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Gary W Small

Publications and source records attributed to Gary W Small.

At least 19 recordsLinked to original sources
PubMed2003

The Q7R Saitohin gene polymorphism is not associated with Alzheimer disease.

Previous studies have reported conflicting results regarding the association of the Q7R polymorphism in the Saitohin gene with late-onset Alzheimer disease (AD). Given that AD is a tauopathy but no mutations or polymorphisms in Tau have been consistently associated with AD, and that Saitohin is nested in intron 9 of Tau and shares a similar expression pattern, we tested this association in 690 multiplex AD families and in a case-control sample (903 patients and 320 controls). We found no evidence of significant association of this polymorphism with risk of AD using family-based and case-control tests of association.

Alzheimer Disease↗
PubMed2003

Robust classifier for the automated detection of ammonia in heated plumes by passive fourier transform infrared spectrometry.

An automated classification algorithm is implemented for the detection of ammonia vapor in heated plumes by passive Fourier transform infrared (FT-IR) spectrometry. This classification methodology allows the real-time detection of chemical signatures in gaseous effluents such as those generated from industrial processes. The characteristics of real-time implementation and excellent robustness are achieved by an analysis strategy based on the application of band-pass digital filters to short segments of the interferogram data collected by the FT-IR spectrometer, followed by the use of piecewise linear discriminant analysis to obtain a yes/no classification regarding the presence of the analyte signature in the filtered data. The optimal classifier developed through this work is based on only 110 interferogram points and employs a single band-pass filter centered at 945 cm(-)(1) with a pass-band full width at half-maximum of 93 cm(-)(1). The average stop-band attenuation of the optimal filter is 42.1 dB. The robustness of the algorithm is tested by exposing it to chemical releases of sulfur hexafluoride, ethanol, methanol, sulfur dioxide, and hydrogen chloride that were not included in the development of the classifier. Excellent classification performance is demonstrated, with missed ammonia detections occurring at a rate of approximately 1%. The occurrence of false detections is less than 0.1% for SF(6) and less than 0.02% for the other interferences tested.

Air Pollutants, Occupational↗
PubMed2003

Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease.

Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34-0.91; P=.02) or K (OR 0.52; 95% CI 0.30-0.90; P=.02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39-0.73; P=.0001). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27-0.71; P=.0009). In addition, SNP 9055A of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22-0.93; P=.03). Our results suggest that ND3 is an important factor in PD susceptibility among white individuals and could help explain the role of complex I in PD expression.

DNA, Mitochondrial↗
PubMed2003

Association study of Parkin gene polymorphisms with idiopathic Parkinson disease.

BACKGROUND: Previously, we detected linkage of idiopathic Parkinson disease (PD) to the region on chromosome 6 that contains the Parkin gene (D6S305; logarithm of odds score, 5.47) in families with at least one individual with age at onset younger than 40 years (families with early-onset disease). Further study demonstrated the presence of Parkin mutations in this data set. However, previous case-control studies have reported conflicting results regarding the role of more common Parkin polymorphisms as susceptibility alleles for idiopathic PD. OBJECTIVE: To investigate the association of 7 previously studied Parkin single-nucleotide polymorphisms (SNPs) throughout the promoter and most of the open reading frame with PD in a large cohort of patients with primarily late-onset PD. METHODS: One promoter, 3 intronic, and 3 exonic Parkin SNPs were genotyped in 1580 individuals belonging to 397 families, and their association with PD was evaluated using family-based association tests. RESULTS: No significant association (P>.05) between PD and any Parkin SNP allele or genotype was detected. Haplotype analysis and stratification by age at onset or family history also failed to produce significant results. CONCLUSIONS: These results suggest that these common variants of Parkin are not associated with PD in white patients, although Parkin mutations are known to cause early- and late-onset PD.

Adolescent↗
PubMed2003

Parkin mutations and susceptibility alleles in late-onset Parkinson's disease.

Parkin, an E2-dependent ubiquitin protein ligase, carries pathogenic mutations in patients with autosomal recessive juvenile parkinsonism, but its role in the late-onset form of Parkinson's disease (PD) is not firmly established. Previously, we detected linkage of idiopathic PD to the region on chromosome 6 containing the Parkin gene (D6S305, logarithm of odds score, 5.47) in families with at least one subject with age at onset (AAO) younger than 40 years. Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early-onset and 2% of late-onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late-onset form of Parkinson disease.

