Abstract: Endothelial cells are among the main physiological targets of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). In endothelial cells TNF-alpha elicits a broad spectrum of biological effects including differentiation, proliferation and apoptosis. alpha1-antitrypsin (AAT), an endogenous inhibitor of serine proteases plays a vital role in protecting host tissue from proteolytic injury at sites of inflammation. Recently, it has been shown that AAT can be internalized by pulmonary endothelial cells, raising speculation that it may modulate endothelial cell function in addition to suppressing protease activity. Using Affymetrix microarray technology, real time PCR and ELISA methods we have investigated the effects of AAT on un-stimulated and TNF-alpha stimulated human primary lung microvascular endothelial cell gene expression and protein secretion. We find that AAT and TNF-alpha generally induced expression of distinct gene families with AAT exhibiting little activity in terms of inflammatory gene expression. Approximately 25% of genes up regulated by TNF-alpha were inhibited by co-administration of AAT including TNF-alpha-induced self expression. Surprisingly, the effects of AAT on TNF-alpha-induced self expression was inhibited equally well by oxidized AAT, a modified form of AAT, which lacks serine protease inhibitor activity. Overall, the pattern of gene expression regulated by native and oxidized AAT was similar with neither inducing pro-inflammatory gene expression. These findings suggest that inhibitory effects of native and oxidized forms of AAT on TNF-alpha stimulated gene expression may play an important role in limiting the uncontrolled endothelial cell activation and vascular injury in inflammatory disease.
Abstract: This study aimed to identify preclinical Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) using measurements of both regional cerebral blood flow (rCBF) and cerebrospinal fluid (CSF) biomarkers. Baseline rCBF assessments ((133)Xe method) were performed in 70 patients with MCI who were cognitively stable for 4-6 years, 69 patients with MCI who subsequently developed AD, and 33 healthy individuals. CSF was collected at baseline and analyzed for beta-amyloid(1-42), total tau and phophorylated tau. In contrast to patients with stable MCI, those who subsequently developed AD had decreased rCBF in the temporo-parietal cortex already at baseline. The relative risk of future progression to AD was particularly increased in MCI patients with decreased rCBF in parietal cortex (hazard ratio 3.1, P<0.0001). Subjects with pathological levels of both CSF tau and beta-amyloid(1-42) were also at high risk of developing AD (hazard ratio 13.4, P<0.0001). The MCI patients with a combination of decreased parietal rCBF and pathological CSF biomarkers at baseline had a substantially increased risk of future development of AD, with a hazard ratio of 24.3 (P<0.0001), when compared to those with normal CSF biomarkers. Moreover, decreased parietal rCBF (but not CSF biomarkers) was associated with a more rapid progression to AD. In conclusion, the combination of rCBF and CSF biomarkers improves the risk assessment of progression to AD in patients with MCI.
Abstract: BACKGROUND: Cognitive-enhancing effects of vagus nerve stimulation (VNS) have been reported during 6 months of treatment in a pilot study of patients with Alzheimer's disease (AD). Data through 1 year of VNS (collected from June 2000 to September 2003) are now reported. METHOD: All patients (N = 17) met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD. Responder rates for the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Mini-Mental State Examination (MMSE) were measured as improvement or absence of decline from baseline. Global change, depressive symptoms, and quality of life were also assessed. Cerebrospinal fluid (CSF) levels for total tau, tau phosphorylated at Thr181 (phosphotau), and Abeta42 were measured by standardized enzyme-linked immunosorbent assay (ELISA). RESULTS: VNS was well tolerated. After 1 year, 7 (41.2%) of 17 patients and 12 (70.6%) of 17 patients improved or did not decline from baseline on the ADAS-cog and MMSE, respectively. Twelve of 17 patients were rated as having no change or some improvement from baseline on the Clinician Interview-Based Impression of Change (CIBIC+). No significant decline in mood, behavior, or quality of life occurred during 1 year of treatment. The median change in CSF tau at 1 year was a reduction of 4.8% (p = .057), with a 5.0% increase in phosphotau (p = .040; N = 14). CONCLUSION: The results of this study support long-term tolerability of VNS among patients with AD and warrant further investigation.
