Biomedical subjects

Gary W Small

Publications and source records attributed to Gary W Small.

At least 19 recordsLinked to original sources

PubMed2006

PET of brain amyloid and tau in mild cognitive impairment.

BACKGROUND: Amyloid senile plaques and tau neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease that accumulate in the cortical regions of the brain in persons with mild cognitive impairment who are at risk for Alzheimer's disease. Noninvasive methods to detect these abnormal proteins are potentially useful in developing surrogate markers for drug discovery and diagnostics. METHODS: We enrolled 83 volunteers with self-reported memory problems who had undergone neurologic and psychiatric evaluation and positron-emission tomography (PET). On the basis of cognitive testing, 25 volunteers were classified as having Alzheimer's disease, 28 as having mild cognitive impairment, and 30 as having no cognitive impairment (healthy controls). PET was performed after injection of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to plaques and tangles in vitro. All subjects also underwent 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET, and 72 underwent magnetic resonance imaging (MRI). RESULTS: Global values for FDDNP-PET binding (average of the values for the temporal, parietal, posterior cingulate, and frontal regions) were lower in the control group than in the group with mild cognitive impairment (P<0.001), and the values for binding in the group with mild cognitive impairment were lower than in the group with Alzheimer's disease (P<0.001). FDDNP-PET binding differentiated among the diagnostic groups better than did metabolism on FDG-PET or volume on MRI. CONCLUSIONS: FDDNP-PET scanning can differentiate persons with mild cognitive impairment from those with Alzheimer's disease and those with no cognitive impairment. This technique is potentially useful as a noninvasive method to determine regional cerebral patterns of amyloid plaques and tau neurofibrillary tangles.

Aged↗

PubMed2006

Serotonin 1A receptors in the living brain of Alzheimer's disease patients.

4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide, a selective serotonin 1A (5-HT(1A)) molecular imaging probe, was used in conjunction with positron emission tomography (PET) for quantification of 5-HT(1A) receptor densities in the living brains of Alzheimer's disease patients (ADs) (n = 8), subjects with mild cognitive impairment (n = 6), and controls (n = 5). ADs had receptor densities significantly decreased in both hippocampi (binding potential: controls 1.62 +/- 0.07; ADs 1.18 +/- 0.26) and also in raphe nuclei (controls 0.63 +/- 0.09; ADs 0.37 +/- 0.20). When volume losses are included, 5-HT(1A) losses are even more severe (i.e., average mean decreases of 24% in mild cognitive impairment patients and 49% in ADs). A strong correlation of 5-HT(1A) receptor decreases in hippocampus with worsening of clinical symptoms (Mini Mental State Exam scores) was also found. Moreover, these decreases in 5-HT(1A) receptor measures correlate with decreased glucose utilization as measured with 2-deoxy-2-[F-18]fluoro-d-glucose PET in the brains of ADs (standardized uptake values; globally: controls 0.89 +/- 0.04, ADs 0.72 +/- 0.04; posterior cingulate gyrus: controls 1.05 +/- 0.09, ADs 0.79 +/- 0.11). They also inversely correlate with increased neuropathological loads measured with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile PET in several neocortical regions in the same subjects. The in vivo observations were confirmed independently by in vitro digital autoradiography with 4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide and 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile on brain tissue specimens from two ADs and three nondemented subjects.

Alzheimer Disease↗

PubMed2006

Visualizing pathology deposits in the living brain of patients with Alzheimer's disease.