Adolescent↗
PubMed2003

An open-label extension trial of galantamine in patients with probable vascular dementia and mixed dementia.

BACKGROUND: Alzheimer's disease (AD) and vascular dementia (VaD) are the most common types of dementia worldwide. Galantamine, an acetylcholinesterase inhibitor and allosteric nicotinic modulator, has shown broad clinical benefits in patients with mild to moderate dementia due to AD, probable VaD, or AD with cerebrovascular disease (CVD)-so-called mixed dementia. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety profiles of galantamine 24 mg/d in patients with VaD or AD with CVD over the longer term (>6 months). METHODS: This was an open-label extension of a 6-month double-blind study of galantamine. Patients who had been randomized to receive galantamine 24 mg/d or placebo in the double-blind phase were eligible to continue open-label treatment with galantamine 24 mg/d for 6 months. The primary efficacy end point was change in cognition, based on scores on the 11-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog/11). Secondary measures included changes in functional ability (as measured on the Disability Assessment for Dementia [DAD]) and behavior (as measured on the Neuropsychiatric Inventory [NPI]). Safety and tolerability were also monitored. RESULTS: Four hundred fifty-nine patients (240 men, 219 women; mean [SE] age, 75.2 [0.33] years) entered the open-label phase. Of these patients, 195 (42.5%) had a diagnosis of probable VaD, and 238 (51.9%) had a diagnosis of AD with CVD; the remainder had an inconclusive diagnosis. At month 12 of the study, improvements from baseline (the start of the double-blind phase) in ADAS-cog/11 scores were observed in both the group that received placebo during the double-blind phase (placebo/galantamine group: -0.3 point; 95% CI, -1.64 to 1.06) and the group that received galantamine during the double-blind phase (galantamine/galantamine group: -0.9 point; 95% CI, -1.73 to 0.03). Improvement in functional ability was demonstrated by statistically significant mean (SE) changes from baseline in DAD score in both the placebo/galantamine group (-7.4 [1.68]; P < or = 0.001) and the galantamine/galantamine group (-3.6 [1.33]; P < or = 0.01). There was no significant change in mean (SE) NPI scores in either group (0.2 [0.98] and 0.1 [0.70], respectively). Galantamine treatment was well tolerated. CONCLUSIONS: In these patients with VaD and AD with CVD, galantamine treatment produced similar sustained benefits in terms of maintenance of or improvement in cognition (ADAS-cog/11), functional ability (DAD), and behavior (NPI) after 12 months.

Aged↗
PubMed2003

MMSE items predict cognitive decline in persons with genetic risk for Alzheimer's disease.

Performance on individual Mini-Mental State Examination (MMSE) items can predict incident Alzheimer's disease (AD). The purpose of the current study is to determine whether, in nondemented persons with and without the apolipoprotein E-4 (APOE-4) genetic risk for AD, a subset of MMSE items predict cognitive decline. Fifty-four nondemented subjects, 23 with at least one copy of the APOE-4 allele and 31 without APOE-4, were given the MMSE and cognitive tests at baseline and 2-year follow-up. MMSE total score and a subset of MMSE items including delayed recall, serial 7s, pentagon, and orientation to time and place were used to predict change on cognitive tests. The subset of MMSE items significantly predicted decline in visuo-spatial construction and naming in APOE-4 carriers but not in noncarriers. Performance on a subset of MMSE items, combined with APOE-4 genotype, may aid in identifying high-risk persons for research or follow-up.

Aged↗
PubMed2002

Use of neuroimaging to detect early brain changes in people at genetic risk for Alzheimer's disease.

The neuropathological and cognitive changes preceding Alzheimer's disease appear to begin subtly decades before symptoms of the disease make the clinical diagnosis obvious. Clinical trials have begun to focus on preventive treatments designed to slow age-related cognitive decline and delay the onset of Alzheimer's disease in people with only mild memory complaints. Because people with few cognitive deficits represent a heterogeneous population, prevention studies require large samples in order to detect active drug effects. To address such challenges, recent neuroimaging studies have focused on middle-aged and older adults with only mild memory complaints and evaluated results according to the major known genetic risk for Alzheimer's disease, the apolipoprotein E-4 (APOE-4) allele. In studies using positron emission tomography during mental rest and functional magnetic resonance imaging during memory task performance, brain patterns differ according to genetic risk and are useful in predicting future decline measures and following disease progression in clinical trials.