Abstract: Rapid automatic naming tasks are clinical tools for probing brain functions that underlie normal cognition. To compare performance for various stimuli in normal subjects and assess the effect of aging, we administered six single-dimension stimuli (color, form, number, letter, animal, and object) and five dual-dimension stimuli (color-form, color-number, color-letter, color-animal, and color-object) to 144 normal volunteers who ranged in age from 15 to 85 years. Rapid automatic naming times for letters and numbers were significantly less than for forms, animals, and objects. Rapid automatic naming times for color-number and color-letter stimuli were significantly less than for color-form, color-animal, or color-object stimuli. Age correlated significantly with rapid automatic naming time for each single-dimension stimulus and for color-form, color-number, color-animal, and color-object stimuli. Linear regression showed that rapid automatic naming times increased with age for aggregated color stimuli, aggregated single-dimension stimuli, and aggregated dual-dimension stimuli. This age effect persisted in subgroups less than 60 years of age and greater than 60 years of age. We conclude that normal performance time is dependent on the task, with letter and number stimuli eliciting most rapid responses, and that most rapid automatic naming times increase with age.
Abstract: Neural networks have been successfully applied to brain perfusion images to classify patients with Alzheimer's disease from normal or other patient populations. Given the recognition that Alzheimer's disease constitutes a heterogeneous disorder, the identification of subgroups sharing common functional brain deficits would constitute a further improvement in the utility of such methods. Therefore, we aimed to investigate whether neural networks could discriminate cortical perfusion deficits of patients with Alzheimer's disease from normal brain perfusion. A second step was to identify subgroups of patients sharing similar perfusion deficits. The study population consisted of one group of 92 normal healthy subjects and one group of 132 patients with mild-to-moderate Alzheimer's disease. The patients were diagnosed according to established criteria (DSM-IV and NINCDS-ADRDA). Regional cerebral blood flow was assessed by the non-invasive (133)Xe inhalation method, using a 64-detector system for measurements of blood flow in superficial cortical areas. The regional blood flow values were used as the only input to artificial neural networks with multilayer Perceptron architecture. The networks were trained using the back-propagation updating algorithm. A fourfold cross validation procedure was used in order to obtain the most reliable performance of the networks. The performance of the neural network, measured as the area under the receiver-operating characteristic curve, was 0.94, with a sensitivity for Alzheimer's disease of 86% at a specificity of 90%. An analysis of the relative importance of cortical areas in the discrimination showed that left parietal areas were more important than the right homologous ones. A clustering analysis of the Alzheimer patients identified three or four subgroups of patients with clearly different combinations of blood flow pathology. A consistent finding in all subgroups was a significant deficit in temporoparietal blood flow of both hemispheres. Distinct group differences were seen in frontal, central and occipital areas with different combinations of involvement. This is the first study in which neural networks have been applied to brain perfusion images obtained with the (133)Xe inhalation method. The results demonstrate that a classification of patients with Alzheimer's disease obtained with this method is compatible with the best results obtained with other brain imaging methods. The identification of clearly distinguishable patterns of blood flow pathology in subgroups of patients lends further support to the notion that Alzheimer's disease is a heterogeneous disorder.
Abstract: Performances on Alzheimer's Quick Test color-form naming and Mini-Mental State Examination were compared for 38 adults with Alzheimer's disease and 38 age- and sex-matched normal controls. Group means differed significantly and indicated longer naming times by adults with Alzheimer's disease. The specificity for AQT color-form naming was 97% and sensitivity 97%, i.e., 3% false negatives. The specificity for Mini-Mental State Examination was 100% and sensitivity 84%, i.e., 16% false negatives. These findings, while supporting AQT color-form naming as a screening test for reductions in cognitive speed associated with Alzheimer's disease, are preliminary given the relatively small sample.
