Alpha-synuclein pathology is highly dependent on the case selection

Lewy bodies and dystrophic neurites have been considered a common substrate for dementia, but they are also frequently found in the normal elderly population. The primary component of this pathology involves alpha-synuclein. The main objective of the present study was to estimate the prevalence of alpha-synuclein pathology in aged population, and to assess its relative significance in relation to dementia. The study also investigated whether differences could be detected in alpha-synuclein pathology in relation to age, gender or concomitant Alzheimer's pathology. Furthermore, the influence of sampling strategies was analysed. Alpha-synuclein pathology was assessed using immunohistochemistry in well-characterized post-mortem material. The investigation included patients from a longitudinal study of dementia of Alzheimer's type (n = 103, 85% demented), subjects from a prospective longitudinal clinical study of ageing (n = 69, 29% demented), a cohort of consecutive clinical post-mortem cases collected for 1 year (n = 262, 12% demented), a sample of forensic post-mortem cases collected for 6 months (n = 121, 15% demented) and a sample of Brain Bank material (n = 234, 26% demented). Overall, alpha-synuclein pathology was found in 14% of all 774 subjects over 40 years of age, and this percentage varied from 8% to 27% according to sampling strategies. These results indicate that the prevalence of alpha-synuclein pathology clearly depends on the selection of material. Furthermore alpha-synuclein pathology was found in 23% of clinically demented patients and in 11% of non-demented subjects. The load of alpha-synuclein pathology was significantly greater in the demented patients versus non-demented subjects indicating that alpha-synuclein pathology is indeed of importance in the pathogenesis of dementia.     

A morphometric MRI study of the hippocampus in first-episode, neuroleptic-naïve schizophrenia

Magnetic resonance imaging (MRI) studies have frequently, although not unambiguously, reported hippocampal volume deficit in schizophrenia. Data on the hippocampal volumes in first-episode schizophrenia, however, are sparse. In addition, a recent topographic MRI study proposed a regionally specific volume loss in the hippocampus of chronic schizophrenics, but to date no reports have replicated this finding. In this study two-dimensional MRI-based topographic brain mapping was used to study the possibility of regional changes in the hippocampus of 22 controls and 18 patients with first-episode, neuroleptic-na?ve schizophrenia. Compared to controls, there were no significant differences between hippocampal volumes, regional volumes, or length of the hippocampus in the patients with schizophrenia. These data are at odds with the previous reports on hippocampal volume loss in first-episode schizophrenia, and with the hypothesis of regionally specific hippocampal volume deficit in schizophrenia.     

Intron 4 polymorphism of the endothelial nitric oxide synthase gene is associated with elevated blood pressure in type 2 diabetic patients with coronary heart disease

The endothelial nitric oxide synthase (eNOS) gene is responsible for constitutive nitric oxide synthesis and arterial vasodilatation. Recently two polymorphisms, the 27-bp repeat sequence in intron 4 and the Glu298Asp substitution in exon 7 of the eNOS gene have been reported to be related to coronary heart disease (CHD). We screened these polymorphisms of the eNOS gene in 308 unrelated nondiabetic subjects with CHD, in 251 unrelated patients with type 2 diabetes with CHD, and in 110 randomly selected healthy subjects without CHD. The 4a and Asp298 allele frequencies of the eNOS gene were 0.19 and 0.36 in nondiabetic patients with CHD, 0.21 and 0.27 in type 2 diabetic patients with CHD, and 0.16 and 0.31 in nondiabetic subjects without CHD (n.s. between the groups). The Asp298 allele in exon 7 of the eNOS gene was not associated with elevated blood pressure in any of the study groups. Among type 2 diabetic patients with CHD the 4a allele in intron 4 of the eNOS gene was associated with elevated levels of systolic (P=0.035) and mean arterial blood pressure (P=0.040). In nondiabetic subjects these associations were not statistically significant. When all study groups were pooled in statistical analysis the 4a allele of the eNOS gene was associated with elevated diastolic (P=0.032) and mean (P=0.030) arterial blood pressure even after adjustment for confounding factors. We conclude that the 4a allele of the eNOS gene is not associated with CHD or type 2 diabetes, but that it is related to elevated blood pressure levels particularly among type 2 diabetic patients with CHD.     

Reactive microglia in aging and dementia: an immunohistochemical study of postmortem human brain tissue

Significantly increased up-regulation of HLA DR (major histocompatibility complex class II antigen) was seen using immunohistochemistry in postmortem brain tissue from demented patients with Alzheimer’s disease (AD) (73 cases, 61 females/12 males, mean age 84 ± 9 years) compared to controls (22 cases, 10 females/12 males, mean age 78 ± 9 years). The counts of HLA DR-expressing activated microglia were significantly higher in female AD patients compared to males, significantly higher in AD patients with the age at death greater than 75 years compared to those dying younger and higher, although not statistically significantly, in AD patients with the apolipoprotein E (ApoE) ɛ4 allele compared to those patients not carrying this allele. In contrast to the situation in AD patients, in the control cases the HLA DR expression was higher in males compared to females. Furthermore, in the very old non-demented patients (age at death > 80 years), a decrease in the up-regulation of HLA DR expression was observed. A significant correlation between activated microglia and neurofibrillary tangles was seen in female AD patients compared to males, in AD cases without ApoE ɛ4 allele compared to those with this allele, in sporadic cases compared to familial and in cases with senile rather than presenile onset of the disease. Our results indicate that there is an age- and/or sex-related variability in up-regulation of HLA DR expression of microglia and that the linkage between this up-regulation and AD lesions is significantly influenced by the ApoE ɛ4 allele, gender of subjects, age at onset and familiality of the disease. Received: 20 May 1998 / Revised: 5 August 1998, 4 October 1998 / Accepted: 21 October 1998     

