Biomedical subjects

B L Miller

Publications and source records attributed to B L Miller.

At least 73 records · Page 4Linked to original sources

PubMed2000

Alzheimer's disease and its focal variants.

Alzheimer's disease (AD) is the most common form of dementia in elderly individuals. Although the diagnosis of AD requires pathological confirmation, several common clinical features of AD have been identified. These include insidious onset, gradual progression, medial temporal atrophy, temporoparietal hypoperfusion, early and prominent deficits in episodic memory and mental tracking, and later deficits in semantic memory. These characteristic features of AD have enabled excellent in vivo diagnostic sensitivity. It has become increasingly clear, however, that AD is a heterogeneous disorder. The left and right cerebral hemispheres can be affected to varying degrees, and variability on the anterior-posterior axis has also been reported. AD can also present as a focal degenerative disease, and clinicians must be aware that there may be diagnostic overlap between AD, primary progressive aphasia, posterior cortical atrophy, corticobasal degeneration, and frontotemporal dementia.

Alzheimer Disease↗

PubMed2000

Functional correlates of musical and visual ability in frontotemporal dementia.

BACKGROUND: The emergence of new skills in the setting of dementia suggests that loss of function in one brain area can release new functions elsewhere. AIMS: To characterise 12 patients with frontotemporal dementia (FTD) who acquired, or sustained, new musical or visual abilities despite progression of their dementia. METHOD: Twelve patients with FTD who acquired or maintained musical or artistic ability were compared with 46 patients with FTD in whom new or sustained ability was absent. RESULTS: The group with musical or visual ability performed better on visual, but worse on verbal tasks than did the other patients with FTD. Nine had asymmetrical left anterior dysfunction. Nine showed the temporal lobe variant of FTD. CONCLUSION: Loss of function in the left anterior temporal lobe may lead to facilitation of artistic or musical skills. Patients with the left-sided temporal lobe variant of FTD offer an unexpected window into the neurological mediation of visual and musical talents.

Aged↗

PubMed2000

Autistic savants. [correction of artistic].

OBJECTIVE: The objectives of this study were to examine common patterns in the lives and artwork of five artistic savants previously described and to report on the clinical, neuropsychological, and neuroimaging findings from one newly diagnosed artistic savant. BACKGROUND: The artistic savant syndrome has been recognized for centuries, although its neuroanatomic basis remains a mystery. METHODS: The cardinal features, strengths, and weaknesses of the work of these six savants were analyzed and compared with those of children with autism in whom artistic talent was absent. An anatomic substrate for these behaviors was considered in the context of newly emerging theories related to paradoxical functional facilitation, visual thinking, and multiple intelligences. RESULTS: The artists had features of "pervasive developmental disorder," including impairment in social interaction and communication as well as restricted repetitive and stereotyped patterns of behavior, interest, and activities. All six demonstrated a strong preference for a single art medium and showed a restricted variation in artistic themes. None understood art theory. Some autistic features contributed to their success, including attention to visual detail, a tendency toward ritualistic compulsive repetition, the ability to focus on one topic at the expense of other interests, and intact memory and visuospatial skills. CONCLUSIONS: The artistic savant syndrome remains rare and mysterious in origin. Savants exhibit extraordinary visual talents along with profound linguistic and social impairment. The intense focus on and ability to remember visual detail contributes to the artistic product of the savant. The anatomic substrate for the savant syndrome may involve loss of function in the left temporal lobe with enhanced function of the posterior neocortex.

Adolescent↗

PubMed2000

Apolipoprotein-E and white-matter hyperintensities in late-life depression.

The authors conducted a follow-up study of 16 patients with late-life depression approximately 6 years after their initial assessment to evaluate the relationships between apolipoprotein-E (APO-E) status and white-matter hyperintensities (WMH). Ten patients had WMH at baseline, and four patients demonstrated an increase in WMH size over time. Three of four patients with the APO-E epsilon 4 allele demonstrated an increase in WMH over time, and only 1 of 12 patients without an epsilon 4 allele had an increase in WMH. Three of four patients with APO-E epsilon 4 allele developed a chronic course of major depression at follow-up. Patients with APO-E epsilon 4 had a higher number of depressive episodes and lower age at onset. APO-E may be a risk factor for cerebrovascular disease associated with late-life depression and may affect the clinical characteristics and disease course of depression.