One of the major neuropathological changes characteristic of Alzheimer's disease (AD) are deposits of beta-amyloid plaques and neurofibrillary tangles in neocortical and subcortical regions of the AD brain. The histochemical detection of these lesions in postmortem brain tissue is necessary for definitive diagnosis of AD. Methods for their in vivo detection would greatly aid the diagnosis of AD in early stages when neuronal loss and related functional impairment are still limited and also open the opportunity for effective therapeutic interventions. Positron emission tomography (PET) using an appropriate radiolabeled imaging probe with high binding affinity for these lesions is one of such techniques. We have developed 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([F-18]FDDNP), a naphthalene-based radiofluorinated PET imaging probe with binding affinity for amyloid and amyloid-like structures, and applied it for in vivo brain imaging of patients with Alzheimer's disease and cognitively normal controls with PET. Analysis of in vivo [F-18]FDDNP imaging data using Logan plot graphical analysis with the cerebellum as a reference region was performed, and the binding levels in several areas of neocortex were determined. We observed increased levels of [F-18]FDDNP binding in patients in several neocortical regions in Alzheimer's disease compared with the cerebellum. In contrast, control subjects have uniformly low levels of [F-18]FDDNP binding in all areas, which is comparable to that of cerebellum.

Alzheimer Disease↗

PubMed2006

Effects of a 14-day healthy longevity lifestyle program on cognition and brain function.

OBJECTIVE: The objective of this study was to determine the effects of a 14-day healthy longevity lifestyle program on cognition and cerebral metabolism in people with mild age-related memory complaints. METHODS: Seventeen nondemented subjects, aged 35-69 years (mean: 53 years, standard deviation: 10) with mild self-reported memory complaints but normal baseline memory performance scores were randomly assigned to 1) the intervention group (N = 8): a program combining a brain healthy diet plan, relaxation exercises, cardiovascular conditioning, and mental exercise (brain teasers and verbal memory training techniques); or 2) the control group (N = 9): usual lifestyle routine. Pre- and postintervention measures included self-assessments of memory ability, objective tests of cognitive performance, and determinations of regional cerebral metabolism during mental rest with [fluorine-18]fluorodeoxyglucose (FDG) positron emission tomography (PET). RESULTS: Subjects in the intervention group objectively demonstrated greater word fluency. Concomitantly, their FDG-PET scans identified a 5% decrease in activity in the left dorsolateral prefrontal cortex. The control group showed no significant change in any of the measures. CONCLUSIONS: A short-term healthy lifestyle program combining mental and physical exercise, stress reduction, and healthy diet was associated with significant effects on cognitive function and brain metabolism. Reduced resting activity in left dorsolateral prefrontal cortex may reflect greater cognitive efficiency of a brain region involved in working memory.

Adult↗

PubMed2006

Seeing is believing: neuroimaging adds to our understanding of cerebral pathology.

PURPOSE OF REVIEW: Recent technological developments in neuroimaging have led to new technologies that provide measures of the cerebral pathology of neurodegeneration in living humans. The purpose of this review is to provide background behind these developments and update readers on new findings. RECENT FINDINGS: Several imaging methods using positron emission tomography have provided measures of amyloid senile plaques in the brain of demented patients and patients with early memory symptoms. ([F-18]FDDNP)-positron emission tomography provides measures of both amyloid plaques and neurofibrillary tangles. Initial results indicate that the pattern of binding values in Alzheimer's disease is consistent with the known neuropathology from autopsy studies, and patients with mild cognitive impairment, who are at risk of Alzheimer's disease, show binding values intermediate between Alzheimer's disease and normal aging. 2-(1-{6-[(2-[F-18]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([F-18]FDDNP) positron emission tomography also shows a pattern of neuropathology distribution for frontotemporal dementia that differs from that of Alzheimer's disease. SUMMARY: In-vivo imaging of cerebral pathology offers the potential for more effective and earlier diagnosis and use of these technologies as surrogate markers to test novel treatments aimed at preventing or eliminating cerebral plaque and tangle accumulation.

Aging↗

PubMed2006

Diagnostic issues in dementia: neuroimaging as a surrogate marker of disease.

