Frank Ezekiel - Academia.edu (original) (raw)

Papers by Frank Ezekiel

Journal of neuro-AIDS, 2002

We examined event-related potential (ERP) measures of priming in a lexical decision task in which... more We examined event-related potential (ERP) measures of priming in a lexical decision task in which two-thirds of the words were presented as sequential antonym pairs. HIV-1+ subjects were divided into cognitively normal and cognitively impaired subgroups on the basis of a neuropsychological battery. Cognitively impaired HIV-1+ subjects showed reduced priming, associated with reduced N400 ERP component amplitudes, suggesting that the processing of linguistic stimuli in these patients may involve reduced activation of semantic networks. Cognitively normal HIV-1+ subjects showed a reduction in N400 amplitude, but no reduction in performance, suggesting that some reduction in neural signal may occur earlier in the course of HIV-1 central nervous system disease than behavioral priming deficit. As the known neurological deficit in HIV-1 disease is primarily in the basal ganglia and periventricular white matter, we propose that a functional disconnection of subcortical and frontal structure...

AJNR. American journal of neuroradiology, 1999

In subjects with subcortical ischemic vascular dementia (SIVD), tissue vacuolization, myelin pall... more In subjects with subcortical ischemic vascular dementia (SIVD), tissue vacuolization, myelin pallor, and demyelination have been found on pathologic examination of white matter signal hyperintensities (WMSH). Magnetization transfer ratio (MTR) values provide a potential measure of compromised white matter integrity. The purpose of this study was to determine if there were differences in MTR of WMSH between subjects with SIVD and cognitively normal healthy control subjects. Fifteen subjects with SIVD and 16 control subjects of comparable age and sex were studied. MTR images were coregistered to MR images segmented into tissue classes (gray matter, white matter, CSF, WMSH, and lacunar infarcts). MTR of WMSH was compared across groups and examined by WMSH location, size, and total burden. WMSH burden was greater in SIVD patients than in control subjects (2.4% vs 0.67%). MTR of WMSH did not differ between groups, but MTR of periventricular WMSH was lower in SIVD patients than in control...

Journal of the International Neuropsychological Society : JINS, 1997

HIV+ subjects have shown impairment on tests of executive function including automatic attention ... more HIV+ subjects have shown impairment on tests of executive function including automatic attention and verbal tasks. Impairment of semantic priming in HIV patients would suggest a disruption of automatic semantic activation. We examined semantic priming in HIV+ individuals and HIV- control participants with no history of substance abuse, neurologic or psychiatric disorder unrelated to HIV. HIV+ participants were divided into cognitively normal and cognitively impaired subgroups on the basis of a neuropsychological battery of 15 tests. Participants were presented with English words and nonword letter strings and indicated if the stimulus was a word or nonword. The nonwords were orthographically and phonologically correct and were created by rearranging the letter sequence of words ("ulpit"). All words had an obvious antonym ("deep"); two-thirds were presented as sequential antonym pairs ("enter"-"exit"). There were no group differences in speed o...

AJNR. American journal of neuroradiology, 1997

To compare brain tissue in patients with Alzheimer disease with that in elderly control subjects ... more To compare brain tissue in patients with Alzheimer disease with that in elderly control subjects by using high-resolution MR imaging and quantitative tissue-segmentation techniques. MR imaging of the brain was performed in 21 patients with Alzheimer disease and 17 control subjects. A computerized segmentation program was used to quantify volumes of ventricular and sulcal cerebrospinal fluid (CSF), white matter, cortical gray matter, and white matter signal hyperintensity. Statistical analysis was performed using analysis of variance. We found a significant decrease in total brain tissue and cortical gray matter and an increase in the ventricular and sulcal CSF in Alzheimer patients compared with control subjects. There was no difference in the volume of white matter. More white matter signal hyperintensities were found in Alzheimer patients, and a significant interaction between age and group was noted. Neuropsychological test scores correlated significantly with sulcal CSF in patie...

Alzheimer disease and associated disorders

The objectives of this study were to (1) compare atrophy rates associated with normal aging and A... more The objectives of this study were to (1) compare atrophy rates associated with normal aging and Alzheimer disease (AD) using the semi-automated Boundary Shift Integral (BSI) method and manual tracing of the entorhinal cortex (ERC) and hippocampus and (2) calculate power of BSI vs. ERC and hippocampal volume changes for clinical trials in AD. We quantified whole brain and ventricular BSI atrophy rates and ERC and hippocampal atrophy rates from longitudinal MRI data in 20 AD patients and 22 age-matched healthy controls. All methods revealed significant brain atrophy in controls and AD patients. AD patients had approximately 2.5 times greater whole brain BSI atrophy rates and more than 5 times greater ERC and hippocampal atrophy rates than controls. ERC and hippocampal atrophy rates were higher in both groups than whole brain BSI atrophy rates, but lower than ventricular BSI atrophy rates. Effect size and power calculations suggest that ERC and hippocampal measurements may be more sens...