Aged↗

PubMed1999

Midlife cardiovascular risk factors and brain morphology in identical older male twins.

OBJECTIVE: Structural changes in the human brain have been reported to a greater extent in subjects with cardiovascular risk factors. We conducted a matched co-twin analysis of elderly monozygotic twins from the National Heart, Lung, and Blood Institute Twin Study to examine the association between midlife cardiovascular risk factors and MRI-based measures of brain atrophy. METHODS: Brain MRIs (1.5-T) were obtained from 74 monozygotic, white, male, World War II veteran twins born in the United States from 1917 to 1927 and age 68 to 79 at the time of the brain scan. A semiautomated algorithm was used to segment brain images into total brain, CSF, and white matter hyperintensity volumes. Cardiovascular risk factors, medical history variables, and health practices were available from data collected over 25 years of adult life. RESULTS: Independent of shared genetic or familial influences, within-pair differences in midlife glucose levels, high-density lipoprotein cholesterol, and systolic blood pressure were significantly associated with differences in white matter hyperintensities. Within-pair differences in coronary heart disease history and in current consumption of alcohol and level of physical activity were significantly associated with differences in brain parenchyma. In addition, within-pair differences in white matter hyperintensity volumes were significantly associated with differences in performance on cognitive and physical function tests and self-reports of depression symptoms. CONCLUSION: Independent of age effects and shared genetic or familial influences, midlife cardiovascular risk factors and lifetime health practices were predictive of structural brain changes in old age.

Brain↗

PubMed1999

Inheritance of frontotemporal dementia.

BACKGROUND: Previous studies of families with fronto-temporal dementia (FTD) support an autosomal dominant inheritance pattern, but most studies have described genetic transmission in individual families specifically selected for the presence of multiple affected individuals. OBJECTIVE: To investigate the familial presentation and inheritance of FTD and related disorders among a large group of FTD index cases unselected for family history of dementia. DESIGN AND SETTING: We interviewed family members and reviewed medical records and autopsy reports at a university hospital and a university-affiliated hospital to determine the frequency of familial FTD and the most likely mode of inheritance. Characteristic families with the disorder are described, along with the history, clinical findings, and neuroimaging results in affected members of these families. PATIENTS AND PARTICIPANTS: The 42 index cases of FTD had a mean age of onset of 56.1 years (range, 40-69 years). Of these patients, 21 (50%) were women. All but one of the patients were white. Participants included male and female spouses and children of the index cases. family member with an FTD spectrum disorder and were considered familial cases. The majority (17 [89%]) of familial FTD cases showed a pattern consistent with dominant inheritance. If depression is excluded, familial cases decrease from 19 (45%) to 17 (40%), of which 15 (88%) showed a dominant transmission pattern. The initial presentations in the nonindex familial cases varied but most frequently consisted of personality and behavioral changes that preceded cognitive impairment (19 [43%]), followed by psychiatric illness (14 [33%]), dementia without behavioral change (5 [11%]), amyotrophic lateral sclerosis (5 [11%]), and parkinsonism (2[5%]). Two of the affected nonindex cases had dual presenting diagnoses. The average age of onset was 56.1 years and did not differ significantly between familial and nonfamilial cases. Onset of FTD-related symptoms occurred after the age of 65 years in only 4(10%) of 42 index cases and 3 (5%) of 60 affected relatives. CONCLUSIONS: Familial FTD is usually inherited in an autosomal dominant pattern. The initial onset is insidious, often consisting of mood and behavioral changes occurring in presenile years that are often erroneously attributed to other nonneurologic causes. Although the precise incidence of FTD in North America is not known, it is one of the most common presenile dementias.

Adult↗

PubMed1999

Differential genetic influence for components of memory in aging adult twins.

