Apolipoprotein E co-localizes with newly formed amyloid β-protein (Aβ) deposits lacking immunoreactivity against N-terminal epitopes of Aβ in a genotype-dependent manner

Different types of amyloid -protein (A)-containing plaques occur in brains of Alzheimers disease (AD) patients. Diffuse plaques seen during early stages of AD differ from neuritic plaques in later stages both with respect to the length of the A peptides and the presence of other proteins, e.g., apolipoprotein-E (apoE). Since apoE is involved in A transport and clearance, and the 4-allele of the apolipoprotein-E gene (APOE) is a major risk factor for sporadic AD, it is plausible to speculate that apoE plays a pathophysiological role in the initiation of A deposition. To address the issue of whether binding of apoE to A is involved in initial A deposition, we studied the human medial temporal lobe of 60 autopsy cases encompassing the full spectrum of AD-related pathology. In temporal lobe regions, which become involved for the first time at a given stage of -amyloidosis, all plaques represent newly formed plaques, and these were studied with immunohistochemical methods. ApoE was present in 36 cases, and was frequently co-localized with newly formed A deposits detectable with anti-A₄₂ but not with antibodies raised against N-terminal epitopes of A. In 10 additional cases, immunoreactivity against apoE was completely lacking in newly formed plaques, which, at the same time, displayed immunoreactivity against N-terminal epitopes of A. The failure of N-terminal epitopes of A to co-localize with apoE in newly formed plaques indicates that these deposits presumably contain apoE-A complexes, in which the N-terminal epitopes of A are often concealed after complexing with apoE, thus preventing subsequent binding of antibodies. Moreover, apoE-positive newly formed plaques were seen more frequently in APOE 4/4 cases than in non-APOE 4/4 individuals, thereby underlining the potentially crucial role of apoE for the development of A deposits.     

A 3’-UTR polymorphism in the oxidized LDL receptor 1 gene increases Aβ40 load as cerebral amyloid angiopathy in Alzheimer’s disease

It is presently unclear whether polymorphic variations in the oxidized low-density lipoprotein receptor 1 (OLR1), or low-density lipoprotein receptor-related protein 1 (LRP1), genes act as risk factors for Alzheimers disease (AD). In the present study, we have investigated the extent of amyloid protein (A) deposition as cerebral amyloid angiopathy (CAA) or senile plaques (SP) in relationship to OLR1 +1071 and +1073 polymorphisms and LRP1 C766T polymorphism in patients with AD There was an increased A₄₀ load as CAA, but not as SP, in frontal cortex of AD patients carrying OLR1+1073 CC genotype, compared to those with CT, TT or CT+TT genotypes, but only in those individuals without apolipoprotein (APOE) 4 allele. No differences in total A or A₄₂ load as CAA or SP between OLR1+1073 genotypes was seen, nor were there any differences between OLR1+1071 and LRP1 genotypes for any measure of A. Present data suggests that homozygosity for the C allele for OLR1+1073 polymorphism, selectively in individuals without APOE 4 allele, may impair clearance of A, and particularly A₄₀, from the brain across the blood-brain barrier, leading to its diversion into perivascular drainage channels, thereby increasing the severity of CAA in such persons.     

Association study between Alzheimer’s disease and genes involved in Aβ biosynthesis,aggregation and degradation: suggestive results with BACE1