Structural neuroimaging is a routine component of the diagnostic evaluation of dementia that is used to rule out potential causes of mental impairment, whereas functional imaging can differentiate different forms of dementia. Neuroimaging also offers promise as a surrogate marker for clinical trials, and new technologies have been developed to provide measures of amyloid plaques and neurofibrillary tangles, the neuropathological hallmarks of Alzheimer's disease. Combining imaging with genetic risk data will likely improve diagnostic accuracy. These new findings warrant reconsideration of current guidelines on the use of neuroimaging in diagnosis and research in dementia.

Aged↗

PubMed2005

Noninvasive glucose sensing.

The ability to measure glucose noninvasively in human subjects is a major objective for many research groups. Success will revolutionize the treatment of diabetes by providing a means to improve glycemic control, thereby delaying the onset of the medical complications associated with this disease. This article focuses on the current state of the art and attempts to identify the principal areas of research necessary to advance the field. Two fundamentally different approaches are identified for the development of noninvasive glucose sensing technology. The indirect approach attempts to measure glucose on the basis of its effect on a secondary process. The direct approach is based on the unique chemical structure of the glucose molecule. Advances for each approach are limited by issues of selectivity. Several critical parameters are discussed for the direct approach, including issues related to the optical path length, wavelength range, dimensionality of the multivariate calibration model, net analyte signal, spectral variance, and assessment of the chemical basis of measurement selectivity. A set of publication standards is recommended as a means to enhance progress toward a successful noninvasive monitor.

Animals↗

PubMed2005

Efficacy of rivastigmine in Alzheimer's disease patients with rapid disease progression: results of a meta-analysis.

BACKGROUND: Alzheimer's disease (AD) patients experiencing more rapid symptom progression are likely to have a poorer prognosis than those experiencing slow symptom progression. In a recent retrospective analysis, treatment effects of rivastigmine were more pronounced in AD patients with rapid cognitive decline than in those with slow cognitive decline. This warranted further investigation. METHODS: Rapidly and slowly progressing patients were identified by rates of cognitive decline [>/=4 points and <4 points, respectively, on the Alzheimer's Disease Assessment Scale -- cognitive subscale (ADAS-cog)] during 26 weeks of placebo treatment in four randomized controlled trials (weeks 0--26). This meta-analysis evaluated rates of cognitive decline in both subgroups during subsequent open-label rivastigmine 26-week extension studies (weeks 26--52). A longitudinal mixed effects model compared cognitive decline in rapidly and slowly progressing patients, including correction for possible regression to the mean. RESULTS: 180 (75%) rapidly and 337 (78%) slowly progressing patients provided ADAS-cog data after 26 weeks of open-label rivastigmine treatment. Improvements in cognitive symptoms were observed during the first 12 weeks, which were more pronounced in patients with rapid progression than in those with slow progression. Rapidly progressing patients experienced significantly greater cognitive benefits than slowly progressing patients (p=0.029), who experienced a modest decline in cognitive symptoms at the end of the study. COMMENT: Patients experiencing rapid symptom progression may receive greater benefit from rivastigmine than those with slow progression. In this study, cholinesterase inhibition appeared to be of particular utility in the management of AD patients whose symptoms were rapidly worsening.

Alzheimer Disease↗

PubMed2005

Scattering and absorption effects in the determination of glucose in whole blood by near-infrared spectroscopy.

Optical properties of whole bovine blood are examined under conditions of different glucose loadings. A strong dependency is established between the scattering properties of the whole blood matrix and the concentration of glucose. This dependency is explained in terms of variations in the refractive index mismatch between the scattering bodies (predominately red blood cells) and the surrounding plasma. Measurements in the presence of a well-known glucose transport inhibitor indicate that variations in refractive index mismatch are related to the penetration of glucose into the red blood cells and demonstrate that increased scattering involves the uptake of glucose by red blood cells. Finally, multivariate calibration models are presented for the measurement of glucose in a whole blood matrix. These models are based on near-infrared spectral data collected from 80 different samples prepared from a single whole blood matrix. Calibration studies are performed over the combination, first-overtone, and short-wavelength spectral regions. The best calibration model is generated from combination region spectra, providing a standard error of prediction (SEP) of less than 1 mM over the concentration range of 3-30 mM. The model based on the first-overtone region is slightly degraded but still provides acceptable performance (SEP = 1.20 mM). The model based on the short-wavelength region is further degraded (SEP = 2.53 mM). To rationalize these results, an analysis of the selectivity of the calibration models is performed by computing the glucose net analyte signal. It is established that the models based on the combination and first-overtone regions are dominated by glucose absorption information, while the model computed from the short-wavelength region is based primarily on scattering information. This result provides evidence that absorption information is needed in order to obtain a glucose calibration model with acceptable performance.