Repeatability of C-peptide response in glucagon stimulation test

Measurement of the plasma C-peptide level before and after iv administration of 1 mg of glucagon was repeated four times in 10 elderly non-diabetic subjects and in 20 elderly non-insulin-dependent diabetics treated with diet or oral drugs to assess the repeatability of the C-peptide responses. Plasma C-peptide levels before and after glucagon administration and C-peptide glucose ratios in the four measurements did not differ significantly from test to test either in diabetic or non-diabetic subjects. The results of the present study indicate that the repeatability of C-peptide response to glucagon is very good both in non-insulin-dependent diabetics and in non-diabetic subjects.     

Plasma insulin, serum lipids and lipoproteins in gall stone disease in non-insulin dependent diabetic subjects: a case control study.

Fasting insulin, lipids and lipoproteins were measured in 22 middle aged female non-insulin dependent diabetics with gall stone disease (cases) and in 22 non-insulin dependent diabetics without gall stone disease (controls). The groups were matched for sex, age, obesity, and fasting glucose concentrations. No differences were observed between the cases and controls in duration of diabetes, glycated haemoglobin A1, alcohol intake, smoking, use of cardiovascular drugs or a history of myocardial infarction. Diabetics with gall stone disease had higher fasting insulin concentrations (p less than 0.5), lower total (p less than 0.01) and low density lipoprotein cholesterol (p less than 0.01) and high density lipoprotein cholesterol (not statistically significant) concentrations than diabetics without gall stone disease. These changes in insulin, lipids and lipoproteins are similar to reported changes in non-diabetic subjects with gall stone disease. Therefore, they are characteristic for gall stone disease and not as such explanatory to an increased risk of gall stones in patients with non-insulin dependent diabetes.     

Hyperglycemia and cardiovascular disease in type 2 diabetes.

Cardiovascular disease (coronary heart disease, stroke, peripheral vascular disease) is the most important cause of mortality and morbidity among patients with type 2 diabetes. Conventional risk factors contribute similarly to macrovascular complications in patients with type 2 diabetes and nondiabetic subjects, and therefore, other explanations have been sought for enhanced atherothrombosis in type 2 diabetes. Among characteristics specific for type 2 diabetes, hyperglycemia has recently been a focus of keen research. A recent meta-analysis of 20 studies on nondiabetic subjects has demonstrated that in the nondiabetic range of glycemia (<6.1 mmol/l), increased glucose is already associated with an increased risk for cardiovascular disease. Similarly, 12 recent prospective studies have convincingly indicated that hyperglycemia contributes to cardiovascular complications in patients with type 2 diabetes. The recently published U.K. Prospective Diabetes Study has shown that intensive glucose control reduces effectively microvascular complications among patients with type 2 diabetes, but that its effect on the prevention of cardiovascular complications was limited. Given the fact that in the U.K. Prospective Diabetes Study, none of the treatment modalities was particularly effective in reducing glucose, this underestimates the true potential of the correction of hyperglycemia in the prevention of cardiovascular disease in type 2 diabetes. However, in addition to intensive therapy of hyperglycemia, other conventional risk factors should also be normalized to prevent cardiovascular disease in patients with type 2 diabetes.     

Somatostatin-like immunoreactivity in the cerebrospinal fluid of patients with Parkinson''s disease and its relation to dementia.

Acetylcholinesterase, somatostatin-like immunoreactivity, and homovanillic acid levels were measured in the cerebrospinal fluid of 36 patients with early stages of Parkinson's disease and in 19 control patients. In patients with Parkinson's disease the levels of somatostatin-like immunoreactivity were lower than in the controls (p less than 0.01); these values were lowest in the demented Parkinsonian patients. Concentrations of homovanillic acid were also significantly lower in Parkinsonian patients (p less than 0.05). In contrast, no changes were observed in the acetylcholinesterase activity of patients with Parkinson's disease. The reduced somatostatin-like immunoreactivity in CSF agrees with previous post-mortem studies and indicates that Parkinson's disease and Alzheimer's disease may have some neurochemical features in common.     

Cardiovascular protection for all individuals at high risk: evidence-based best practice

Patients with cardiovascular risk factors are largely undertreated, for many reasons. Vulnerable individuals may not be aware of the risks they are facing or an individual’s risk of cardiovascular disease may be underestimated, particularly among those at high risk. Furthermore, in individuals identified as being at high total cardiovascular risk, the full spectrum of therapeutic options may not be implemented or patients may not adhere to the treatment prescribed. We address these critical issues by summarizing the existing guidelines: our ultimate goal is to encourage the optimal management of individuals at high total cardiovascular risk according to evidence-based medicine, with the expectation that this will improve outcomes.