Differentiation of adult Leydig cells in the neonatal rat testis is arrested by hypothyroidism

OBJECTIVES: To quantify the rate of cognitive decline on the Mini-Mental State Examination (MMSE) in autopsy-diagnosed Lewy body variant (LBV) of Alzheimer's disease (AD) cases. We hypothesized that LBV patients would have a faster cognitive decline and shorter survival compared with patients with pure AD. BACKGROUND: Prior reports have shown extrapyramidal signs to be associated with a poorer prognosis in AD. It has been suggested that LBV is often characterized by a rapidly progressive course. Few data are available regarding the rate of cognitive decline in autopsy-confirmed LBV dementia cases. METHODS: We searched the databases of the University of California-San Diego Alzheimer's Disease Research Center and the Consortium to Establish a Registry in Alzheimer's Disease (CERAD) for dementia cases with 1) an autopsy diagnosis of definite or probable AD (CERAD criteria) with concomitant Lewy bodies and 2) longitudinal MMSE assessments. This resulted in a series of 40 LBV cases and 148 AD cases without Lewy bodies, with comparable baseline MMSE scores, age, and education. The rate of cognitive decline was calculated as the baseline MMSE -- final MMSE. Methods were devised to reduce floor effects on the MMSE. RESULTS: The average rate of cognitive decline was -5.8 +/- 4.5 points/y in LBV and -4.1 +/- 3.0 points/y in AD (t-test, p < 0.01). The LBV group declined a similar amount on the MMSE (means, -10.0 versus -9.6 points) over a significantly shorter time interval (1.9 versus 2.7 years; p = 0.005) than did AD patients. At baseline, the mean MMSE scores were nearly identical (18.2 in LBV; 17.8 in AD), but on follow-up examinations approximately 1, 2, and 3 years later, there were intergroup mean differences of 1.8 points (two-tailed p = 0.19), 4.2 points (p = 0.04), and 5.6 points (p = 0.03), respectively. The LBV cases had shorter survival time from the onset of cognitive symptoms (7.7 +/- 3.0 years versus 9.3 +/- 3.5 years; p = 0.007) and a shorter mean survival after entry/baseline, which was of marginal significance (3.6 versus 4.1 years; p = 0.11). CONCLUSIONS: This study demonstrates that LBV is characterized by a faster cognitive decline and accelerated mortality compared with AD.     

The EMG development of the longissimus and multifidus muscles after plugging the horizontal semicircular canals

The intercellular adhesion molecule-1 (ICAM-1) expressed by endothelial cells is crucial in promoting adhesion and transmigration of circulating leukocytes across the blood-brain barrier (BBB). Migrated immunocompetent cells, in turn, release mediators that stimulate glial and endothelial cells to express ICAM-1 and release cytokines, possibly sustaining cerebral damage. Following activation, proteolytic cleavage of membrane-anchored ICAM-1 results in measurable levels of a soluble form, sICAM-1. The aims of this study were to investigate the changes of sICAM-1 levels in ventricular CSF and serum and to elucidate the influence of structural brain damage as estimated by computerized tomography (CT) as well as the extent of BBB dysfunction as calculated by the CSF/serum albumin ratio (QA) in patients with severe traumatic brain injury (TBI). All investigated parameters revealed two subgroups. Patients belonging to group A had sICAM-1 levels in CSF above normal range, presented marked cerebral damage and a disturbance of the BBB (range 0.6-24.7 ng/ml, n = 8). In contrast, patients belonging to group B had no elevation of sICAM-1 values in CSF (range 0.3-3.9 ng/ml, n = 5; p < 0.017) and showed minor cerebral damage with an intact BBB in most cases. In addition, overall analysis showed that sICAM-1 in CSF correlated with the extent of BBB damage as indicated by the QA (r = 0.76; p < 0.001). These results suggest that increased sICAM-1 levels in CSF might depict ongoing immunologic activation and that sICAM-1 correlates with the extent of tissue and BBB damage. The origin of soluble ICAM-1 in CSF and its pathophysiologic role after TBI remains to be clarified.     