OBJECTIVE: To investigate the relative proportion of genetic and environmental contributions to verbal memory in community-dwelling World War II veteran twins. DESIGN: The California Verbal Learning Test (CVLT) was administered to 94 monozygotic (MZ) and 89 dizygotic (DZ) elderly male twin pair participants in the fourth examination of the National Heart, Lung, and Blood Institute Twin Study. SETTING: Subjects voluntarily participated on an outpatient basis at a research or medical center facility in 1 of 4 sites in the United States. PARTICIPANTS: Subjects had a mean age of 71.8 years (SD, 2.9 years), a mean educational level of 13.6 years (SD, 2.8 years), and no history of stroke and/or a Mini-Mental State Examination score of 23 or greater. MAIN OUTCOME MEASURES: Twin pair similarity in performance on 4 factor analytically derived components of the CVLT measuring verbal learning and memory, response discrimination, learning strategy, and recognition memory. RESULTS: The MZ intraclass correlation was significantly larger than the DZ correlation for verbal learning and memory (I<.001) but not for the other 3 components of memory. Using maximum likelihood methods, the best-fitting genetic model indicated that verbal learning and memory has a substantial genetic component (56% of total variance), whereas response discrimination has a much smaller, although still detectable, genetic component (24% of total variance). There is no evidence of genetic influence on learning strategy or recognition memory. CONCLUSION: Differential contribution of genetic and environmental influences to specific components of memory suggest that, in this group of elderly male twin pairs, some components may be more amenable to intervention than others.

Aged↗

PubMed1999

From genotype to phenotype: a clinical pathological, and biochemical investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused by the P301L tau mutation.

Frontotemporal dementia is a heterogeneous, often inherited disorder that typically presents with the insidious onset of behavioral and personality changes. Two genetic loci have been identified and mutations in tau have been causally implicated in a subset of families linked to one of these loci on chromosome 17q21-22. In this study, linkage analysis was performed in a large pedigree, the MN family, suggesting chromosome 17q21-22 linkage. Mutational analysis of the tau coding region identified a C-to-T change in exon 10 that resulted in the conversion of proline to a leucine (P301L) that segregated with frontotemporal dementia in this family. The clinical and pathological findings in the MN family emphasize the significant overlap between Pick's disease, corticobasal degeneration, and frontotemporal dementia and challenge some of the current dogma surrounding this condition. Pathological studies of two brains from affected members of Family MN obtained at autopsy demonstrate numerous tau-positive inclusions that were most prominent in the frontal lobes, anterior temporal lobes, and brainstem structures, as well as Pick-like bodies and associated granulovacuolar degeneration. These Pick-like bodies were observed in 1 patient with motor neuron disease. Because exon 10 is present only in tau mRNA coding for a protein with four microtubule binding repeats (4R), this mutation should selectively affect 4Rtau isoforms. Indeed, immunoblotting demonstrated that insoluble 4Rtau is selectively aggregated in both gray and white matter of affected individuals. Although there was significant pathological similarity between the 2 cases, the pattern of degenerative changes and tau-positive inclusions was not identical, suggesting that other genetic or epigenetic factors can significantly modify the regional topology of neurodegeneration in this condition.

Brain↗

PubMed1999

Dynamic diversity and small-molecule evolution: a new paradigm for ligand identification.

A longstanding goal of organic, medicinal and bioorganic chemists has been the discovery of efficient methods for designing or identifying biologically active compounds. Recently, several groups have reported using the directed evolution of combinatorial libraries as a new method of identifying compounds capable of binding tightly to a target molecule. Although significant development remains to be done, the initial results suggest that dynamic diversity and associated selection methods will prove to be valuable additions to the drug-discovery process.

Biological Evolution↗

PubMed1999

Neuropsychological patterns in right versus left frontotemporal dementia.