Animals↗

PubMed2005

Object naming and semantic fluency among individuals with genetic risk for Alzheimer's disease.

OBJECTIVES: This study longitudinally examined the object naming and semantic fluency of individuals who are at risk for developing Alzheimer's disease (AD) by virtue of having APOE-4 or a family history of AD. METHODS: A total of 108 participants (40 with a family history of AD and 43 with APOE-4) completed the Boston Naming Test and the Animal Naming task at initial assessment and after two years. RESULTS: At baseline, object naming was significantly lower for those with both risk factors, F(2, 99) = 5.72, p < 0.01, but those with either risk factor had significantly lower scores at follow-up, F(2, 99) = 3.41, p < 0.05. Semantic fluency (animal naming) was reduced among subjects with the APOE-4 allele at baseline, F(1, 100) = 4.02, p < 0.05, but it was not associated with either risk factor at follow-up. CONCLUSIONS: These deficits may be associated with a prodromal risk for AD and may serve as pre-symptomatic markers for the development of AD.

Aged↗

PubMed2005

Estrogen use and brain metabolic change in postmenopausal women.

OBJECTIVE: We used positron emission tomography to evaluate cerebral glucose metabolic change in postmenopausal women in a naturalistic observational study. METHOD: Women estrogen users (n = 11) and non-users (n = 9) were studied at baseline and 2 years later. Analyses focused on glucose metabolism in regions previously reported to decline in older persons at risk for Alzheimer's disease (AD) (posterior cingulate and lateral temporal cortex). RESULTS: Region of interest (ROI) analysis at baseline showed no regional differences between women estrogen users and non users. ROI follow-up analysis revealed that women non-users declined significantly in the posterior cingulate cortex (P= 0.04). Statistical parametric mapping (SPM) analysis confirmed a significant decrease in metabolism of the posterior cingulate cortex among non-users at 2-year follow-up (P = 0.004). In contrast, women estrogen users did not exhibit significant metabolic change in the posterior cingulate. CONCLUSIONS: Estrogen use may preserve regional cerebral metabolism and protect against metabolic decline in postmenopausal women, especially in posterior cingulate cortex, the region of the brain found to decline in the earliest stages of AD.

Aged↗

PubMed2005

Imaging beta-amyloid fibrils in Alzheimer's disease: a critical analysis through simulation of amyloid fibril polymerization.

The polymerization of beta-amyloid (A beta) peptides into fibrillary plaques is implicated, in part, in the pathogenesis of Alzheimer's disease. A beta molecular imaging probes (A beta-MIPs) have been introduced in an effort to quantify amyloid burden or load, in subjects afflicted with AD by invoking the classic PET receptor model for the quantitation of neuronal receptor density. In this communication, we explore conceptual differences between imaging the density of amyloid fibril polymers and neuronal receptors. We formulate a mathematical model for the polymerization of A beta with parameters that are mapped to biological modulators of fibrillogenesis and introduce a universal measure for amyloid load to accommodate various interactions of A beta-MIPs with fibrils. Subsequently, we hypothesize four A beta-MIPs and utilize the fibrillogenesis model to simulate PET tissue time activity curves (TACs). Given the unique nature of polymer growth and resulting PET TAC, the four probes report differing amyloid burdens for a given brain pathology, thus complicating the interpretation of PET images. In addition, we introduce the notion of an MIP's resolution, apparent maximal binding site concentration, optimal kinetic topology and its resolving power in characterizing the pathological progression of AD and the effectiveness of drug therapy. The concepts introduced in this work call for a new paradigm that goes beyond the classic parameters B(max) and K(D) to include binding characteristics to polymeric peptide aggregates such as amyloid fibrils, neurofibrillary tangles and prions.