Abstract: It has been suggested that a number of molecules associated with inflammation are involved in the pathogenesis of Alzheimer's disease (AD). We measured the levels of alpha(1)-antichymotrypsin (ACT), alpha(1)-antitrypsin (AAT), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and oxidised low-density lipoprotein (oxLDL) in matched cerebrospinal fluid (CSF) and plasma of 141 patients with probable AD. We found a significant relationship between CSF and plasma levels of ACT (r = 0.4, p < 0.001), IL-6 (r = 0.74, p < 0.001), MCP-1 (r = 0.71, p < 0.001), and a borderline relationship between CSF and plasma oxLDL (r = 0.22, p < 0.05). In addition, linear regression analysis revealed a positive correlation between levels of CSF-ACT and oxLDL (p < 0.001), but an inverse relation between levels of CSF ACT, CSF AAT and MCP-1 (p < 0.001). A significant correlation was also found between levels of CSF ACT, oxLDL and the ratio of CSF to serum albumin, which is used as a measure of the blood-brain barrier function. Our data extend previous reports regarding the inflammatory markers in the plasma and CSF of patients with AD and provide good evidence that levels of ACT, IL-6, MCP-1 and oxLDL in plasma and CSF might be candidates as biomarkers for monitoring the inflammatory process in AD.
Abstract: Three automatic naming tasks (Wiig & Nielsen, 1999) were administered to 60 normally functioning adults. The mean time required for naming 40 single-dimension (colors, forms, numbers, and letters) and 40 dual-dimension stimuli (color-form, color-number, and color-letter combinations) were compared in young (17-38 yr.) and older (40-68 yr.) men and women. Analysis of variance for the combined groups indicated significant naming-time differences for age but not for sex. There were no significant interaction effects. For men there was a significant naming time difference between age groups for forms, and for women for colors and forms. The sex-specific analyses indicated no significant differences in naming time based on age groups for color-form, color-number, or color-letter combinations. In a second study of adult subjects (n = 14), functional brain activity was measured with regional cerebral blood flow during the performance of the color, form, and color-form naming tasks. One subject was repeatedly measured during the performance of each task, whereas 13 subjects were measured during the performance of color-form naming. In comparison to normal reference values for rest and FAS verbal fluency, blood-flow measurements showed a consistent parietal-lobe activation during form and color-form naming, but only a slight activation during color naming. During all naming tasks, a significant frontal and frontotemporal flow decrease was seen in comparison to both rest and verbal fluency reference values. This functional brain activation pattern of a parietal increase and a frontotemporal decrease was consistently confirmed across subjects during the color-form naming task.
Abstract: This study examined the neurophysiological effects of cannabis. Cerebral blood flow (CBF) was measured in 12 long-term cannabis users shortly after cessation of cannabis use (mean 1.6 days). The findings showed significantly lower mean hemispheric blood flow values and significantly lower frontal values in the cannabis subjects compared to normal controls. The results suggest that the functional level of the frontal lobes is affected by long-term cannabis use.
Abstract: We investigated the relation between cobalamin deficiency, clinical changes and brain function in dementia patients. On admittance to the clinic, 24 patients had cobalamin deficiency, and dementia with additional symptoms of delirium. During cobalamin supplementation, the patients underwent repeated regional cerebral blood flow (rCBF) studies, psychiatric evaluations, and in some cases assessment with MMSE and the Organic Brain Syndrome scale. Fifteen patients who showed mild to moderate dementia improved clinically, and also showed a concomitant increase in their general CBF after treatment. In contrast, 9 patients who were severely demented showed no obvious clinical improvement, and no general blood flow change, although some regional flow increases were seen in sensory motor areas. We conclude that symptoms which probably indicated superimposed delirium such as clouding of consciousness, disorientation and clinical fluctuation, responded to the vitamin B12 supplementation, while the underlying dementia condition remained basically unchanged. The clinical improvement was also mirrored in general and focal rCBF changes.
