterior cortical atrophy (PCA, n = 5) and logopenic-variant primary progressive aphasia (lvPPA, n = 4). Amnestic AD patients had deficits in memory; lvPPA in language; and both amnestic AD and PCA patients in visuospatial function. Associations with cognition were tested using sparse regression and compared to associations in anatomical regions-of-interest (ROIs). F-flortaucipir uptake was expected to show regionally-specific correlations with each domain. In multivariate analyses, uptake was elevated in neocortical areas specifically associated with amnestic and non-amnestic syndromes. Uptake in left anterior superior temporal gyrus accounted for 67% of the variance in language performance. Uptake in right lingual gyrus predicted 85% of the variance in visuospatial performance. Memory was predicted by uptake in right fusiform gyrus and cuneus as well as a cluster comprising right anterior hippocampus and amygdala; this eigenvector explained 57% of the variance in patients' scores. These results provide converging evidence for associations between F-flortaucipir uptake, tau pathology, and patients' cognitive symptoms.
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http://dx.doi.org/10.1002/hbm.23874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764792PMC
February 2018

F-Flortaucipir PET/MRI Correlations in Nonamnestic and Amnestic Variants of Alzheimer Disease.

J Nucl Med 2018 02 26;59(2):299-306. Epub 2017 Jul 26.

Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania; and.

Nonamnestic Alzheimer disease (AD) variants, including posterior cortical atrophy and the logopenic variant of primary progressive aphasia, differ from amnestic AD in distributions of tau aggregates and neurodegeneration. We evaluated whether F-flortaucipir (also called F-AV-1451) PET, targeting tau aggregates, detects these differences, and we compared the results with MRI measures of gray matter (GM) atrophy. Five subjects with posterior cortical atrophy, 4 subjects with the logopenic variant of primary progressive aphasia, 6 age-matched patients with AD, and 6 control subjects underwent F-flortaucipir PET and MRI. SUV ratios and GM volumes were compared using regional and voxel-based methods. The subgroups showed the expected F-flortaucipir-binding patterns. Group effect sizes were generally stronger with F-flortaucipir PET than with MRI volumes. There were moderate-to-high correlations between regional GM atrophy and F-flortaucipir uptake. F-flortaucipir binding and GM atrophy correlated similarly to cognitive test performance. F-flortaucipir binding corresponds to the expected neurodegeneration patterns in nonamnestic AD, with potential for earlier detection of pathology than is possible with MRI atrophy measures.
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http://dx.doi.org/10.2967/jnumed.117.194282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348438PMC
February 2018

Comparison of PASL, PCASL, and background-suppressed 3D PCASL in mild cognitive impairment.

Hum Brain Mapp 2017 10 24;38(10):5260-5273. Epub 2017 Jul 24.

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

We compared three implementations of single-shot arterial spin labeled (ASL) perfusion magnetic resonance imaging: two-dimensional (2D) pulsed ASL (PASL), 2D pseudocontinuous ASL (PCASL), and background-suppressed (BS) 3D PCASL obtained in a cohort of patients with mild cognitive impairment (MCI) and elderly controls. Study subjects also underwent F-fluorodeoxyglucose positron emission tomography ( F-FDG PET). While BS 3D PCASL showed the lowest (P < 0.001) gray matter-white matter cerebral blood flow (CBF) contrast ratio, it provided the highest (P < 0.001) temporal signal-to-noise ratio. Mean relative CBF estimated using the PCASL methods in posterior cingulate cortex (PCC), precuneus, and hippocampus showed hypoperfusion in the MCI cohort compared to the controls consistent with hypometabolism measured by F-FDG PET. BS 3D PCASL demonstrated the highest discrimination between controls and patients with effect size comparable to that seen with F-FDG PET. 2D PASL did not demonstrate group differentiation with relative CBF in any ROI, whereas 2D PCASL demonstrated significant differences only in PCC and hippocampus. Mean global CBF values did not differ across methods and were highly correlated; however, the correlations were significantly higher (P < 0.001) when either the same labeling (PCASL) or the same acquisition strategy (2D) was used as compared to when both the labeling and readout methods differed. In addition, there were differences in regional distribution of CBF between the three modalities, which can be attributed to differences in sequence parameters. These results demonstrate the superiority of ASL with PCASL and BS 3D readout as a biomarker for regional brain function changes in MCI. Hum Brain Mapp 38:5260-5273, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hbm.23732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593784PMC
October 2017

19-Year-Old Male with Headaches and a Possible Seizure.

Brain Pathol 2017 07;27(4):557-558

Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1111/bpa.12529DOI Listing
July 2017

Regional brain amyloid-β accumulation associates with domain-specific cognitive performance in Parkinson disease without dementia.

PLoS One 2017 25;12(5):e0177924. Epub 2017 May 25.

Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Parkinson disease patients develop clinically significant cognitive impairment at variable times over their disease course, which is often preceded by milder deficits in memory, visuo-spatial, and executive domains. The significance of amyloid-β accumulation to these problems is unclear. We hypothesized that amyloid-β PET imaging by 18F-florbetapir, a radiotracer that detects fibrillar amyloid-β plaque deposits, would identify subjects with global cognitive impairment or poor performance in individual cognitive domains in non-demented Parkinson disease patients. We assessed 61 non-demented Parkinson disease patients with detailed cognitive assessments and 18F-florbetapir PET brain imaging. Scans were interpreted qualitatively (positive or negative) by two independent nuclear medicine physicians blinded to clinical data, and quantitatively by a novel volume-weighted method. The presence of mild cognitive impairment was determined through an expert consensus process using Level 1 criteria from the Movement Disorder Society. Nineteen participants (31.2%) were diagnosed with mild cognitive impairment and the remainder had normal cognition. Qualitative 18F-florbetapir PET imaging was positive in 15 participants (24.6%). Increasing age and presence of an APOE ε4 allele were associated with higher composite 18F-florbetapir binding. In multivariable models, an abnormal 18F-florbetapir scan by expert rating was not associated with a diagnosis of mild cognitive impairment. However, 18F-florbetapir retention values in the posterior cingulate gyrus inversely correlated with verbal memory performance. Retention values in the frontal cortex, precuneus, and anterior cingulate gyrus retention values inversely correlated with naming performance. Regional cortical amyloid-β amyloid, as measured by 18F-florbetapir PET, may be a biomarker of specific cognitive deficits in non-demented Parkinson disease patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177924PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444629PMC
September 2017

Advanced structural multimodal imaging of a patient with subcortical band heterotopia.

Epilepsia Open 2016 Dec 3;1(3-4):152-155. Epub 2016 Oct 3.

Department of Neurology, Hospital of the University of Pennsylvania, 3400 Spruce Street, 3 West Gates Bldg., Philadelphia PA 19104, U.S.A.

Subcortical band heterotopia (SBH) is a disorder of neuronal migration most commonly due to mutations of the gene. A range of phenotypes is seen, with most patients having some degree of epilepsy and intellectual disability. Advanced diffusion and structural magnetic resonance imaging (MRI) sequences may be useful in identifying heterotopias and dysplasias of different sizes in drug-resistant epilepsy. We describe a patient with SBH and drug-resistant epilepsy and investigate neurite density, neurite dispersion, and diffusion parameters as compared to a healthy control through the use of multiple advanced MRI modalities. Neurite density and dispersion in heterotopia was found to be more similar to white matter than gray matter. Neurite density and dispersion maps obtained using diffusion imaging may be able to better characterize different subtypes of heterotopia.
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http://dx.doi.org/10.1002/epi4.12019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387998PMC
December 2016

Trends in Fluoroscopy Time in Fluoroscopy-Guided Lumbar Punctures Performed by Trainees Over an Academic Year.

Acad Radiol 2017 03 16;24(3):373-380. Epub 2017 Jan 16.

Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

Rationale And Objectives: Fluoroscopy-guided lumbar puncture (FGLP) is an operator-dependent procedure that can contribute to lifetime cumulative radiation dose. Benchmark fluoroscopic times (FTs) have been published for ranges of body mass index (BMI), but trends in FT in FGLPs performed by neuroradiology trainees during their training have not been studied. The purpose of this study was to investigate the trends in FTs in FGLPs performed by neuroradiology fellows in an academic year.

Materials And Methods: We retrospectively reviewed FGLPs performed at our institution from July 2013 to June 2015 and determined the FT average and standard deviation of residents and non-neuroradiology fellows, neuroradiology fellows, and neuroradiology attendings. We used the Kruskal-Wallis test to evaluate group differences in FT in operator groups and academic quarters and by patient age, BMI, and needle length. Linear and Poisson regression analyses were performed to directly examine the relationship between the number of FGLPs performed and FTs.

Results: A total of 776 patients had successful FGLPs; 594 cases (77%) were performed by neuroradiology fellows (n = 14). The average FT and variance for neuroradiology fellows significantly decreased over the year (P = 0.004 and P < 0.001) with an estimated decrease of 0.01 minute of FT per FGLP. BMI, long needle length, and age ≥65 years old significantly affected the average FT (P = 0.03, P < 0.001, and P < 0.001) and FT decreased in all of these subgroups in the academic year.

Conclusions: FT in FGLP cases performed by neuroradiology fellows decreases during the year. Our data can be utilized by radiology training programs and practices as a benchmark to monitor individual operator FT.
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http://dx.doi.org/10.1016/j.acra.2016.11.004DOI Listing
March 2017

Relative differences in resting-state brain connectivity associated with long term intensive lifestyle intervention.

