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Biomedical subjects

C Holmes

Publications and source records attributed to C Holmes.

At least 55 records · Page 3Linked to original sources
PubMed1998

Apolipoprotein E: depressive illness, depressive symptoms, and Alzheimer's disease.

BACKGROUND: The apolipoprotein E (ApoE) epsilon 4 and epsilon 2 alleles may influence the age of onset of depressive illness. Depressive illness of late onset is also a risk factor for Alzheimer's disease (AD), and there is some evidence that the ApoE epsilon 2 allele is associated with depressive symptomatology in AD. Depressive symptomatology in AD may thus share common genetic risk factors with late-onset depressive illness. METHODS: The frequency of the epsilon 2 and epsilon 4 alleles of ApoE and their effects on age of onset of disease in three independent groups of subjects, with depressive illness, with AD, and controls, were compared in a defined population from Southeast London. RESULTS: The frequency of the ApoE epsilon 2 allele was significantly lower in the depressive illness group compared with the control group and was associated with a later mean age at onset. Subjects with depressive symptomatology in AD had a higher frequency of the ApoE epsilon 2 allele and had a significantly later age of onset of depressive illness compared with the nondepressed AD group. CONCLUSIONS: The presence of the ApoE epsilon 2 allele in AD is found to be highly associated with depressive symptomatology, and it is proposed that this subgroup represents the presence of delayed depressive illness and that there are common genetic risk factors between AD and depressive illness.

Age of Onset↗
PubMed1998

Dopamine is released spontaneously from developing midbrain neurons in organotypic culture.

While neuronal activity is important in CNS development, little is known of the behaviour of the actual neurotransmitters released during this period. None the less, indirect evidence has suggested that the neurotransmitter dopamine actually has a morphogenic role. This study is the first attempt to monitor directly and in real-time, the release of dopamine from midbrain neurons developing as an isolated organotypic slice culture. The observed release of dopamine was both spontaneous and synchronized and occurred with an average periodicity that is two orders of magnitude longer than the characteristic neuronal discharge activity of midbrain dopamine cells. Moreover, elevations in the extracellular concentrations of dopamine were markedly more prolonged in these and other developing systems than in axon terminal regions in mature striatum in which dopaminergic innervation is fully established. Thus, dopamine may have an action in developing circuits over spatial and temporal scales that vastly exceed those in mature, synaptic-like transmission.

2-Amino-5-phosphonovalerate↗
PubMed1998

Previous psychiatric history as a risk factor for late-life dementia: a population-based case-control study.

OBJECTIVE: To test the hypothesis that risk for dementia in late life is increased by a history of earlier psychiatric illness, and to examine the specificity of any such association. METHODS: Frequency of earlier treated psychiatric illness was established by record searches and informant histories for all persons aged over 60 who were entered on the Camberwell dementia case register over a 2-year period and for an individually matched control group of the local elderly population, drawn from the files of the area Family Health Services Authority. RESULTS: Of 559 persons with a clinical diagnosis of dementia, 70 (12.5%) had a history of psychiatric illness long preceding, and apparently unrelated to, the onset of dementia. When these patients were compared with a matched comparison group of dementia register patients who had no recorded psychiatric history, the two groups appeared broadly similar in type of dementia, severity and clinical features. Sixty-three of the earlier psychiatric histories could be identified from the available medical records alone. Applying the same procedure to the matched control group of Camberwell residents yielded from the 559 only 19 (3.4%) with a history of treated psychiatric illness before the age of 70. The difference in case frequency between the two groups was highly significant and corresponded to an estimated odds ratio of 3.6. The increase in risk, which was not restricted to dementia of Alzheimer type, appeared to be characteristic of major psychiatric illness, rather than specific for depression. CONCLUSION: There is a positive association between previous psychiatric history and late-life dementia which is of predictive significance. The underlying causal links merit further research.

Aged↗
PubMed1998

5-HT2A and 5-HT2C receptor polymorphisms and psychopathology in late onset Alzheimer's disease.