Patients with frontotemporal dementia (FTD) often present with an asymmetric left or right-sided anterior cerebral perfusion abnormality that is associated with differential behavioral symptoms. However, whether patients with primarily right versus left FTD also have unique neuropsychological characteristics has not been previously investigated. Comparisons of 11 patients with right-sided FTD and 11 with left FTD indicated that the 2 patient groups showed relatively distinct cognitive profiles. Patients with right FTD exhibited relatively worse performance on PIQ than VIQ, and on select nonverbal executive tasks relative to their verbal analogs (e.g., design fluency < word generation; Picture Arrangement < word sequencing). In contrast, patients with left FTD showed the opposite pattern. In addition, the 2 patient groups differed on several absolute test scores; patients with right FTD demonstrated more errors and perseverative responses, and worse percent conceptual level responses, on the Wisconsin Card Sorting Test, while the left FTD patients obtained significantly worse scores on the Boston Naming Test, and Stroop word reading and color naming. Verbal and nonverbal memory, mental speed, visual perceptual-constructional skill, and IQ subtest scaled scores did not significantly differ between groups. These data indicate that FTD should not be viewed as a unitary disorder, and that neuropsychological testing holds promise for the differential diagnosis of right versus left FTD.

Dementia↗

PubMed1999

Neuroimaging in the diagnosis of frontotemporal dementia.

The role of neuroimaging for the diagnosis of frontotemporal dementia (FTD) remains controversial. The modern history of imaging in the study of FTD is outlined. Also, the findings on MRI and SPECT in 15 consecutive FTD patients is noted. Both MRI and SPECT detected focal frontal involvement in nearly every single case (MRI 14/15 and SPECT 15/15). Also, the majority of patients showed asymmetry on MRI (8/15) and SPECT (12/15). This study confirms that neuroimaging is sensitive to the frontotemporal degeneration associated with FTD. Additionally, it suggests that this is often asymmetric in the relative involvement of these brain regions.

Dementia↗

PubMed1999

Tau mutations in frontotemporal dementia.

Genetic analysis has determined that a series of disorders related clinically and pathologically to frontotemporal dementia (FTD) are etiologically related. The relationship between these disorders was initially established based on linkage analysis and has been solidified by the identification of mutations in the tau gene in many families. Mutations affecting the expression or structure of the microtubule binding domain of the tau gene have been found in many large families with chromosome 17q21-22-linked disease. These mutations only account for a small fraction of cases of FTD that are either sporadic or that contain only a few affected relatives.

Animals↗

PubMed1999

Predictors of brain morphology for the men of the NHLBI twin study.

BACKGROUND AND PURPOSE: Cross-sectional studies show that cerebrovascular risk factors are associated with increased brain atrophy, accumulation of abnormal cerebral white matter signals, and clinically silent stroke. We extend these findings by examining the relationship between midlife cerebrovascular risk factors and later-life differences in brain atrophy, amount of abnormal white matter, and stroke on MRI. METHODS: Subjects were the 414 surviving members of the prospective National Heart, Lung, and Blood Institute Twin Study, who have been examined on 4 separate occasions, spanning the 25 years between 1969-1973 and 1995-1997. Quantitative measures of brain volume, volume of abnormal white matter signal (WMHI), and volume of stroke, when present, were obtained from those participating in the fourth examination. RESULTS: The mean+/-SD age of the subjects was 47.2+/-3.0 years at initial examination and 72. 5+/-2.9 years at final examination. Average blood pressure (BP) levels were normal, although 32% of the subjects had received or were currently taking antihypertensive medications. As a group, 31% had symptomatic cardiovascular disease, 11% had symptomatic cerebrovascular disease, and 8% had symptomatic peripheral vascular disease. Both systolic and diastolic BP levels at initial examination were inversely related to brain volume and positively related to WMHI volume. Multiple regression analysis identified BP-related measures and vascular risk factors as significant predictors of brain and WMHI volumes. In addition, the magnitude of orthostatic BP change was significantly associated with WMHI volume. Subjects with extensive amounts of WMHI had significantly higher systolic BP at the final examination and a higher prevalence of symptomatic cardiovascular and cerebrovascular disease, without significant differences in the prevalence of hypertension treatment. CONCLUSIONS: Midlife BP measures are significantly associated with later-life brain and WMHI volumes and the prevalence of symptomatic vascular disease. Since WMHI share cerebrovascular risk factors and extensive WMHI are associated with symptomatic vascular disease, extensive WMHI may be a subclinical expression of cerebrovascular disease. Careful treatment of midlife BP elevations may diminish these later-life brain changes.