Abstract: In order to evaluate the functional significance of synaptic pathology, synaptic density was quantitated and related to clinical symptomatology and regional cerebral blood flow (rCBF) in 8 patients with frontal lobe degeneration of non-Alzheimer type (FLD) and 19 patients with Alzheimer's disease (AD). Synaptic density was measured in all layers of prefrontal and parietal cortex. The clinical picture of FLD was dominated by a frontal lobe syndrome with changes in personality and behavior, while AD was dominated by temporoparietal symptoms. This parallels the finding of frontal rCBF reductions in FLD patients and temporoparietal reductions in AD patients. Synaptic density was significantly decreased in both FLD and AD, with a regional severity which closely correlated with that of the degeneration, symptomatology and rCBF deficit. The results suggest that synaptic pathology is a likely cause of clinical symptoms and regional metabolic decrement in dementia.
Abstract: Measurements of regional cerebral blood flow (rCBF) were performed in 16 women suffering from spider phobia. The non-invasive 133Xe inhalation method, giving information about the blood flow of superficial areas, was used. The subjects were studied under three conditions: during resting, when exposed to a videotape showing nature scenery, and finally when watching a video with living spiders. During the rCBF measurements the subjects' behaviour was registered systematically and respiration, blood pressure, Pco2, and heart rate were monitored. Eight subjects who showed and reported severe panic during the spider exposure had marked rCBF decreases in frontal areas, especially in the right hemisphere. The remaining eight subjects displayed a more efficient control of their emotions and became frightened, but not panic-stricken, during the spider exposure. These showed a consistent rCBF increase in the right frontal area compared to neutral stimulation. Thus, results revealed significant functional changes in the frontal cortex in subjects with spider phobia during phobogenic exposure. It seems likely that these frontal changes are related to the experience and control of phobic anxiety.
Abstract: Patterns of functional cortical activation were studied by means of regional cerebral blood flow measurements, performed during rest and during a word fluency task in normal subjects (n = 22), in patients with Alzheimer's disease (n = 17), and in patients with frontotemporal dementia (n = 15). Although all groups showed a significant activation of the Broca's area during word production, the activation of the dorsolateral prefrontal cortex was clearly subnormal in both dementia groups. The frontal dysfunction was not explained by number of words produced, illness duration, or age. Thus, the results demonstrate that the word fluency task is a sensitive measure of frontal lobe function, and its incorporation in imaging studies may facilitate the detection of subtle functional impairment of the frontal lobes in organic dementia.
Abstract: OBJECTIVE: To determine the prevalence of orthostatic hypotension (OH), low blood pressure and dizziness, falls and fractures in patients with organic dementia. DESIGN: We prospectively studied 151 patients, assessing the prevalence of OH, hypertension, heart disorders, diabetes mellitus and the use of medication possibly associated with OH. SETTING: The patients were admitted to our psychogeriatric clinic as part of routine clinical investigation of their dementia. PATIENTS: Forty-six patients with Alzheimer's disease (AD), 28 patients with frontotemporal dementia (FTD) and 77 patients with vascular dementia (VaD) were investigated. MAIN OUTCOME MEASURE: Due to the paucity of information about the prevalence of OH in organic dementia, this study is mainly explorative in nature, thus preventing explicit hypothesis formulation. However, clinical impressions indicated a higher prevalence of OH in organic dementia than normally seen in healthy elderly. RESULTS: OH/low blood pressure was present in 39-52% of the patients. The majority reached their maximum systolic decrease within 5 minutes of standing, but in 20-30% the maximum blood pressure drop occurred after 5 minutes or later. In 38%, the systolic blood pressure drop was more than 40 mm Hg. Hypertension and heart disease was found only in AD and VaD, with no difference between those with and without OH/low blood pressure. Falls and fractures were common in orthostatic and hypotensive patients, with an incidence of more than 50% in AD and VaD. CONCLUSIONS: The results support our clinical impressions that OH and low blood pressure is common and an important factor in organic dementia.