The psychopathology of Alzheimer's disease (AD) is varied and includes both behavioural and psychological symptoms. Behavioural and psychological symptoms are common and contribute to the difficulties experienced by carers. However, the mechanism whereby these symptoms occur in some individuals with AD is not understood. We hypothesized that common genetic polymorphisms in neurotransmitter systems are risk factors for these symptoms in the course of AD. A total of 211 subjects from a population-based prospective study of psychopathology within late-onset AD were genotyped for the 5-HT2A receptor polymorphism 102-T/C and the 5-HT2C receptor polymorphism Cys23Ser. Associations were found between the presence of the C102 allele and the presence of visual (Fisher's exact test, one-tailed, P = 0.003) and auditory hallucinations (Fisher's exact test, one-tailed, P = 0.004) and between the presence of the Ser23 allele and visual hallucinations (chi2 = 7.5, df = 1, P = 0.006) (P = 0.03, 0.04 and 0.06, respectively, after Bonferroni correction). In addition, there was an association between the Cys23Ser polymorphism and hyperphagia (chi2 = 6.7, df = 2, P = 0.03) (P = 0.3 after Bonferroni correction). We conclude that common 5-HT2A and 5-HT2C genetic polymorphisms previously showing only weak associations with psychotic illness are associated with psychotic symptoms in AD but are clinically silent until the onset of the neurodegenerative process.

Age of Onset↗
PubMed1998

Comparison of in vitro AGE formation between standard PD fluid and a novel bicarbonate/lactate formulation.

Peritoneal advanced glycation end-product (AGE) formation may be accelerated by glucose degradation products produced as a consequence of heat sterilization of peritoneal dialysis (PD) fluid. The formation of these degradation products is reduced if the glucose is separated from the buffers during heat sterilization. This pilot study compared in vitro AGE formation in PD fluid (1.36% and 3.86% glucose) heat sterilized in a two-compartment bag (bicarbonate/lactate buffer) with that in a standard, single-compartment bag (lactate buffer, Dianeal). Peritoneal dialysis fluids were incubated with human serum albumin (HSA, 1 g/L), as a model protein, at 37 degrees C for 0, 5, and 20 days. Formation of AGEs was assessed by measuring fluorescence at each time point. Advanced glycation end-product formation was greater in lactate PD fluid compared with bicarbonate/lactate PD fluid of equivalent glucose strength. Advanced glycation end-product formation in the lactate PD fluid containing 1.36% glucose was comparable to that in the bicarbonate/lactate PD fluid containing 3.86% glucose. The rate of increase in fluorescence per day was greater in the first 5 days of incubation than in the subsequent 15 days. These results are compatible with the presence of greater amounts of glucose-degradation products in the standard single-compartment bag resulting in enhanced AGE formation.

Bicarbonates↗
PubMed1997

Arylsulphatase A pseudodeficiency in vascular dementia and Alzheimer's disease.

The carrier rates of a genetic marker for arylsulphatase A pseudodeficiency (ASA-PD) were determined in three series of patients with vascular dementia (VaD) or Alzheimer's disease (AD). In the first community-based sample, the 1524 + 95A-->G mutation, which is known to be associated with ASA-PD, was present in 35% of VaD cases and none of the AD cases. In a second sample of cases drawn from a Dementia Register, the mutation rates were 18% (VaD) and 16% (AD). Brain DNA from a post-mortem sample revealed the ASA-PD mutation in 60% of VaD cases and 34% of AD cases. These rates are higher than previous studies of culturally similar populations and suggest that ASA-PD may be a risk factor for dementia.

Adenine↗
PubMed1997

Non-cholinergic, trophic action of recombinant acetylcholinesterase on mid-brain dopaminergic neurons.

Acetylcholinesterase (AChE) is secreted from various brain regions such as the substantia nigra, where levels of this molecule are disproportionately higher than those of choline acetyltransferase. It is thus possible that AChE may have alternative, non-cholinergic functions, one of which could be in development. Indeed, several recent studies have already demonstrated a neurotrophic action of AChE independent of hydrolysis of acetylcholine. In the developing nervous system the dominant forms of AChE differ from the tetramers (G4) that prevail in maturity, in that they are lower molecular weight monomers (G1) and dimers (G2). Therefore, the aims of this study were to explore the neurotrophic role of AChE by comparing the effects of mouse recombinant G1 and G4 AChE on the survival and development of mid-brain tyrosine hydroxylase immunoreactive neurons. Butyrylcholinesterase (BuChE), which also hydrolyses acetylcholine, and basic fibroblast growth factor (bFGF), an established trophic factor for midbrain neurons, were also tested. bFGF had no significant stimulatory effect: moreover, BuChE was also inefficacious, suggesting that the action of AChE was independent of its catalytic site. In contrast, mouse recombinant G1 and G4 AChE both increased the survival as well as the outgrowth of the cultured neurons. However, G1 AChE was more potent than G4 AChE suggesting that developmental forms of AChE exist. The implications of this finding for physiological and pathological functioning of the nervous system are discussed.