Circulating leptin has saturable transport into intrathecal space in humans

BACKGROUND: Leptin is an adipocyte-derived hormone that is thought to provide a negative feedback signal to control body fat mass by interacting with its hypothalamic receptor. The present study was undertaken to examine the uptake of leptin in cerebrospinal fluid (CSF) space in humans and whether the transport of leptin into CSF space is an active phenomenon or due to free access through the blood-CSF barrier. METHODS: We determined serum and CSF leptin concentrations by radioimmunoassay in 17 men [42 +/- 4 years, mean +/- SE; body mass index (BMI) 27.3 +/- 1.8 kg m-2] and 22 women (40 +/- 3 years, BMI 25.1 +/- 1.0 kg m-2). The function of the blood-CSF barrier was evaluated by determining the CSF/serum albumin ratio. RESULTS: Serum leptin concentration was lower in male (5.8 +/- 1.6 microgram L-1) than in female subjects (13.1 +/- 1.7 microgram L-1, P = 0. 001), whereas the concentrations of leptin in CSF were virtually identical in male (0.34 +/- 0.03 microgram L-1) and female (0.36 +/- 0. 03 microgram L-1) subjects. Serum leptin was correlated positively with BMI both in men (r = 0.89, P < 0.01, n = 10) and in women (r = 0.61, P < 0.05, n = 14), whereas no correlation between CSF leptin concentration and BMI was found in either group. The CSF/serum leptin ratio correlated negatively with serum leptin concentration both in men (r = -0.93, P < 0.001) and in women (r = -0.77, P < 0. 001) and with BMI both in men (r = -0.75, P = 0.02, n = 10) and in women (r = -0.64, P < 0.02, n = 14). The CSF/serum albumin ratio was not correlated with the CSF/serum leptin ratio in either group. CSF leptin concentrations and the CSF/serum leptin ratio were virtually identical in subjects with impaired and normal blood-CSF barrier function. CONCLUSION: Thus, our data support the presence of a saturable and active transporter of leptin from circulation into intrathecal space.     

External beam radiotherapy versus radical prostatectomy for clinical stage T1-2 prostate cancer: therapeutic implications of stratification by pretreatment PSA levels and biopsy Gleason scores

There is a diversity of opinions concerning the function of the blood-brain barrier and the blood-cerebrospinal fluid barrier (BCB) in Alzheimer disease and other neuropsychiatric disorders. In this paper we investigate and review the evidence for BCB dysfunction in Alzheimer disease and major depression. The hypothetical roles of immunologically mediated mechanisms in the central nervous system (CNS) are discussed. Special consideration is given to methodological factors influencing BCB function and analysis. Serum and cerebrospinal fluid (CSF) of 29 patients with major depression (MD) and 51 patients with "probable Alzheimer disease" (AD) were investigated. The AD patients were subdivided in two groups of 21 early-onset (EO) and 30 late-onset (LO) cases and assayed for concentrations of albumin and IgG. The results were compared with those for 11 age-matched healthy controls. The severity of dementia was assessed with the Mini-Mental State Examination (MMSE). AD and MD patients showed significantly lower serum albumin [AD: p < 0.05 (LO: p < 0.038); MD p < 0.01] and IgG (AD: p < 0.01; MD: p < 0.013) concentrations compared with controls. MD (p < 0.001) and LO-AD (p < 0.07) patients displayed significantly lower absolute serum albumin levels than did EO-AD patients. The CSF/serum ratio for albumin and IgG was used to evaluate BCB function. There were no significant group differences; however, subsets of MD (29%) and AD (16%) patients showed a higher frequency of a pathological albumin ratio than did control subjects. Furthermore, a subset of 24% of MD and18% of AD patients and none of the controls showed an elevated IgG ratio. Different mechanisms of alteration of IgG distribution are presented. The degree of cognitive impairment in AD did not correlate positively with protein and ratio parameters. The BCB is critical to the maintenance of homeostasis within nervous system tissue. We suggest that the altered function can result from immune-mediated events such as altered levels of circulating inflammatory mediators. Furthermore, we assume that in the AD and MD subgroups, the BCB dysfunction for high molecular weight proteins permits access of components of the immune system to the CNS, which may contribute to disease pathology.     

Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4 genotype

Sleep disruption, nightly restlessness, sundowning, and other circadian disturbances are frequently seen in Alzheimer's disease (AD) patients. Changes in the suprachiasmatic nucleus and pineal gland are thought to be the biological basis for these behavioral disturbances. Melatonin is the main endocrine message for circadian rhythmicity from the pineal. To determine whether melatonin production was affected in AD, melatonin levels were determined in the cerebrospinal fluid (CSF) of 85 patients with AD (mean age, 75 +/- 1.1 yr) and in 82 age-matched controls (mean age, 76 +/- 1.4 yr). Ventricular postmortem CSF was collected from clinically and neuropathologically well defined AD patients and from control subjects without primary neurological or psychiatric disease. In old control subjects (>80 yr of age), CSF melatonin levels were half of those in control subjects of 41-80 yr of age [176 +/- 58 (n = 29) and 330 +/- 66 (n = 53) pg/mL, respectively; P = 0.016]. We did not find a diurnal rhythm in CSF melatonin levels in control subjects. In AD patients the CSF melatonin levels were only one fifth (55 +/- 7 pg/mL) of those in control subjects (273 +/- 47 pg/mL; P = 0.0001). There was no difference in the CSF melatonin levels between the presenile (42 +/- 11 pg/mL; n = 21) and the senile (59 +/- 8 pg/mL; n = 64; P = 0.35) AD patients. The melatonin level in AD patients expressing apolipoprotein E-epsilon3/4 (71 +/- 11 pg/mL) was significantly higher than that in patients expressing apolipoprotein E-epsilon4/4 (32 +/- 8 pg/ml; P = 0.02). In the AD patients no significant correlation was observed between age of onset or duration of AD and CSF melatonin levels. In the present study, a dramatic decrease in the CSF melatonin levels was found in old control subjects and even more so in AD patients. Whether supplementation of melatonin may indeed improve behavioral disturbances in AD patients should be investigated.     

Disposition and elimination of meropenem in cerebrospinal fluid of hydrocephalic patients with external ventriculostomy

The broad antibacterial spectrum and the low incidence of seizures in meropenem-treated patients qualifies meropenem for therapy of bacterial meningitis. The present study evaluates concentrations in ventricular cerebrospinal fluid (CSF) in the absence of pronounced meningeal inflammation. Patients with occlusive hydrocephalus caused by cerebrovascular diseases, who had undergone external ventriculostomy (n = 10, age range 48 to 75 years), received 2 g of meropenem intravenously over 30 min. Serum and CSF were drawn repeatedly and analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations in serum were 84.7 +/- 23.7 microg/ml. A CSF maximum (CmaxCSF) of 0.63 +/- 0.50 microg/ml (mean +/- standard deviation) was observed 4.1 +/- 2.6 h after the end of the infusion. CmaxCSF and the area under the curve for CSF (AUCCSF) depended on the AUC for serum (AUCS), the CSF-to-serum albumin ratio, and the CSF leukocyte count. Elimination from CSF was considerably slower than from serum (half-life at beta phase [t1/2beta] of 7.36 +/- 2.89 h in CSF versus t1/2beta of 1.69 +/- 0.60 h in serum). The AUCCSF/AUCS ratio for meropenem, as a measure of overall CSF penetration, was 0.047 +/- 0.022. The AUCCSF/AUCS ratio for meropenem was similar to that for other beta-lactam antibiotics with a low binding to serum proteins. The concentration maxima of meropenem in ventricular CSF observed in this study are high enough to kill fully susceptible pathogens. They may not be sufficient to kill bacteria with a reduced sensitivity to carbapenems, although clinical success has been reported for patients with meningitis caused by penicillin-resistant pneumococci and Pseudomonas aeruginosa.     