Psychiatry Research: Neuroimaging, 2001

Before using MRI tissue segmentation in clinical studies as a dependent variable or as a means to... more Before using MRI tissue segmentation in clinical studies as a dependent variable or as a means to correct functional data for differential tissue contribution, we must first establish the volume reliability and spatial distribution reproducibility of the segmentation method. Although several reports of volume reliability can be found in the literature, there are no articles assessing the reproducibility of the spatial distribution of tissue. In this report, we examine the validity, volume reliability, and spatial distribution reproducibility for our K-means cluster segmentation. Validation was examined by classifying gray matter, white matter, and CSF on images constructed using an MRI simulator and digital brain phantom, with percentage volume differences of less than 5% and spatial distribution overlaps greater than 0.94 (1.0 is perfect). We also segmented repeat scan MRIs from 10 healthy subjects, with intraclass correlation coefficients greater than 0.92 for cortical gray matter, white matter, sulcal CSF, and ventricular CSF. The original scans were also coregistered to the repeat scan of the same subject, and the spatial overlap for each tissue was then computed. Our overlaps ranged from 0.75 to 0.86 for these tissues. Our results support the use of K-means cluster segmentation, and the use of segmented structural MRIs to guide the analysis of functional and other images. 0 (V.A. Cardenas). 0925-4927/01/$see front matter 0 2001 Elsevier Science Ireland Ltd. All rights resewed. PII: S 0 9 2 5 -4 9 2 7 ( 0 1 )O 0 0 7 5 -0

Neurobiology of Aging, 2004

Background: According to the 'amyloid hypothesis of Alzheimer's disease', ~-amyloid is the primar... more Background: According to the 'amyloid hypothesis of Alzheimer's disease', ~-amyloid is the primary driving force in Alzheimer's disease pathogenesis. Despite the development of many transgenic mouse lines developing abundant [3-amyloid-containing plaques in the brains, the actual link between amyloid plaques and neuron loss has not clearly been established yet as reports on neuron loss in these models have remained controversial. Objective(s): We investigated double-transgenic mice expressing human mutant amyloid precursor protein APP751 (KM670/671NL and V717I) and human mutant presenilin-1 (PS1 M146L) named APP751/PS1, or with the M233T/L235P early onset FAD mutations knocked-in in the presenilin-1 gene named APP751/PSIKL Methods: We used molecularneuropathological methods and unbiased stereologic image analyses. Resuits: We identified substantial age-related neuron loss in the hippocampal pyramidal cell layer of APP751/PS1 double-transgenic mice at 16 months of age. The loss of neurons was observed at sites of A[~ aggregation and surrounding astrocytes but, most importantly, was also clearly observed in areas of the parenchyma distant from plaques. Moreover, the APP75 UPS 1KA mice produce abundant AIM2 with an advanced onset of plaque formation, which correlated to the PS-1 knock-in gene dosage. At the age of six months the mice hemizygous for APP751 and homozygous for PS1KI revealed a dramatic hippocampal neuron loss predominantly in CA1. Before plaque formation, we identified Thioflavin-S positive intraneuronal aggregates, which where also positive for A[3 immunoreactivity in cortical and hippocampal neurons. Predominantly CA1 and subicular pyramidal neurons were affected, however, many other neurons in the cortex were also positive depending on the number of PS1KI alleles. The same held true for the amount of neuron loss in an age related manner. Conclusions: Both models elicit abundant neuron loss in the hippocampus. The APP751/PS1KI mouse model shows major neuropathological hallmarks with abundant neuron loss that is clearly independent from extracelhilar amyloid deposition and identifies intraneuronal A[3 as a major neurotoxic risk factor.

Neurobiology of Aging, 2003

Purpose: The goal of this project was to compare MRI measures of hippocampal, entorhinal cortex (... more Purpose: The goal of this project was to compare MRI measures of hippocampal, entorhinal cortex (ERC), and whole brain longitudinal change in cognitively normal elderly controls (C), non-demented subjects with cognitive impairment (CI), and demented (D) subjects.

Magnetic Resonance in Medicine, 2000

The in vivo neuronal contribution to human cerebral metabolic rate of glucose (CMRglc), measured ... more The in vivo neuronal contribution to human cerebral metabolic rate of glucose (CMRglc), measured by 18 FDG-PET, is unknown. Examining the effect of 1 H MRSI-derived N-acetyl aspartate (NAA) concentration on positron emission tomography (PET) measures of metabolic activity might indicate the relationship of CMRglc to neuron density. In a population of 19 demented, cognitively impaired, and control subjects, the Müller-Gärtner algorithm was applied to whole-brain PET data to isolate the PET signal originating in cortical gray matter alone (GMPET). An analogous procedure applied to multislice proton MRSI data yielded the N-acetyl aspartate concentration in cortical gray matter (GMNAA). In 18 of 19 subjects, a significant linear regression (P < 0.05) resulted when GMPET was plotted against GMNAA, whereby GMPET was higher for higher GMNAA. This suggests that CMRglc rises linearly with increasing neuron density in gray matter. This method may be used to investigate the relationship of CMRglc to neurons in various conditions.