Acetylcholinesterase↗
PubMed1997

Sympathetic cardioneuropathy in dysautonomias.

BACKGROUND: The classification of dysautonomias has been confusing, and the pathophysiology obscure. We examined sympathetic innervation of the heart in patients with acquired, idiopathic dysautonomias using thoracic positron-emission tomography and assessments of the entry rate of the sympathetic neurotransmitter norepinephrine into the cardiac venous drainage (cardiac norepinephrine spillover). We related the laboratory findings to signs of sympathetic neurocirculatory failure (orthostatic hypotension and abnormal blood-pressure responses associated with the Valsalva maneuver), central neural degeneration, and responsiveness to treatment with levodopa-carbidopa (Sinemet). METHODS: Cardiac scans were obtained after intravenous administration of 6-[18F]fluorodopamine in 26 patients with dysautonomia. Fourteen had sympathetic neurocirculatory failure--three with no signs of central neurodegeneration (pure autonomic failure), two with parkinsonism responsive to treatment with levodopa-carbidopa, and nine with central neurodegeneration unresponsive to treatment with levodopa-carbidopa (the Shy-Drager syndrome). The rates of cardiac norepinephrine spillover were estimated on the basis of concentrations of intravenously infused [3H]norepinephrine during catheterization of the right side of the heart. RESULTS: Patients with pure autonomic failure or parkinsonism and sympathetic neurocirculatory failure had no myocardial 6-[18F]fluorodopamine-derived radioactivity or cardiac norepinephrine spillover, indicating loss of myocardial sympathetic-nerve terminals, whereas patients with the Shy-Drager syndrome had increased levels of 6-[18F]fluorodopamine-derived radioactivity, indicating intact sympathetic terminals and absent nerve traffic. Patients with dysautonomia who did not have sympathetic neurocirculatory failure had normal levels of 6-[18F]fluorodopamine-derived radioactivity in myocardium and normal rates of cardiac norepinephrine spillover. CONCLUSIONS: The results of 6-[18F]fluorodopamine positron-emission tomography and neurochemical analyses support a new clinical pathophysiologic classification of dysautonomias, based on the occurrence of sympathetic neurocirculatory failure, signs of central neurodegeneration, and responsiveness to levodopa-carbidopa.

Adult↗
PubMed1997

Allelic functional variation of serotonin transporter expression is a susceptibility factor for late onset Alzheimer's disease.

We examined a deletion/insertion promoter polymorphism of the serotonin transporter gene, which confers an approximately 40% reduction in expression of the protein, in 196 subjects with late onset Alzheimer's disease (AD) and 271 controls. The frequency of the 484 bp low activity allele was elevated in the subjects with AD (p = 0.004), and an excess of the low activity genotype (30%) was also found in comparison with the controls (20%) (chi 2 = 7.16; p = 0.03). This association was unrelated to the age of the subjects or controls, or to epsilon 4 alleles of the ApoE gene. The odds ratio for the effect of the homozygous low activity genotype was 1.7 (95% CI 1.08-2.67), with a population attributable risk of 33% (95% CI 5-54%). These findings indicate that the low activity allele of the serotonin transporter is a risk factor for late onset AD.

Age of Onset↗
PubMed1997

6-[18F]fluorodopamine positron emission tomographic scanning in the assessment of cardiac sympathoneural function--studies in normal humans.