Psychoneuroendocrinology 2016 12 23;74:231-239. Epub 2016 Sep 23.

Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, USA. Electronic address:

A number of studies have reported that type 2 diabetes mellitus (T2DM) is associated with alterations in resting-state activity and connectivity in the brain. There is also evidence that interventions involving physical activity and weight loss may affect brain functional connectivity. In this study, we examined the effects of nearly 10 years of an intensive lifestyle intervention (ILI), designed to induce and sustain weight loss through lower caloric intake and increased physical activity, on resting-state networks in adults with T2DM. We performed a cross-sectional comparison of global and local characteristics from functional brain networks between individuals who had been randomly assigned to ILI or a control condition of health education and support. Upon examining brain networks from 312 participants (average age: 68.8 for ILI and 67.9 for controls), we found that ILI participants (N=160) had attenuated local efficiency at the network-level compared with controls (N=152). Although there was no group difference in the network-level global efficiency, we found that, among ILI participants, nodal global efficiency was elevated in left fusiform gyrus, right middle frontal gyrus, and pars opercularis of right inferior frontal gyrus. These effects were age-dependent, with more pronounced effects for older participants. Overall these results indicate that the individuals assigned to the ILI had brain networks with less regional and more global connectivity, particularly involving frontal lobes. Such patterns would support greater distributed information processing. Future studies are needed to determine if these differences are associated with age-related compensatory function in the ILI group or worse pathology in the control group.
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http://dx.doi.org/10.1016/j.psyneuen.2016.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159283PMC
December 2016

Will PET amyloid imaging lead to overdiagnosis of Alzheimer dementia?

Acad Radiol 2015 Aug 19;22(8):988-94. Epub 2015 Jun 19.

Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 3400 Spruce Street, 110 Donner Building, Philadelphia, PA 19104.

Alzheimer disease (AD), a progressive neurodegenerative disease that causes dementia, affects millions of elderly Americans and represents a growing problem with the aging of the population. There has been an increasing effort for improved and earlier diagnosis for AD. Several newly developed radiolabeled compounds targeting β-amyloid plaques, one of the major pathologic biomarkers of AD, have recently become available for clinical use. These radiopharmaceuticals allow for in vivo noninvasive visualization of abnormal β-amyloid deposits in the brain using positron emission tomography (PET). Amyloid PET imaging has demonstrated high sensitivity for pathologic cerebral amyloid deposition in multiple studies. Principal drawbacks to this new diagnostic test are declining specificity in older age groups and uncertain clinical role given lack of disease-modifying therapy for AD. Although there is strong evidence for the utility of amyloid PET in certain situations, detailed in a set of guidelines for appropriate use from the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging, the question of overdiagnosis, the diagnosis of a disease that would result in neither symptoms nor deaths, using this new medical tool needs to be carefully considered in light of efforts to secure reimbursement for the new technology that is already widely available for use as a clinical tool.
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http://dx.doi.org/10.1016/j.acra.2015.02.005DOI Listing
August 2015

Fine-needle aspiration of superficial myxoid neurofibroma in the region of the breast.

Diagn Cytopathol 2015 May 26;43(5):427-31. Epub 2015 Feb 26.

Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

Myxoid neurofibromas are benign spindle cell tumors of perineural cell origin with a broad pathologic differential diagnosis, which includes myxoma, myxoid liposarcoma, myxoid dermatofibrosarcoma protuberans, and low-grade fibromyxoid sarcoma. We present an unusual case of superficial myxoid neurofibroma in the region of the breast that underwent pre-operative fine-needle aspiration (FNA). The differential diagnosis for a myxoid subcutaneous lesion should include myxoid neurofibroma when myxoid material is encountered in an otherwise hypocellular FNA.
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http://dx.doi.org/10.1002/dc.23261DOI Listing
May 2015

Multimodality imaging of Alzheimer disease and other neurodegenerative dementias.

J Nucl Med 2014 Dec 20;55(12):2003-11. Epub 2014 Nov 20.

Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania.

Neurodegenerative diseases, such as Alzheimer disease, result in cognitive decline and dementia and are a leading cause of mortality in the growing elderly population. These progressive diseases typically have an insidious onset, with overlapping clinical features early in the disease course that make diagnosis challenging. The neurodegenerative diseases are associated with characteristic, although not completely understood, changes in the brain: abnormal protein deposition, synaptic dysfunction, neuronal injury, and neuronal death. Neuroimaging biomarkers-principally regional atrophy on structural MR imaging, patterns of hypometabolism on (18)F-FDG PET, and detection of cerebral amyloid plaque on amyloid PET--are able to evaluate the patterns of these abnormalities in the brain to improve early diagnosis and help predict the disease course. These techniques have unique strengths and synergies in multimodality evaluation of the patient with cognitive decline or dementia. This review discusses the key imaging biomarkers from MR imaging, (18)F-FDG PET, and amyloid PET; the imaging features of the most common neurodegenerative dementias; the role of various neuroimaging studies in differential diagnosis and prognosis; and some promising imaging techniques under development.
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http://dx.doi.org/10.2967/jnumed.114.141416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702268PMC
December 2014

High-resolution magnetic resonance microscopy and diffusion tensor imaging to assess brain structural abnormalities in the murine mucopolysaccharidosis VII model.