Alzheimer Disease↗
PubMed2002

Calibration standardization algorithm for partial least-squares regression: application to the determination of physiological levels of glucose by near-infrared spectroscopy.

Calibration standardization methodology for near-infrared (near-IR) spectroscopy is described for updating a partial least-squares calibration model to take into account changes in instrumental response. The guided model reoptimization (GMR) algorithm uses a transfer set of eight samples to characterize the new response and a database of previously acquired spectra used to develop the original calibration model. The samples in the transfer set need not have been measured under the old instrumental conditions, making the algorithm compatible with samples that change over time. The spectra comprising the transfer set are used to guide an iterative optimization procedure that (1) finds an optimal subset of samples from the original database to use in computing the updated model and (2) finds an optimal set of weights to apply to the spectral resolution elements in order to minimize the effects of instrumental changes on the computed model. The optimization relies on an alternating grid search and stepwise addition/deletion steps. The algorithm is evaluated through the use of combination region near-IR spectra to determine physiological levels of glucose in a synthetic biological matrix containing bovine serum albumin and triacetin in phosphate buffer. The ability to update a calibration to account for changes in the response of a Fourier transform spectrometer over four to six years is examined in this study. Separate spectral databases collected in 1994 and 1996 are used with a transfer set and separate test set of spectra collected in 2000. With the 1994 database, the standardization algorithm achieves a standard error of prediction (SEP) of 0.69 mM for the 2000 test set. This compares favorably to SEP values > 2 mM when the original 1994 calibration model is used without standardization. A similar improvement in the prediction performance of the 2000 test set is obtained after standardization with the 1996 database (SEP = 0.70 mM).

Algorithms↗
PubMed2002

Age at onset in two common neurodegenerative diseases is genetically controlled.

To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, a genomic screen was performed for AAO in families with Alzheimer disease (AD; n=449) and Parkinson disease (PD; n=174). Heritabilities between 40%--60% were found in both the AD and PD data sets. For PD, significant evidence for linkage to AAO was found on chromosome 1p (LOD = 3.41). For AD, the AAO effect of APOE (LOD = 3.28) was confirmed. In addition, evidence for AAO linkage on chromosomes 6 and 10 was identified independently in both the AD and PD data sets. Subsequent unified analyses of these regions identified a single peak on chromosome 10q between D10S1239 and D10S1237, with a maximum LOD score of 2.62. These data suggest that a common gene affects AAO in these two common complex neurodegenerative diseases.

Age of Onset↗
PubMed2002

The impact of symptom severity on the cost of Alzheimer's disease.

OBJECTIVES: ITo examine the economic impact of Alzheimer's disease (AD) as the disease progresses on patients' medical costs and caregivers' productivity. DESIGN: A 12-page, self-administered mail survey, fielded in November 1999. SETTING: Households with AD caregivers, selected from a nationwide (U.S.) consumer database. PARTICIPANTS: One thousand seven hundred fifteen caregivers of noninstitutionalized AD patients. MEASUREMENTS: Disease progression was measured using a scale of symptom frequency and measures of instrumental and physical functioning. Cost components included hospital days, physician visits, and emergency room visits. Lost productivity was assessed using hours per week that caregivers provided care and the number of days that they missed from work because of caregiving. RESULTS: The direct costs of caring for AD patients for 6 months totaled $3,129, whereas the indirect costs were $26,080. Patients with more-frequent symptoms used all healthcare resources, including the hospital, emergency room, and physicians, more often than those with less-frequent symptoms. Those with lower levels of physical and instrumental functioning also used the hospital and physicians more often than those with higher levels of physical and instrumental functioning. Caregivers of these more severely impaired patients spent more hours providing care and reported missing more work than those caring for higher-functioning patients. These relationships remained after controlling for potentially confounding factors. CONCLUSIONS: This large study of patients at all stages of AD shows that the direct and indirect costs of AD are considerably lower for patients with fewer symptoms. Longitudinal studies will determine the impact on the overall cost of care of interventions that reduce symptoms and maintain patients at earlier stages of the disease.