Psychopathology in younger versus older persons with very mild and mild dementia of the Alzheimer type

OBJECTIVE: The psychopathology associated with early-onset dementia of the Alzheimer type was investigated by comparing the prevalence of psychiatric symptoms in younger subjects (mean age = 59 years) who had very mild or mild dementia with that in older adults (mean age = 72) whose dementia was of equivalent severity. METHOD: Nondemented comparison subjects and persons with very mild or mild dementia of the Alzheimer type were recruited to participate in longitudinal studies. All subjects met strict inclusion and exclusion criteria. Information pertaining to personality changes, affective symptoms, and psychotic symptoms was included in the 90-minute semistructured, physician-administered interview, which was used to assign a clinical dementia rating according to published guidelines. The younger group were age 64 or younger and consisted of 20 nondemented subjects, 11 subjects with very mild dementia, and 18 subjects with mild dementia. The older group, described previously, were 64-83 years old and consisted of 83 nondemented subjects, 41 persons with very mild dementia, and 68 subjects with mild dementia. RESULTS: The psychopathology in the younger subjects was similar to that in the older group. Personality changes occurred in over 80% of the younger persons with very mild illness. Psychotic symptoms were present in over 40% of the younger persons with mild illness but were rare in the group with very mild dementia. CONCLUSIONS: Similar patterns of psychopathology in younger and more elderly persons with dementia of the Alzheimer type support the suggestion that these changes are direct effects of the illness on the CNS. Increased attention to documenting these noncognitive symptoms and studying various treatments is urgently needed.     

Beta-trace protein in cerebrospinal fluid: a blood-CSF barrier-related evaluation in neurological diseases

Beta-trace protein concentrations in cerebrospinal fluid (CSF) and serum from 113 patients with various neurological diseases and 65 controls were determined with a sensitive and specific immunonephelometric assay. In adult control patients, beta-trace concentrations were 14.6+/-4.6 mg/L in CSF and 0.46+/-0.13 mg/L in serum, that is, 32-fold higher in CSF. beta-trace levels in CSF correlated with age as well as with the albumin CSF/serum ratio (Q(Alb)), which is considered a measure for blood-CSF barrier function. The relationship between CSF beta-trace levels and elevated Q(Alb) values was studied in various neurological diseases with CSF protein increase. In spinal canal stenosis, CSF beta-trace (mean=29.5+/-10.5 mg/L) correlated positively with increasing Q(Alb) values. In bacterial meningitis, CSF beta-trace (mean=8.7+/-3.9 mg/L) remained invariant to changes of Q(Alb) values. In Guillain-Barré syndrome, CSF beta-trace (mean=14.4+/-6.8 mg/L) was below the Q(Alb)-dependent reference range. In multiple sclerosis and viral meningoencephalitis, beta-trace levels were within the reference range. Beta-trace concentration in CSF can be used in conjunction with Q(AlB) to distinguish between different neurological pathologies associated with CSF protein increase.     

Mannan-binding lectin in human serum, cerebrospinal fluid and brain tissue and its role in Alzheimer's disease

Mannan-Binding lectin (MBL) is a serum lectin which can activate the classical complement pathway. Complement proteins of the classical pathway have been found in the brains of patients with Alzheimer's disease (AD) in association with AD brain pathology. To investigate the role for MBL in AD we have looked for its presence in the brain by immunohistochemistry and determined the levels of MBL in paired samples of cerebrospinal fluid and serum from AD patients and controls. MBL was detected in association with blood vessels in the brain tissue of both AD patients and control subjects. There was no apparent difference in the distribution of MBL in the brain tissue between the two groups. The mean concentration of MBL in the CSF was 44% lower in AD patients than in controls (AD 154 +/- 35 pg/ml, n = 19; non-AD 276 +/- 50 pg/ml, n = 15, p < 0.05). The levels of MBL in serum were not significantly different in the two groups. Thus, this study shows that MBL is associated with blood vessels in the brains of both AD and control subjects. Moreover, CSF levels of MBL appear to be lower in AD patients than in control subjects which may indicate a higher degree of MBL consumption connected with complement activation in the AD patients.     