Alzheimer Disease↗

PubMed2004

Comparison of combination and first overtone spectral regions for near-infrared calibration models for glucose and other biomolecules in aqueous solutions.

Partial least squares calibration models are compared for the measurement of glucose, lactate, urea, ascorbate, triacetin, and alanine in aqueous solutions from single-beam spectra collected over the first overtone (6500-5500 cm(-1)) and the combination (5000-4000 cm(-1)) regions of the near-infrared spectrum. Spectra are collected under two sets of conditions with one designed for combination spectra and the other designed for first overtone spectra. As part of the optimization of conditions, an exponential function is presented that accurately characterizes the strong dependency between spectral quality and sample thickness. Sample thickness set for the first overtone and combination spectra are 7.5 and 1.5 mm, respectively. Independent calibration models are established for each solute from both combination and first overtone spectra. Direct comparison reveals superior performance by models generated from combination spectra, particularly for glucose and urea. Standard error of prediction (SEP) values are 1.12 and 0.45 mM for glucose models generated from first overtone and combination spectra, respectively. SEP values for urea are 7.33 and 0.10 mM for first overtone and combination spectra, respectively. Such high SEP values for urea with first overtone spectra correspond to an inability to quantify urea from these spectra because of a lack urea-specific molecular absorption features in this spectral region. Net analyte signal (NAS) is used to quantify the degree of selectivity provided within the first overtone and combination spectral regions. The superior selectivity of combination spectra is confirmed by comparing the length of the NAS vectors for each matrix component.

Calibration↗

PubMed2004

Analysis of European mitochondrial haplogroups with Alzheimer disease risk.

We examined the association of mtDNA variation with Alzheimer disease (AD) risk in Caucasians (989 cases and 328 controls) testing the effect of individual haplogroups and single nucleotide polymorphisms (SNPs). Logistic regression analyses were used to assess risk of haplogroups and SNPs with AD in both main effects and interaction models. Males classified as haplogroup U showed an increase in risk (OR = 2.30; 95% CI, 1.03-5.11; P = 0.04) of AD relative to the most common haplogroup H, while females demonstrated a significant decrease in risk with haplogroup U (OR = 0.44 ; 95% CI, 0.24-0.80; P = 0.007). Our results were independent of APOE genotype, demonstrating that the effect of mt variation is not confounded by APOE4 carrier status. We suggest that variations within haplogroup U may be involved in AD expression in combination with environmental exposures or nuclear proteins other than APOE.

Aged↗

PubMed2004

Pure component selectivity analysis of multivariate calibration models from near-infrared spectra.

A novel procedure is proposed as a method to characterize the chemical basis of selectivity for multivariate calibration models. This procedure involves submitting pure component spectra of both the target analyte and suspected interferences to the calibration model in question. The resulting model output is analyzed and interpreted in terms of the relative contribution of each component to the predicted analyte concentration. The utility of this method is illustrated by an analysis of calibration models for glucose, sucrose, and maltose. Near-infrared spectra are collected over the 5000-4000-cm(-)(1) spectral range for a set of ternary mixtures of these sugars. Partial least-squares (PLS) calibration models are generated for each component, and these models provide selective responses for the targeted analytes with standard errors of prediction ranging from 0.2 to 0.7 mM over the concentration range of 0.5-50 mM. The concept of the proposed pure component selectivity analysis is illustrated with these models. Results indicate that the net analyte signal is solely responsible for the selectivity of each individual model. Despite strong spectral overlap for these simple carbohydrates, calibration models based on the PLS algorithm provide sufficient selectivity to distinguish these commonly used sugars. The proposed procedure demonstrates conclusively that no component of the sucrose or maltose spectrum contributes to the selective measurement of glucose. Analogous conclusions are possible for the sucrose and maltose calibration models.