Abstract: Regional cerebral blood flow was measured in 35 patients with organic dementia (Alzheimer's disease, n = 13, vascular dementia, n = 17, frontotemporal dementia, n = 5) and orthostatic hypotension. Measurements were performed during supine rest and during head-up tilt (60 degrees). Despite marked blood pressure falls, few patients had symptoms of orthostatic hypotension. All three dementia groups had a decrease in regional cerebral blood flow in the frontal lobes during head-up tilt, but no change in mean hemispheric flow. All patients had a consistent drop in their systolic blood pressure upon head-up tilt, with a wide variation over time. The findings suggest that orthostatic hypotension needs to be considered, and actively sought for, in organic dementia as many patients may lack the typical symptoms of orthostatic hypotension, despite a marked fall in blood pressure.
Abstract: Neuropsychological test performance and clinical symptoms were assessed in 14 schizophrenic patients at admission to and discharge from an acute inpatient psychiatric service. Despite significant clinical improvement at discharge, no major change in cognitive performance was observed. Furthermore, patients at discharge were significantly impaired compared with normal control subjects case-matched for gender, age, handedness and level of education. The results suggest that some degree of cognitive impairment may be relatively independent from schizophrenic symptoms and that such impairment may represent part of a residual enduring "trait" vulnerability.
Abstract: The present study examined the utility of the Word Fluency Test (WFT) as a frontal-lobe-activating test in brain imaging. Regional cerebral blood flow (rCBF) was measured during rest and during the WFT in 49 healthy volunteers and in 15 patients with frontal lobe dementia (FLD). The results showed a highly significant frontal lobe activation in 85% of the normal subjects. This finding was not related to age or to the level of performance on the WFT. A significant frontal activation was seen in 13 of the 15 FLD patients. The frontal flow increase did not reach normal levels, and was not related to age, illness duration or severity of clinical symptoms. The results suggest that the WFT is an ideal test to use in conjunction with functional imaging in normals as well as in patients with organic dementia.
Abstract: Twenty-five out of 26 cases of autopsy-verified frontal lobe degeneration of non-Alzheimer type (FLD) were found to have focal frontal or frontotemporal blood flow reductions involving both hemispheres. The deviant case had an asymmetric frontal pathology only apparent on the right side. Focal reduction of blood flow in the frontal lobes is, however, a common and unspecific flow abnormality found in e.g. Pick's disease. Creutzfeldt-Jakob's disease, and in some cases of Alzheimer's disease. Low frontal flow has also been reported in schizophrenia and in toxic encephalopathy. Since a characteristic feature of FLD is a steady progress of the pathology, serial flow measurements extending over several years are especially informative.
Abstract: Regional cerebral blood flow was measured with the 133-Xenon inhalation method in seven healthy subjects with orthostatic hypotension not due to autonomic failure (i.e. non-neurogenic clinical disorder). Measurements were performed during supine rest and during head-up tilt (70 degrees). All subjects had a consistent drop in systolic blood pressure and the typical symptomatology of orthostatic hypotension. The results showed lower mean hemispheric blood flow during head-up tilt than during supine rest. In addition, a consistent and significant redistribution of the regional flow values was seen, with a reduction in frontal and an increase in postcentral areas. The frontal flow decrease during tilt was more marked than in subjects without orthostatic hypotension and was not related to variations in the level of PCO2 or to respiration. In contrast to the clinical symptoms of orthostatic hypotension (dizziness, nausea, visual disturbances, and in some cases syncope), the cortical blood flow reduction was, however, relatively moderate.
Abstract: Eight patients meeting Leonhard's criteria for cycloid psychosis were investigated on repeated occasions during a psychotic episode, with regional cerebral blood flow measurements and clinical ratings. The results showed that, at admission to the hospital, when the patients were clinically exacerbated, the mean hemispheric blood flow was significantly elevated compared with values from a normal control group. The hemispheric blood flow level covaried significantly with the degree of clinical symptoms, such that the more elevated the cortical blood flow was, the more behaviorally disturbed was the patient. At discharge from the hospital, the patients had no residual symptoms and the cortical blood flow was normal. These findings differ distinctly from those commonly made in other psychoses, such as schizophrenia.