Correlation of nicotinic binding with neurochemical markers in Alzheimer's disease

The loss of neocortical synapses that occurs in Alzheimer's disease (AD) has been shown to correlate with cognitive decline. In addition, marked losses in the cholinergic system in AD, specifically choline acetyltransferase (ChAT) activity and high affinity presynaptic neuronal nicotinic cholinergic receptors (nAChRs), have also been described. We hypothesized that in AD, the loss of [3H]-ligand binding to nAChRs, which are largely presynaptic, would correlate with changes in two other presynaptic markers: synaptophysin (Syn), a measure of synaptic density, and ChAT activity. The midfrontal (MF) cortex of 36 autopsy confirmed (NIA and CERAD criteria) AD patients (mean death age +/- SD 80.1 +/- 8.4 years) who met NINDS-ADRDA criteria for a clinical diagnosis of probable or possible AD, and 11 nondemented controls (mean death age +/- SD 77.9 +/- 8.0) were examined. Synapse counts were quantified by a dotimmunobinding assay for Syn. ChAT activity was assessed by standard biochemical assays. Nicotinic cholinergic receptor binding was assayed using the high affinity nicotinic agonist [3H]-(+/-)-epibatidine ([3H]-EPI). The mean +/- SD Syn in AD (83.4 +/- 31.9 arbitrary units (AU)/mg protein) was significantly lower than controls (126.1 +/- 19.9, p = 0.0003; t-test). The mean ChAT activity in AD (139.0 +/- 75.6 nmol ACh/hr/100 mg protein) was significantly lower than controls (219.6 +/- 70.8, p = 0.004). The mean [3H]-EPI total binding in AD (6.2 +/- 2.8 fmol/mg protein) was significantly lower than controls (14.8 +/- 3.2; p < 0.0001). Syn correlated with [3H]-EPI binding in AD (r = 0.48, p = 0.006; Pearson) but ChAT did not (r = -0.20, p = 0.34). We conclude that loss of high affinity nAChR binding correlates with loss of synapses in AD. The lack of correlation between [3H]-EPI binding and ChAT activity suggests that the targeted receptor populations may not be located exclusively on cholinergic neurons.     

CD44 is an independent prognostic factor in early-stage cervical cancer

Leptin and neuropeptide Y (NPY) are involved in the regulation of food intake and body weight. Both hormones act through specific receptors in the central nervous system. The objective of this study was to investigate the relation of leptin and NPY in human plasma and cerebrospinal fluid (CSF). Leptin and NPY in CSF and in serum/plasma were measured by radioimmunoassays in 35 patients. Leptin concentrations in serum were 100-200 fold higher than in CSF. There was a significant correlation between leptin levels in CSF and in serum (r=0.88, P<0.0001). Female patients had significantly higher leptin serum concentrations than males (16.6+/-10.9 microg/l vs. 6.5+/-7.3 microg/l, P=0.002). In contrast, NPY levels were only twofold higher in CSF than in plasma. There was no relation between leptin and NPY in CSF and serum/plasma, respectively. The ratio of CSF and peripheral leptin levels did not correlate with the respective albumin ratio, indicating that leptin did not merely leak into the CSF via a defective blood-CSF barrier. It is concluded that leptin uptake from the circulation into CSF is a regulated process. The NPY concentration in CSF is not directly related to leptin CSF levels.     