Thoracic positron emission tomographic (PET) scanning after injection of 6-[18F]fluorodopamine ([18F]-6F-DA) visualizes cardiac sympathetic innervation. We tested whether changes in curves relating myocardial [18F]-6F-DA-derived radioactivity with time (time-activity curves, TACs) can reflect changes in important aspects of cardiac sympathetic function. Thoracic PET scans were obtained after intravenous administration of [18F]-6F-DA or the perfusion imaging agent [13N]ammonia into normal volunteers. Ganglion blockade with trimethaphan (TRI) was used to decrease sympathoneural traffic, desipramine (DMI) to block neuronal uptake of catecholamines, and tyramine (TYR) to displace vesicular amines. After [18F]-6F-DA administration, myocardial concentrations of [18F]-6F-DA-derived radioactivity declined bi-exponentially from the peak value. TRI increased the y-intercept (yo) value for the early phase (p = 0.01), and DMI decreased the yo for the late phase (p = 0.01). The TRI effect did not result from increased arterial [18F]-6F-DA concentrations or from increased myocardial perfusion. TYR infusion, begun 90 min after [18F]-6F-DA administration, accelerated the decline of myocardial radioactivity by 2.6-fold (p = 0.003). Alterations in post-ganglionic sympathoneural traffic, neuronal catecholamine uptake, and vesicular turnover of monoamines produce distinct changes in myocardial TACs after [18F]-6F-DA injection. [18F]-6F-DA PET scanning may therefore enable assessments of effects of stressors, drugs, and neurocardiological disorders on specific aspects of cardiac sympathoneural function.

Adrenergic Uptake Inhibitors↗
PubMed1997

The epidemiology of DSM-III-R bipolar I disorder in a general population survey.

BACKGROUND: Data are presented on the general population epidemiology of DSM-III-R bipolar I disorder in the United States. METHODS: Data come from the US National Comorbidity Survey (NCS), a general population survey of DSM-III-R disorders. A modified version of the Composite International Diagnostic Interview was used to make diagnoses. RESULTS: A small (N = 59) clinical reappraisal study showed that the only manic symptom profile that could validly be assessed with the CIDI is characterized by euphoria, grandiosity and the ability to maintain energy without sleep, which described approximately half of all clinically validated bipolar I cases in the NCS. Further analysis focused on this symptom profile, which involved N = 29 cases in the total sample. Lifetime prevalence was estimated to be 0.4% and 12-month prevalence only slightly lower. Caseness was negatively related to income, education and age, positively related to urbanicity, and elevated among the previously married, never married and non-whites. All cases reported at least one other NCS/DSM-III-R disorder and 59.3% reported that their episode of bipolar disorder (either mania or depression) occurred at a later age than at least one other NCS/DSM-III-R disorder. Although 93.2% of lifetime cases reported some lifetime treatment, only 44.7% of recent cases were in treatment. CONCLUSIONS: The type of bipolar disorder examined here is highly chronic, co-morbid and impairing. Increased efforts are required to attract current cases into appropriate treatment. Methodological research is needed to develop more accurate measures of other bipolar symptom profiles for use in general population epidemiological studies.

Age of Onset↗
PubMed1997

Effects of elevated plasma epinephrine on glucose utilization and blood flow in conscious rat brain.

Acute glucoprivation increases cerebral blood flow (CBF), which is often attributed to the associated rise in plasma epinephrine levels. This study examined directly the effects of comparable increases in plasma epinephrine levels achieved by continuous intravenous infusions of epinephrine in normoglycemic, unanesthetized rats on local and overall CBF and cerebral glucose utilization (1CMRglc). CBF was determined by the autoradiographic [14C]iodoantipyrine method in six unanesthetized rats in which epinephrine dissolved in 1% ascorbic acid-1 mM EDTA was infused at a rate of 1 microg/min and in five normal controls infused with the vehicle alone. 1CMRglc was determined by the autoradiographic [14C]deoxyglucose method in six conscious rats infused similarly with the epinephrine solution and in six normal controls treated with the vehicle alone. The epinephrine infusions raised arterial plasma epinephrine levels 10- to 20-fold and increased arterial blood pressure and plasma glucose levels. Local CBF, however, was significantly changed (P < 0.05, Student's t-test) in only 2 of 25 structures examined, and the changes were decreases not increases. 1CMRglc was not changed significantly in any of 42 brain structures examined, and average blood flow and glucose utilization in the brain as a whole were unaffected. These results show that high circulating levels of epinephrine similar to those accompanying glucoprivation alter neither local nor overall CBF and glucose utilization and cannot explain the increases in CBF associated with glucoprivation.

Animals↗