Calibration↗

PubMed2004

What does imaging add to the management of Alzheimer's disease?

The prevalence of Alzheimer's disease (AD) and dementia continues to rise. However, a significant number of patients are undiagnosed or untreated. Given the complexities of detecting cognitive impairment and the early signs of AD, this review discusses how advances in brain imaging can help assist in improving overall management. Imaging techniques and surrogate markers may provide unique opportunities to diagnose accurately AD in presymptomatic stages with practical consequences for patients, caregivers, and physicians. The possible outcomes for using imaging and surrogate markers as adjuncts to clinical examination and as screening tools for AD, as well as tangible and intangible advantages to early diagnosis and treatment, will be discussed. The specific value of using advanced serial imaging in patients with a genetic disposition to AD will be evaluated. If neurons can be protected from neurodegenerative damage in early stages, this may preserve patient cognition, function, and quality of life, and may confer considerable societal healthcare benefits.

Adult↗

PubMed2004

Neuroimaging as a diagnostic tool in dementia with Lewy bodies.

Due to similar presenting symptoms, many physicians find it difficult to distinguish cases of dementia with Lewy bodies (DLB) from Alzheimer's disease or Parkinson's disease with dementia. The pathologic diagnosis of DLB has improved because of the discovery of probes for alpha-synuclein, a protein found in Lewy bodies. However, pathologic diagnosis can be employed postmortem only, and therefore diagnostic techniques that can be employed to guide patient management are still needed. Consensus criteria have been developed for establishing a clinical diagnosis of DLB, but they lack sensitivity. Therefore, a review of the recent literature was conducted to establish whether neuroimaging studies are useful diagnostic tools to help differentiate these syndromes. At least six types of tests can be used to image the brain of patients with dementia. Structural studies (x-ray, magnetic resonance imaging and computerized tomography) can disclose the presence of stroke sequelae and other lesions, whereas functional studies (magnetic resonance spectroscopy, positron emission tomography and single-photon emission computed tomography) can disclose metabolic and blood flow alterations that may be characteristic for different types of dementia. Although more formal studies are needed to confirm that these imaging techniques are reliable diagnostic tools for DLB and permit the establishment of guidelines for their use, neuroimaging techniques currently are being employed in practice to differentiate dementia types as a guide to treatment.

Acetylcholinesterase↗

PubMed2004

Digital filtering implementations for the detection of broad spectral features by direct analysis of passive Fourier transform infrared interferograms.

Finite impulse response (FIR) filters and finite impulse response matrix (FIRM) filters are evaluated for use in the detection of volatile organic compounds with wide spectral bands by direct analysis of interferogram data obtained from passive Fourier transform infrared (FT-IR) measurements. Short segments of filtered interferogram points are classified by support vector machines (SVMs) to implement the automated detection of heated plumes of the target analyte, ethanol. The interferograms employed in this study were acquired with a downward-looking passive FT-IR spectrometer mounted on a fixed-wing aircraft. Classifiers are trained with data collected on the ground and subsequently used for the airborne detection. The success of the automated detection depends on the effective removal of background contributions from the interferogram segments. Removing the background signature is complicated when the analyte spectral bands are broad because there is significant overlap between the interferogram representations of the analyte and background. Methods to implement the FIR and FIRM filters while excluding background contributions are explored in this work. When properly optimized, both filtering procedures provide satisfactory classification results for the airborne data. Missed detection rates of 8% or smaller for ethanol and false positive rates of at most 0.8% are realized. The optimization of filter design parameters, the starting interferogram point for filtering, and the length of the interferogram segments used in the pattern recognition is discussed.

Journal Article↗