Age Factors↗

PubMed1999

Impact of apolipoprotein E epsilon4 and vascular disease on brain morphology in men from the NHLBI twin study.

BACKGROUND AND PURPOSE: Apolipoprotein E epsilon4 genotype (ApoE4) has been associated with increased risk for cardiovascular disease morbidity or mortality. This appears to be mediated by an ApoE4-related increase in cardiovascular atherosclerosis. Given the similarities between risk factors for heart disease and risk factors for stroke, a positive association between ApoE4 and stroke would be expected. Since age-related brain atrophy and the extent of white matter hyperintensities (WMH) share similar risk factors, we examined the combined effect of ApoE4 and history of vascular disease on brain volume, WMH, and MRI evidence of stroke. METHODS: Subjects were the surviving members of the National Heart, Lung, and Blood Institute Twin Study. This is a longitudinal study of the effects of cardiovascular disease risk factors in community-dwelling male veterans. The fourth and final examination of this cohort included cerebral MRI and was completed in 1997. Apolipoprotein E (ApoE) genotype, quantitative measures of brain volume, WMH, and the presence of stroke on MRI were obtained from the 396 participants in the final examination. The presence or absence of a history of coronary heart disease, cerebrovascular disease, peripheral arterial disease, and ApoE genotype were determined for each subject. RESULTS: Of the 396 men, 88 (22%) had at least 1 ApoE4 allele. ApoE4 was not associated with differences in age or education. While the prevalence of vascular disease was generally greater in the ApoE4 group, this was only significant for coronary heart disease (29.8% in subjects without ApoE4 versus 40.7% in subject with ApoE4; P=0.03). ApoE4 subjects had significantly smaller brain volumes (942.4+/-34.5 versus 952.2+/-40.1 cm(3); P=0. 02). MRI evidence of stroke was detected in 88 (22%) of the subjects. The distribution of ApoE genotype was marginally different between subjects with MRI-detected stroke compared with those without. Further analysis revealed that the co-occurrence of cerebrovascular disease and ApoE4 was associated with significantly greater brain atrophy and WMH than either ApoE4 or cerebrovascular disease alone. Similar relations were seen for coronary heart disease and peripheral arterial disease. CONCLUSIONS: We conclude that ApoE4 enhances the extent of brain abnormalities in the presence of various vascular diseases. We speculate that this effect may be mediated by an increased susceptibility to brain injury or impaired repair mechanisms associated with ApoE4.

Adult↗

PubMed1999

The gambler's ruin problem, genetic algorithms, and the sizing of populations.

This paper presents a model to predict the convergence quality of genetic algorithms based on the size of the population. The model is based on an analogy between selection in GAs and one-dimensional random walks. Using the solution to a classic random walk problem-the gambler's ruin-the model naturally incorporates previous knowledge about the initial supply of building blocks (BBs) and correct selection of the best BB over its desired quality of the solution, as well as the problem size and difficulty. The accuracy of the model is verified with experiments using additively decomposable functions of varying difficulty. The paper demonstrates how to adjust the model to account for noise present in the fitness evaluation and for different tournament sizes.

Algorithms↗

PubMed1999

Twice daily suckling but not milking with calf presence prolongs postpartum anovulation.