High levels of cerebrospinal fluid IgM binding to myelin basic protein are associated with early benign course in multiple sclerosis

We assessed human myelin basic protein (MBP) binding IgM levels in CSF. MBP is the most studied putative antigen in multiple sclerosis (MS) and immune responses against it may be involved in the demyelination process. We also correlated these levels with EDSS score and other parameters of disease progression and prognosis, both at the time of CSF analysis and during follow-up. CSF IgM anti-MBP levels were assayed by measuring total IgM levels with solid-phase ELISA in CSF samples from 66 patients with relapsing-remitting MS, 11 subjects without neurological diseases, 20 patients with non-inflammatory neurological diseases and 7 patients with lymphocytic meningitis, before and after immunoabsorption with human MBP. Confirmation of IgM binding specificity was performed by immunoblotting of positive CSF samples onto MBP coated-nitrocellulose sheets. Clinical evaluation (disability score, number and time of attacks) was performed during a mean follow-up of 2.7 +/- 1.1 years. 23 of the 66 relapsing-remitting MS patients (33.8%) had elevated IgM anti-MBP levels. In this patient subgroup, IgM anti-MBP levels correlated with the IgM index (r = 0.71; P = 0.0001), but not with CSF/serum albumin (r = 0.08; P = 0.72). In the first year of follow-up, patients with low IgM anti-MBP suffered from more numerous attacks than those with elevated levels (0.86 +/- 0.63 versus 0.43 +/- 0.58; P = 0.017). Patients with high IgM binding to MBP had a first attack during follow-up in a significantly higher time than those with low binding (28.87 +/- 4.7 versus 17 +/- 2.6 months, respectively; P = 0.005) and reached a decrease of 0.5 EDSS point significantly faster than those with low IgM (16.17 +/- 1.2 versus 29.7 +/- 2.6 months, respectively; P = 0.0002). A similar significant finding was observed when the time to reach low disability score (EDSS < or = 2.0) was analyzed (10.7 +/- 2.57 +/- 3.3 months, respectively; P = 0.014). These findings demonstrate that in a subgroup of MS patients, elevated CSF levels of IgM anti-MBP are associated with early favorable course and therefore suggest that IgM binding to MBP could be a possible prognostic marker in relapsing-remitting MS to select early MS patients for future trials.     

Screening for dementia with the memory impairment screen

OBJECTIVES: To validate a sensitive and specific screening test for AD and other dementias, assess its reliability and discriminative validity, and present normative data for its use in various applied settings. BACKGROUND: To improve discrimination in screening for AD and dementia, we developed the Memory Impairment Screen (MIS), a 4-minute, four-item, delayed free- and cued-recall test of memory impairment. The MIS uses controlled learning to ensure attention, induce specific semantic processing, and optimize encoding specificity to improve detection of dementia. METHODS: Equivalent forms of the MIS were given at the beginning and end of the testing session to assess alternate forms reliability. Discriminative validity was assessed in a criterion sample of 483 aged individuals, 50 of whom had dementia according to Diagnostic and Statistical Manual of Mental Disorders (3rd ed., revised) criteria. RESULTS: The MIS had good alternate forms reliability, high construct validity for memory impairment, and good discriminative validity in terms of sensitivity, specificity, and positive predictive value. We present normative data for use in settings with different base rates (prevalences) of AD and dementia. CONCLUSION: The MIS provides efficient, reliable, and valid screening for AD and other dementias.     

The effects of New York''s bypass surgery provider profiling on access to care and patient outcomes in the elderly

OBJECTIVES: To determine the annual rates of volumetric change of the hippocampus and temporal horn in cognitively normal elderly control subjects and individually matched patients with AD, and to test the hypothesis that these rates were different. BACKGROUND: Cross-sectional studies consistently reveal cerebral atrophy in elderly nondemented subjects compared with healthy young adults, and greater atrophy in patients with AD relative to elderly control subjects. However, rates of atrophy are estimated most accurately by performing serial measurements in the same individuals. METHODS: MRI-based volumetric measurements of the hippocampi and temporal horns were performed in 24 cognitively normal subjects aged 70 to 89 years who were individually matched with respect to gender and age with 24 patients with AD. Each subject underwent an MRI protocol twice, separated by 12 months or more. RESULTS: The mean annual rate of hippocampal volume loss among control subjects was -1.55+/-1.38% and the temporal horns increased in volume by 6.15+/-7.69% per year. These rates were significantly greater among AD patients: hippocampus, -3.98+/-1.92% per year, p < 0.001; temporal horn, 14.16+/-8.47% per year, p = 0.002. CONCLUSION: A statistically significant yearly decline in hippocampal volume and an increase in temporal horn volume was identified in elderly control subjects who represent typical aging individuals. These rates were approximately 2.5 times greater in patients with AD than in individually age- and gender-matched control subjects.     