Magnetic Resonance in Medicine, 2001

Quantitative measurements of regional and tissue specific concentrations of brain metabolites wer... more Quantitative measurements of regional and tissue specific concentrations of brain metabolites were measured in elderly subjects using multislice proton magnetic resonance spectroscopic imaging ( 1 H MRSI). Selective k-space extrapolation and an inversion-recovery sequence were used to minimize lipid contamination and linear regression was used to account for partial volume problems. The technique was applied to measure the concentrations of N-acetyl aspartate (NAA), and creatine (Cr)and choline (Cho)-containing compounds in cortical gray and white matter, and white matter lesions of the frontal and the parietal lobe in 40 normal elderly subjects (22 females and 18 males, 56-89 years old, mean age 74 ± 8). NAA was about 15% lower in cortical gray matter and 23% lower in white matter lesions when compared to normal white matter. Cr was 11% higher in cortical gray matter than in white matter, and also about 15% higher in the parietal cortex than in the frontal cortex. Cho was 28% lower in cortical gray matter than in white matter. Furthermore, NAA and Cr changes correlated with age. In conclusion, regional and tissue differences of brain metabolites must be considered in addition to age-related changes when interpreting 1 H MRSI data.

International Congress Series, 2006

The goal of this study was to examine the relationship between subcortical vascular disease and b... more The goal of this study was to examine the relationship between subcortical vascular disease and brain atrophy in patients with Alzheimer's disease (AD) and mixed dementia (i.e., AD and subcortical vascular disease together). MRI was performed on 77 cognitively normal (CN) subjects, 50 AD and 13 mixed dementia patients. Subcortical vascular disease was determined by white matter hyperintensities (WMH) volume and presence of subcortical lacunes. Brain atrophy was measured using total brain cortical gray matter (CGM), entorhinal cortex (ERC) and hippocampal volumes. CGM volume, but not ERC or hippocampal volume was inversely related to WMH volume in patients and controls. In contrast, no relationship was detected between CGM, ERC, or hippocampal volumes and subcortical lacunes. Furthermore, no interaction was found between WMH and diagnosis on cortical atrophy, implying that WMH affect cortical atrophy indifferently of group. These results suggest that subcortical vascular disease, manifested as WMH, may affect cortical atrophy more than ERC and hippocampal atrophy. Further, AD pathology and 0531-5131/ D

IEEE Transactions on Medical Imaging, 2004

This paper examines an alternative approach to separating magnetic resonance imaging (MRI) intens... more This paper examines an alternative approach to separating magnetic resonance imaging (MRI) intensity inhomogeneity from underlying tissue-intensity structure using a direct template-based paradigm. This permits the explicit spatial modeling of subtle intensity variations present in normal anatomy which may confound common retrospective correction techniques using criteria derived from a global intensity model. A fine-scale entropy driven spatial normalisation procedure is employed to map intensity distorted MR images to a tissue reference template. This allows a direct estimation of the relative bias field between template and subject MR images, from the ratio of their low-pass filtered intensity values. A tissue template for an aging individual is constructed and used to correct distortion in a set of data acquired as part of a study on dementia. A careful validation based on manual segmentation and correction of nine datasets with a range of anatomies and distortion levels is carried out. This reveals a consistent improvement in the removal of global intensity variation in terms of the agreement with a global manual bias estimate, and in the reduction in the coefficient of intensity variation in manually delineated regions of white matter.

Alzheimer's & Dementia, 2009

Background: Our objectives were to compare the effects of subcortical ischemic vascular dementia ... more Background: Our objectives were to compare the effects of subcortical ischemic vascular dementia (SIVD) and Alzheimer's disease (AD) on cerebral blood flow (CBF), and then to analyze the relationship between CBF and subcortical vascular disease, measured as volume of white-matter lesions (WMLs). Methods: Eight mildly demented patients with SIVD (mean 6 SD; aged 77 6 8 years; Mini-Mental State Examination score 26 6 3 years) and 14 patients with AD were compared with 18 cognitively normal elderly subjects. All subjects had CBF measured using arterial spin-labeling magnetic resonance imaging, and brain volumes were assessed using structural magnetic resonance imaging. Results: AD and SIVD showed marked CBF reductions in the frontal (P 5 0.001) and parietal (P 5 0.001) cortices. In SIVD, increased subcortical WMLs were associated with reduced CBF in the frontal cortex (P 5 0.04), in addition to cortical atrophy (frontal, P 5 0.05; parietal, P 5 0.03). Conclusions: Subcortical vascular disease is associated with reduced CBF in the cortex, irrespective of brain atrophy.