Two experiments were conducted to determine whether milking beef cows two or five times daily in the presence or absence of their own nonsuckling calves would alter postpartum interval to first ovulation. Multiparous Angus x Hereford cow-calf pairs were assigned randomly between 13 and 18 d postpartum to treatments for 4 wk. In Exp. 1, pairs were assigned to six treatments: 1) calf was weaned permanently from its dam (CW; n = 9); 2) same as CW, but dam was milked twice daily (CW+2xM; n = 9); 3) calf was present continuously with its dam but restricted from contact with the udder (CR; n = 9); 4) same as CR, but dam was milked twice daily (CR+2xM; n = 9); 5) same as CR, but calf was allowed to suckle twice daily (CR+2xS; n = 8); and 6) calf was present continuously with its dam and suckled ad libitum (CP; n = 9). The interval from onset of treatments to first postpartum ovulation was shorter (P<.05) in the CW (14.1+/-3.1 d), CR (14.2+/-3.1 d), CW+2xM (13.0+/-3.1 d), and CR+2xM (17.2+/-3.1 d) than in the CP (34.7+/-3.1 d) and CR+2xS (33.9+/-3.3 d) treatments. Daily milk yield during treatment was greater (P<.01) for CR+2xM cows (7.1+/-.6 kg) than for CW+2xM cows (3.5+/-.6 kg). In Exp. 2, cow-calf pairs were assigned to three treatments: 1) CR+2xM (n = 10); 2) same as CR+2xM but cows were milked five times daily (CR+5xM; n = 10); or 3) CP (n = 10). The interval to first postpartum ovulation was shorter (P<.05) in the CR+2xM (23.6+/-3.5 d) and CR+5xM (26.1+/-3.7 d) treatments than in the CP (37.7+/-3.7 d) treatment. Daily milk yield during treatment was greater (P<.05) for CR+5xM cows (7.7+/-.6 kg) than for CR+2xM cows (6.4+/-.6 kg) by 17%. We conclude that suckling twice daily was sufficient to prolong postpartum anestrus as much as suckling ad libitum. Furthermore, milk removal by suckling, but not by milking two or five times daily, even in the presence of the cow's own nonsuckling calf, is essential to prolong postpartum anovulation.

Animals↗

PubMed1999

Suckling reinitiated milk secretion in beef cows after an early postpartum hiatus of milking or suckling.

We determined whether milk secretion in beef cows could be reinitiated by renewed suckling after a hiatus from milking or suckling. Fifty-three Angus x Hereford cows were suckled ad libitum by their own calves for 13 to 18 d postpartum and then assigned to treatments for 4 wk in which cows were 1) neither milked nor suckled (weaned; n = 18), 2) milked 2 x daily (milked; n = 18), or 3) suckled by their own calves (suckled; n = 17). Thereafter, all calves (including earlier weaned calves) suckled their own dams until permanent weaning at 203 d of age, except when their dams were milked once after receiving (i.m.) 40 IU of oxytocin at reinitiation of suckling (0 wk) and again 1 and 5 wk later. Prolactin was increased in milked and suckled cows during 20 min after milking or suckling at the termination of treatments (0 wk). Concentrations of insulin-like growth factor-I were greater for weaned than suckled cows; milked cows had intermediate concentrations. At 0 wk, milk yield was greater for suckled than milked or weaned treatment cows. After 1 wk of renewed suckling, milk secretion of weaned treatment cows increased, and by 5 wk, composition of milk was normal, but yield was still reduced. We concluded that milk secretion was renewed by suckling in early postpartum cows after they were neither suckled nor milked for 4 wk.

Animals↗

PubMed1999

Clinical and neuroradiologic features associated with chronicity in late-life depression.

The authors conducted a 6-year follow-up of 16 patients with late-life depression to evaluate the relationships between clinical and neuroradiologic variables and disease outcome. Patients had a comprehensive neuropsychiatric evaluation and magnetic resonance imaging (MRI) at baseline and follow-up. Eight of the 16 developed a chronic course of unremitting major depression sufficient to cause significant psychosocial impairment. Six patients with a chronic course and four patients with a non-chronic course of depression had white matter hyperintensities (WMH) on MRI at baseline. Four patients whose WMH increased in size over time developed a chronic unremitting course of depression. No patients with non-chronic depression had large areas of WMH at baseline or exhibited increased WMH size over time. Chronic depression was associated with severity of cerebrovascular risk factors, apathy, and poor quality of life. Treatment and prevention of cerebrovascular disease may improve the outcome of late-life depression.

Adult↗