Gender differences in the phenotypic expression of Alzheimer's disease in Down's syndrome (trisomy 21)

Twenty-eight individuals with typical Down's syndrome (DS) phenotype (17 males and 11 females; age range: 10-74 years) were investigated for gender differences in the phenotypic expression of Alzheimer-type pathology (ATP). Quantitative neuropathology was performed in the 4 neocortical lobes of the right hemisphere, by counting senile plaques (SP), and neurofibrillary tangles (NFT). ATP was present in 25 middle-aged (> 40 years) individuals (16 males and 9 females). Females had significantly higher (p = 0.03) mean neocortical NFT densities (36.6 per mm2; s.e.m. +/- 6.6) than males (17.9 per mm2; s.e.m. +/- 4.7). None of the females had NFT densities below 10 per mm2, compared with 6 males in whom NFT were either absent or seen in very low densities (< 4 per mm2). Assessment of SP densities in the same cortical regions showed non-significant differences in females (42.4 per mm2; s.e.m. +/- 5.1) compared with males (33.6 per mm2; s.e.m. +/- 2.1). There was clinical evidence of dementia in all the female (8/8) individuals who were prospectively assessed, compared with only 54% (7/13) of males. The male individuals without clinical dementia had absent or low neocortical NFT densities regardless of high SP densities. Female DS cases (mean age: 48.8 years; s.e.m. +/- 1.9) had an earlier onset of dementia than males (mean age: 53.6 years; s.e.m. +/- 1.3; p = 0.05). Female middle-aged DS individuals have an earlier onset, and a more severe form of AD which correlates with higher neocortical NFT rather than SP density.     

The effect of intraventricular albumin in experimental brain oedema

Therapy for vasogenic brain oedema (VBE) is still an unsolved problem. Experimental work with the aim of establishing an oncotherapeutic option is presented. VBE is performed by focal freeze injury in rats. Using a stereotactic head holder hypo- or hyperosmolar human serum albumin is administered via the intraventricular route. The goal is to enhance the migration of oedema fluid with the aid of oncotic pressures. Early and late results are obtained for each group respectively four and twenty-four hours after the infliction of cold injury. The efficacy of therapy is evaluated by cerebrospinal fluid (CSF) osmolality, cerebral water content, tissue specific gravity, and blood-brain barrier (BBB) permeability. Posttherapeutic values for CSF osmolality are obtained by cisterna magna puncture. Hyperosmolar CSF after performance of cold injury (p < 0.05) is thought to be a result of fluid accumulation in the traumatized region partially from the intraventricular space. Posttherapeutic values after hyperosmolar albumin administration have revealed iso-osmolar CSF, increase in specific gravity (p < 0.001), and decrease in BBB permeability (p < 0.05). These results are in accordance with withdrawal of oedema fluid into the ventricles which can be interpreted as a positive therapeutic effect. Late results in hyperosmolar group have disclosed a hypo-iso-osmolar CSF, persistent increase in specific gravity, and no regression. These values have shown that hyperosmolar albumin administration does not interfere with CSF circulation. Early results of hypoosmolar albumin application are discouraging. This preliminary work of a therapeutic trial on VBE may be a basis for future investigations with different dosages and time modalities.     