J Neuropathol Exp Neurol 2014 Jan;73(1):39-49

From the Departments of Radiology (MK, IMN, RI, SP, HP), Neurology (JL), and Pediatrics (JHW), Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania; W.F. Goodman Center for Comparative Medical Genetics, School of Veterinary Medicine, University of Pennsylvania (MKP, JHW); Department of Radiology, New York University School of Medicine, New York, New York (SK); and Research Institute of the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (MKP, JHW).

High-resolution microscopic magnetic resonance imaging (μMRI) and diffusion tensor imaging (DTI) were performed to characterize brain structural abnormalities in a mouse model of mucopolysaccharidosis type VII (MPS VII). Microscopic magnetic resonance imaging demonstrated a decrease in the volume of anterior commissure and corpus callosum and a slight increase in the volume of the hippocampus in MPS VII versus wild-type mice. Diffusion tensor imaging indices were analyzed in gray and white matter. In vivo and ex vivo DTI demonstrated significantly reduced fractional anisotropy in the anterior commissure, corpus callosum, external capsule, and hippocampus in MPS VII versus control brains. Significantly increased mean diffusivity was also found in the anterior commissure and corpus callosum from ex vivo DTI. Significantly reduced linear anisotropy was observed from the hippocampus from in vivo DTI, whereas significantly decreased planar anisotropy and spherical anisotropy were observed in the external capsule from only ex vivo DTI. There were corresponding morphologic differences in the brains of MPS VII mice by hematoxylin and eosin staining. Luxol fast blue staining demonstrated less intense staining of the corpus callosum and external capsule; myelin abnormalities in the corpus callosum were also demonstrated quantitatively in toluidine blue-stained sections and confirmed by electron microscopy. These results demonstrate the potential for μMRI and DTI for quantitative assessment of brain pathology in murine models of brain diseases.
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http://dx.doi.org/10.1097/NEN.0000000000000023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120119PMC
January 2014

Cavernous hemangioma of the skull: surgical treatment without craniectomy.

J Neurosurg Pediatr 2009 Dec;4(6):575-9

Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

The authors report the case of a large cranial cavernous hemangioma that was treated using embolization and craniotomy with preservation of the outer cranial table. A 3-year follow-up demonstrated no recurrence. Results in this case suggest that cavernous hemangiomas of the cranium may be safely and effectively treated without craniectomy in some cases.
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http://dx.doi.org/10.3171/2009.7.PEDS09105DOI Listing
December 2009

Identification of Arx transcriptional targets in the developing basal forebrain.

Hum Mol Genet 2008 Dec 16;17(23):3740-60. Epub 2008 Sep 16.

Neuroscience Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Mutations in the aristaless-related homeobox (ARX) gene are associated with multiple neurologic disorders in humans. Studies in mice indicate Arx plays a role in neuronal progenitor proliferation and development of the cerebral cortex, thalamus, hippocampus, striatum, and olfactory bulbs. Specific defects associated with Arx loss of function include abnormal interneuron migration and subtype differentiation. How disruptions in ARX result in human disease and how loss of Arx in mice results in these phenotypes remains poorly understood. To gain insight into the biological functions of Arx, we performed a genome-wide expression screen to identify transcriptional changes within the subpallium in the absence of Arx. We have identified 84 genes whose expression was dysregulated in the absence of Arx. This population was enriched in genes involved in cell migration, axonal guidance, neurogenesis, and regulation of transcription and includes genes implicated in autism, epilepsy, and mental retardation; all features recognized in patients with ARX mutations. Additionally, we found Arx directly repressed three of the identified transcription factors: Lmo1, Ebf3 and Shox2. To further understand how the identified genes are involved in neural development, we used gene set enrichment algorithms to compare the Arx gene regulatory network (GRN) to the Dlx1/2 GRN and interneuron transcriptome. These analyses identified a subset of genes in the Arx GRN that are shared with that of the Dlx1/2 GRN and that are enriched in the interneuron transcriptome. These data indicate Arx plays multiple roles in forebrain development, both dependent and independent of Dlx1/2, and thus provides further insights into the understanding of the mechanisms underlying the pathology of mental retardation and epilepsy phenotypes resulting from ARX mutations.
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http://dx.doi.org/10.1093/hmg/ddn271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581427PMC
December 2008