Aged↗
PubMed2002

Mood symptoms and cognitive performance in women estrogen users and nonusers and men.

OBJECTIVES: Previous studies have suggested sex differences in mood and cognition and that estrogen effects may partially explain such differences. In this study, we explore sex differences for a range of mood symptoms and for neuropsychological performance in men and postmenopausal women and assess the potential influence of estrogen on these measures. DESIGN: Cross-sectional study of men and women examining mood, neuropsychological test data, and estrogen replacement therapy (ERT) use. SETTING: Outpatient study at an urban teaching hospital with subjects recruited from the community. PARTICIPANTS: All subjects (N = 96) were between the ages of 57 and 75 and included 31 women using ERT, 16 non-ERT users, and 49 men. Subjects did not have major depression and were nondemented. MEASUREMENT: The three groups were compared according to profile of mood states and neuropsychological performance, and statistical analyses were controlled for socioeconomic status, age, and education level. RESULTS: Female ERT users were less depressed and less angry and performed better on measures of verbal fluency and working memory than the other subject groups. CONCLUSION: Postmenopausal estrogen use is associated with better mood and cognitive performance on tasks of fluency and working memory. These results suggest that estrogen should be examined as a potentially critical variable influencing late-life sex differences in mood and cognition.

Affect↗
PubMed2002

In vivo brain imaging of tangle burden in humans.

Cerebral neurofibrillary tangles (NFTs) accumulate in a predictable sequence decades before the clinical symptoms of Alzheimer's disease emerge, and the degree of tangle degeneration correlates with the severity of cognitive impairment. A valid in vivo marker of tangle burden, therefore, would be useful for presymptomatic and symptomatic disease detection and treatment monitoring. Recent advances using positron emission tomography (PET) indicate the feasibility of in vivo imaging that provides a combined signal of both neurofibrillary tangles and senile plaques. Such results are encouraging that a tangle-specific marker will be found; however, several methodological issues first need to be addressed, including scanner spatial resolution in the relatively small brain regions where tangles accumulate. NFT-specific imaging probes will need to be lipophilic in order to cross the blood-brain barrier and neuronal membranes and have a high binding affinity to NFTs with minimal nonspecific binding, which would result in a high signal-to-background ratio in PET images.

Alzheimer Disease↗
PubMed2002

Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors.

Cholinesterase inhibitors are the 'first-line' agents in the treatment of Alzheimer's disease. This article presents the latest information on their pharmacokinetic properties and pharmacodynamic activity. Tacrine was the first cholinesterase inhibitor approved by regulatory agencies, followed by donepezil, rivastigmine and recently galantamine. With the exception of low doses of tacrine, the cholinesterase inhibitors exhibit a linear relationship between dose and area under the plasma concentration-time curve. Cholinesterase inhibitors are rapidly absorbed through the gastrointestinal tract, with time to peak concentration usually less than 2 hours; donepezil has the longest absorption time of 3 to 5 hours. Donepezil and tacrine are highly protein bound, whereas protein binding of rivastigmine and galantamine is less than 40%. Tacrine is metabolised by hepatic cytochrome P450 (CYP) 1A2, and donepezil and galantamine are metabolised by CYP3A4 and CYP2D6. Rivastigmine is metabolised by sulfate conjugation. Two cholinesterase enzymes are present in the body, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Tacrine and rivastigmine inhibit both enzymes, whereas donepezil and galantamine specifically inhibit AChE. Galantamine also modulates nicotine receptors, thereby enhancing acetylcholinergic activity at the synapse. These different pharmacological profiles provide distinctions between these agents. Cholinesterase inhibitors show a nonlinear relationship between dose and cholinesterase inhibition, where a plateau effect occurs. Cholinesterase inhibitors display a different profile as each agent achieves its plateau at different doses. In clinical trials, cholinesterase inhibitors demonstrate a dose-dependent effect on cognition and functional activities. Improvement in behavioural symptoms also occurs, but without a dose-response relationship. Gastrointestinal adverse events are dose-related. Clinical improvement occurs with between 40 and 70% inhibition of cholinesterase. A conceptual model for cholinesterase inhibitors has been proposed, linking enzyme inhibition, clinical efficacy and adverse effects. Currently, measurement of enzyme inhibition is used as the biomarker for cholinesterase inhibitors. New approaches to determining the efficacy of cholinesterase inhibitors in the brain could involve the use of various imaging techniques. The knowledge base for the pharmacokinetics and pharmacodynamics of cholinesterase inhibitors continues to expand. The increased information available to clinicians can optimise the use of these agents in the management of patients with Alzheimer's disease.