Membrane modifications of red blood cells in Alzheimer's disease

Red blood cells (RBC) from 24 Alzheimer's disease (AD) patients, 18 age- and sex-matched nondemented (ND) patients, hospitalized in the same facility for orthopedic problems, and 18 healthy volunteers aged 30-52 years were studied in order to gain insight into the nature of RBC membrane modifications in AD. Significant differences were found between RBC from AD and ND patients or young controls respectively for annexin V-binding (45.5 +/- 18.0% vs 27.1 +/- 14.7 and 2.7 +/- 1.9, p = .003), fraction of glycerol resistant cells (30.8 +/- 11.1% vs 19.6 +/- 6.4 and 10.2 +/- 3.1, p = .026), cell electrophoretic mobility in polymer (1.028 +/- 0.022 microns sec-1 V-1 cm vs 1.046 +/- 0.022 and 1.053 +/- 0.021, p = .02) and only limited significance for the filterability (1.46 +/- 0.12 msec vs 1.58 +/- 0.11 and 1.54 +/- 0.11, p = 0.1). A logistic analysis, using simultaneously several features as independent variables, suggested the combined use of annexinV- binding, glycerol resistance, and cell filterability which allowed the assignment of 95% of patients from this cohort to the right group. A prospective analysis of a larger cohort is required for the estimation of the diagnostic value of this test battery. In addition, the high level of annexin binding is characteristic of a disruption of the phospholipid asymmetry in aged or damaged cells, while the high glycerol resistance combined with low electrophoretic mobility an rigidity characterize young RBC, thus indicating an enhanced turnover of RBC in Alzheimer's disease.     

Decreased lumbar cerebrospinal fluid levels of monoamine metabolites in vascular dementia

The levels of the monoamine metabolites 5-hydroxy-indoleacetic acid (5-HIAA), homovanillic acid (HVA), and 4-hydroxy-3-methoxy-phenylglycol (HMPG) were determined in lumbar cerebrospinal fluid (CSF) of 56 patients with vascular dementia (VAD) and 57 healthy controls. Despite CSF sampling under standardized conditions, the variability in values was wide among both patients and controls. This suggests that yet unknown factors affect the lumbar CSF concentrations of monoamine metabolites. The VAD group showed significantly lower mean concentrations of 5-HIAA (p < .001) and HVA (p < .001) than the control group. These low concentrations appear to be no disease-specific phenomenon, but may be attributable to subcortical white-matter changes or a decreased production of monoamines, which are dependent on oxygen for their synthesis.     

Systemic changes of the immune system in patients with Alzheimer's dementia

OBJECTIVE: The etiology of Alzheimer's disease (AD) is still unknown. Recent investigations have shown that immune and inflammatory mechanisms could be of importance in the pathophysiology of AD. In this study 10 different immune parameters were measured to further investigate immunological changes in AD. PATIENTS AND METHODS: In 30 randomized patients with AD (20 females and ten males aged 74.5 +/- 6.5 years) as well as 13 controls aged 70.7 +/- 8.4 years, mostly relatives of the patients, all free of acute infection, serum concentrations of IgA, IgG, IgM, C3, C4, circulating immune complexes, sCD23, cardiolipin and the soluble cytokine receptors interleukin 2-receptor (sIL2-R) and tumor necrosis factor-receptor (sTNF-R) were measured. Diagnosis of AD was made according to NINCDS/ ADRDA criteria. The degree of dementia was determined by Mini-Mental-State-Examination (MMSE). RESULTS: Compared to the control group, patients with AD had significantly increased IgA (369,3 +/- 160,9 mg/dl vs 253.5 +/- 101.8 mg/dl [P = 0.02]), sCD23 [207.4 +/- 217.7 I. U./ml vs 80.6 +/- 35.5 I. U./ml [P = 0.004]), sIL2-R (829.6 +/- 742.1 I. U./ml vs 299.7 +/- 168.5 I. U./ml [P = 0.001]) and sTNF-R (4.6 +/- 2.0 I. U./ml vs 2.9 +/- 1.1 I. U./ml [P = 0.001]) levels. A negative correlation was seen between MMSE and sTNF-R (r = -0.34; P < 0.05). CONCLUSION: These findings indicate a chronic state of immune activation in AD and support the hypothesis of immune mediated mechanisms as part of the pathogenesis of AD. Prospective studies of the effect of anti-inflammatory drugs on the progression of AD will be needed.