Abstract: Regional cerebral blood flow was measured in 21 normotensive subjects during supine rest and during head-up tilt to 70 degrees. The results showed significant and consistent regional cerebral blood flow changes in the frontal areas with lower relative flow distribution values (percentage of mean flow) during head-up tilt than during supine rest. The lower frontal flow distribution values during tilt were not related to habituation, to repeated measurements, or to the estimated level of arterial CO2 which was derived from expired end-tidal CO2 levels. None of the subjects had orthostatic hypotension and there was no significant difference in mean hemispheric blood flow between lying down and standing up. There was no significant gender difference in regional cerebral blood flow, although female subjects tended to have higher mean hemispheric flow than males in both postures. It remains to be established whether the flow decreases in the frontal cortex are caused by cerebral functional factors or by haemodynamic mechanisms.
Abstract: Regional cerebral blood flow (rCBF) asymmetries were studied in 189 subjects (96 males and 93 females) at rest with the 133Xenon inhalation method using a fixed detector system. rCBF asymmetries in the resting condition were very small, nevertheless a significant (p less than 0.001) effect for their topographical distribution was present, reflecting higher rCBF in the right fronto-temporal and left parieto-occipital regions. rCBF asymmetries were not correlated with age, and there were no significant differences between males and females. Asymmetries are therefore useful from a statistical point of view in detecting rCBF abnormalities in the resting condition: they are more stable than absolute values in normal subjects and no matching according to age or sex is required when statistical comparisons are performed.
Abstract: Regional cerebral blood flow (rCBF) measurements and psychiatric ratings were performed on seven schizophrenic patients (mean age = 41.4 years) who had been examined 18 years previously in a study that used similar psychiatric ratings and a comparable rCBF technique. Neither the clinical symptomatology nor the rCBF level and distribution had changed appreciably between 1972 and 1990. The findings indicate that cerebral functional activity in chronic schizophrenia remains constant in spite of continuous neuroleptic medication.
Abstract: Regional cerebral blood flow (rCBF) measurements and clinical ratings were performed on 17 schizophrenic patients and a subgroup of 10 medication-free patients before and after treatment. While clinically exacerbated patients had normal blood flow, patients in remission showed a redistribution of flow with lower values in frontal areas. Anteroposterior ratios correlated with the degree of behavioral disturbances, suggesting that the level of frontal lobe activity in schizophrenia may be a function of the patient's clinical state at the time of study.
Abstract: Regional cerebral blood flow was measured by the 133-xenon inhalation method during resting in 38 healthy men and 38 healthy women matched pairwise for age in the range 18-72 years. The results showed 11% higher global flow level in the women in all ages. A similar and significant regression of flow by age was seen for both sexes. The regional flow distribution also showed some sex-related differences. Frontal regions showed an asymmetry in the men with higher values on the right side. The female flows were more symmetric. As a hypothesis, it is suggested that the higher flow level in women may be a systemic phenomenon. In fact, other authors have found a higher cardiac index in females. The sex differences in regional flow pattern might be due to differences in the functional organization of the cortex and/or to differences in the mental processes of the "resting" state.
Abstract: Regional cerebral blood flow (rCBF) was measured by the 133Xenon inhalation method in nine male chronic cannabis users. The rCBF level in cannabis users was significantly (11%) lower than that of age- and sex-matched healthy controls. Four of the subjects were reexamined after 9-60 days of detoxification and showed a significant (12%) increase of the CBF level at followup. No significant regional flow abnormalities were noted. The global CBF reduction seen in the early phase of detoxification is most likely the consequence of the dysfunction of the central nervous system accompanying chronic cannabis use.