Aging↗
PubMed2002

Evaluating early dementia with and without assessment of regional cerebral metabolism by PET: a comparison of predicted costs and benefits.

UNLABELLED: Evaluating dementia in patients with early symptoms of cognitive decline is clinically challenging. Growing evidence indicates that appropriate incorporation of PET into the clinical work-up can improve diagnostic and prognostic accuracy with respect to Alzheimer's disease (AD), the most common cause of dementia in the geriatric population. The precise diagnostic role of PET and its economic impact in this context, however, have not been systematically examined previously. METHODS: We compared the relative value of 2 strategies for assessing whether early AD is responsible for cognitive symptoms in geriatric patients: (a) a conventional approach, based largely on establishing clinical criteria for the presence of dementia and excluding non-AD etiologies that could contribute to the patient's symptoms, and (b) a proposed approach using PET to examine regional cerebral metabolism and look for characteristic patterns of abnormal metabolism. The total costs (measured in dollars) and benefits (measured in number of accurate diagnoses) of diagnostic testing and clinical outcomes accruing to each strategy were calculated using formalized tools of decision analysis. The primary outcome measure by which the strategies were compared was the ratio of costs to benefits obtained following each approach. RESULTS: Following the proposed approach led to improved accuracy in identifying early AD, without adding to the overall costs of diagnosis and treatment ($3,433 vs. $3,564 per patient approached by the proposed or conventional algorithm, respectively). The strategy making use of PET was associated with a reduced rate of false-negative and false-positive findings compared with the conventional approach (3.1% vs. 8.2% and 12.0% vs. 23.0%, respectively, at a prevalence of 51.6% in the studied symptomatic population) and a cost savings of $1,138 per correct diagnosis rendered ($4,047 vs. $5,185). The lower cost per unit benefit for the proposed strategy was maintained over a wide range of tested values for variables of sensitivity, specificity, costs of PET and long-term care, and varying approaches to the use of structural neuroimaging. CONCLUSION: Appropriate use of PET for evaluating early dementia in geriatric patients can add valuable information to the clinical work-up, without adding to the overall costs of evaluation and management, resulting in a greater number of patients being accurately diagnosed for the same level of financial expenditure. Thus, the opportunity exists for diminishing the morbidity of dementia economically, with earlier institution of more appropriate management in evaluated patients.

Aged↗
PubMedDate not supplied

Brain-imaging surrogate markers for detection and prevention of age-related memory loss.

Recent evidence points to the importance of neuropathological and cognitive changes preceding Alzheimer's disease (AD), and clinical trials have begun to focus on preventive treatments designed to slow age-related cognitive decline and delay the onset of AD in people with age-associated memory impairment (AAMI). Studying subjects with few deficits leads to diagnostic heterogeneity and a need for larger samples in order to detect active drug effects. In this report, I review results of recent studies designed to address such issues. Middle-aged and older adults with mild memory complaints were studied using brain imaging and measures of the major known genetic risk for AD, the apolipoprotein E-4 (APOE-4) allele. In a study of positron emission tomography during mental rest, glucose metabolic rates were significantly lower in APOE-4 carriers in brain regions affected by AD. Another study using functional magnetic resonance imaging showed increased brain activation during memory tasks in APOE-4 carriers in similar brain regions. Longitudinal follow-up after 2 yr indicated the potential utility of such brain-imaging measures, combined with genetic-risk information, as surrogate markers in treatment trials for AAMI to prevent further cognitive decline. Current development focuses on novel technologies using positron emission tomography to directly image the neuritic plaques and neurofibrillary tangles of AD in order to provide more specific measures of disease progression in future clinical trials.

Aging↗