Alzheimer Disease & Associated Disorders, 2006

Previous magnetic resonance (MR) spectroscopy studies of Alzheimer disease (AD) reporting reduced... more Previous magnetic resonance (MR) spectroscopy studies of Alzheimer disease (AD) reporting reduced N-acetyl aspartate (NAA) and increased myo-Inositol (mI) used single voxel techniques, which have limited ability to assess the regional distribution of the metabolite abnormalities. The objective of this study was to determine the regional distribution of NAA and mI alterations in AD by using MR spectroscopic imaging. Fourteen patients with AD and 22 cognitively normal elderly were studied using structural MR imaging and MR spectroscopic imaging. Changes of NAA, mI, and various metabolite ratios were measured in frontal and parietal lobe gray matter (GM) and white matter. This study found: (1) when compared with cognitively normal subjects, AD patients had increased mI and mI/creatine (Cr) ratios primarily in parietal lobe GM, whereas frontal lobe GM and white matter were spared; (2) in the same region where mI was increased, AD patients had also decreased NAA and NAA/Cr ratios, replicating previous findings; (3) however, increased mI or mI/ Cr ratios did not correlate with decreased NAA or NAA/Cr ratios; and (4) using mI/Cr and NAA/Cr together improved sensitivity and specificity to AD from control as compared with NAA/Cr alone. In conclusion, decreased NAA and increased mI in AD are primarily localized in parietal lobe GM regions. However, the NAA and mI changes are not correlated with each other, suggesting that they represent different processes that might help staging of AD.

Alcoholism: Clinical and Experimental Research, 1995

We used computer-aided magnetic resonance image analysis and an age-normed battery of neuropsycho... more We used computer-aided magnetic resonance image analysis and an age-normed battery of neuropsychological tests to measure brain atrophy and cognitive function in 14 older abstinent alcoholic men and 11 older controls in the expectation that these subject groups would show the greatest and most persistent cerebral effects consequent to chronic alcoholism. The abstinent alcoholics exhibited cognitive impairments (primarily in memory and visual-spatial-motor skills) compared with the controls. In contrast, we found no difference in global cerebral atrophy between the groups, although two alcoholics had extensive atrophy compared with all other subjects. However, there was a stronger association between age and ventricular dilation in the alcoholic sample compared with controls. We conclude that a substrate other than magnetic resonance imagingdetectable global atrophy must underlie the persistent cognitive impairments evident in the sampled alcoholics. Furthermore, if there are global atrophic changes in the brain associated with chronic alcoholism, these effects are not ubiquitous and/or may be reversible in most patients with sufficient abstinence.

Alcoholism: Clinical and Experimental Research, 2006

Background-Although approximately 80% of individuals with alcohol use disorders are chronic smoke... more Background-Although approximately 80% of individuals with alcohol use disorders are chronic smokers and despite reported associations between chronic cigarette smoking and lower cerebral perfusion in nonalcoholics, previous brain perfusion studies with alcoholics did not account for the potential effects of concurrent chronic cigarette smoking.

Addiction Biology, 1999

Chronic abuse of cocaine or alcohol is associated with structural, neuropathological and cognitiv... more Chronic abuse of cocaine or alcohol is associated with structural, neuropathological and cognitive impairments that have been documented extensively. Little is known, however, about neurobiochemical changes in chronic substance abusers. We performed MRI and multi-slice brain proton magnetic resonance spectroscopic imaging (MRSI) to assess neuronal viability (via Nacetylaspartate (NAA)) and white matter metabolite status in 22 4-months-abstinent individuals dependent on crack cocaine only and on both crack cocaine and alcohol. Compared to 11 nondependent controls we found (1) significantly lower NAA measures in the dorsolateral prefrontal cortex of the combined cocaine-dependent groups; (2) comparable spatial distribution and magnitude of these NAA effects for both cocaine-dependent groups; (3) higher choline-containing metabolites in frontal white matter of individuals dependent on both cocaine and alcohol; (4) absence of brain atrophy in both abstinent cocaine-dependent samples; and (5) partial recovery from prefrontal cortical NAA loss, primarily with abstinence from alcohol. The MRSI findings suggest preferential neuronal damage to the frontal cortex of both cocaine-dependent samples and gliosis in frontal white matter of individuals dependent on both alcohol and cocaine, conditions that persist for more than 4 months of abstinence.

Fig 2. (A) 1 H single voxel spectrum; (B) E 1 spectrum after B 0 , phase and baseline correction.