Background Amyloid -peptide (A) biosynthesis, aggregation and degradation constitute three important steps to consider in the study of pathological mechanisms involved in Alzheimers disease (AD). Several proteins have been suggested as involved in each of these processes: proteolytic cleavage of the amyloid precursor protein by the -site APP cleaving enzyme (BACE), increased amyloid fibril formation by the activity of the acetylcholinesterase (ACHE gene), and degradation of A aggregates by the plasmin system have been exhaustively documented.Methods A case-control design was used to evaluate the possible association between candidate genes involved in these three processes and AD. We analysed three polymorphisms located at the BACE1 gene, one polymorphism at the ACHE gene, and two variants located at the tissue plasminogen activator and plasminogen activator inhibitor-1 (genes TPA and PAI- 1, respectively), both part of the plasmin system.Results We found an association between BACE1 exon 5 GG genotype and AD (ageand gender-adjusted odds ratio = 2.14, P =0.014). Although a similar association was reported previously by Nowotny and collaborators only in subjects carrying the 4-allele of the apolipoprotein E gene (APOE), we did not detect this effect. However,when we combined our results with those previously reported, a clear increase of the risk to develop AD appeared in subjects carrying both the BACE1 exon 5 GG genotype and the APOE 4-allele (crude OR = 2.2, P = 0.004).Conclusion These data suggest a possible genetic relation between BACE1 and AD.     

Experimental traumatic brain injury in rats stimulates the expression,production and activity of Alzheimer’s disease β-secretase (BACE-1)

Summary. Traumatic brain injury (TBI) is a risk factor for the development of Alzheimers disease (AD). After a traumatic brain injury depositions of amyloid beta (A) in the brain parenchyma were found. In this study we investigated the expression pattern of -secretase (BACE-1) in ipsi- or contralateral hippocampus and cortex following controlled cortical TBI in rats. BACE-1 mRNA levels, estimated by real time RT-PCR, were elevated 24h post injury, and persisting up to 72h, in the ipsi- and contralateral hippocampus and cerebral cortex as compared to the sham-treated animals (p<0.01). The TBI-induced changes in BACE-1 mRNA are due to enhanced hippocampal and cortical expression of BACE-1 mRNA in neurons and reactive astrocytes as revealed by in situ hybridization. The alterations in hippocampal BACE-1 mRNA levels are accompanied by corresponding increases in BACE-1 protein levels in ipsi- and contralateral hippocampus and ipsilateral cortex as demonstrated by Western blot analysis. In contrast, in the contralateral cortex only a weak increase of traumatically induced BACE-1 protein production was found. The activity of BACE-1 as measured by the formation of the cleavage product of amyloid beta precursor protein, transiently increased up to 48h after injury, but returned to basal level 7 days post injury. This study demonstrates that the -secretase is stimulated following TBI and may suggest a mechanism for the temporal increase of A levels observed in patients with brain trauma.     

Mitochondrial genotype and risk for Alzheimer’s disease: cross-sectional data from the Vienna-Transdanube-Aging “VITA” study

Summary. The Vienna Transdanube Aging (VITA) study searches for early markers of Alzheimers disease (AD) by examining the mental status in a community-based cohort of 606, 75-years old volunteers that are then related to various clinical and genetic analyses. To determine whether mutations in mtDNA are involved in expression of AD, the mtDNA of 79 control participants is screened for alterations by sequencing of hot-spot-regions. This study on mtDNA mutations has eliminated the influence of aging on the occurrence of mtDNA alterations by sequencing samples from persons at the age of exactly 75 years. Thus, our cohort reveals a snap-shot of mitochondrial sequences of elderly persons.So far, a high percentage (56%) of persons with known or unknown mutations in the fragments analyzed were found. These data will be compared in due time to a cohort of participants with proven late-onset AD.     

Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology—a pilot study

Data on the relationship between cerebral amyloid angiopathy (CAA) (congophilic angiopathy) and Alzheimers disease (AD) pathology are conflicting. In the present study, CAA and capillary CAA (CapCAA) (dyshoric angiopathy) were examined in the frontal cortex of 100 human brains obtained at autopsy from both male and female, demented and non-demented patients (mean age ± SD 84.3±9.3 years); 50 brains with high (mean 5.0) and 50 with low (mean 2.4) Braak stages. CAA was assessed according to the method of Olichney et al. [25]; CapCAA was grouped into four grades by counting the affected capillaries in 10 high power fields. General CAA was present in 61% (87.5% demented, 55.6% non-demented; 70% with high and 52% low Braak stages). CAA did not correlate with either clinical diagnosis of dementia or high-grade AD pathology; CapCAA showed a low correlation with dementia and a medium positive correlation with high Braak stages. The severity of both lesions did not correlate with clinical dementia; whereas that of CAA showed low correlation with CERAD, Braak, and NIA-Reagan-Institute criteria, the severity of CapCAA correlated significantly with all three AD criteria. The presence and severity of CAA and CapCAA showed only low correlation, suggesting a different pathogenesis of these types of lesion. Since CapCAA represents insoluble amyloid peptide (A) deposits in and around capillaries, its correlation with neuritic AD pathology supports the concept of neuronal origin of A via drainage from interstitial fluid from the central nervous system to capillary walls. Studies to answer the question whether CapCAA represents an epiphenomenon or an indicator of a pathogenic association between tau cytopathology and A deposition in capillaries are in progress.     

Amyloid β peptide 1–42 highly correlates with capillary cerebral amyloid angiopathy and Alzheimer disease pathology

Recent studies reported both positive [Thal et al. (2003) J Neuropathol Exp Neurol 62:1287–1301] and negative [Tian et al. (2003) Neurosci Lett 352:137–140] correlations between cerebral amyloid angiopathy (CAA) and Alzheimers disease (AD) pathology. We have recently shown high correlations between neuritic AD pathology and amyloid peptide (A) deposits in the capillary/pericapillary compartment (CapCAA) with only low correlations to general CAA (non-capillary). We have now studied the relationship between CapCAA and AD pathology with respect to the distribution of A40 and 42 in the frontal cortex of 100 human postmortem brains from both male and female, demented and non-demented patients (mean age ± SD 84.3±9.3 years). Using polyclonal antibodies to A40 and 42, capillary and plaques positivity were assessed semiquantiatively on a four-point scale. A42 deposits in capillaries correlated highly with both A42 deposits in plaques and morphological AD criteria (CERAD, Braak stages, and NIA-Reagan-Institute criteria), while only a low correlation with CAA was observed. A40 deposits in capillaries differed morphologically from A42 ones: they were limited to capillary walls, were significantly less frequent in both capillaries and plaques compared to A42 (P<0.01), and showed a low correlation with morphological AD criteria (P<0.05) and general CAA (P<0.01). By contrast, A42 deposits were seen in the glia limitans rather than in capillary walls themselves, and showed high correlation with morphological AD criteria (P<0.01). These data indicate that CapCAA is characterized by A42 deposits in pericapillary spaces or in the glia limitans. A low correlation between CAA and CapCAA, but high correlations between morphological AD criteria and CapCAA suggest different pathomechanisms for both types of CAA, and a close relation between CapCAA and AD pathology (both neuritic and plaque type). These data support the concept of a neuronal origin of A via drainage from interstitial fluid from the central nervous system along basement membranes to capillaries.List of Abbreviations AD Alzheimer disease - A beta amyloid peptide - A 40/42 CapS score of deposits of A 1–40/42 in capillaries - A 40/42 C number of A 1–40/42 positive cortical vessels - A 40/42 PS score of deposits of A 1–40/42 in plaques - A 40/42 TS total score of A 1–40/42 deposits - A 40/42 Csev severity of A 1–40/42 affection of cortical vessels - A 40/42 CS A 1–40/42 cortical score - A 40/42 L percentage of A 40/42 positive leptomeningeal vessels - A 40/42 Lsev severity of A 40/42 affection of leptomeningeal vessels - A 40/42 LS A 40/42 leptomeningeal score - ACTS A cortical total score - ALTS A leptomeningeal total score - CAA cerebral amyloid angiopathy - CAATS CAA total score - CapCAA capillary CAA - CERAD Consortium to Establish a Registry of Alzheimers Disease - NFT neurofibrillary tangle - NIA National Institute of Aging - NIA-RI National Institute of Aging and Reagan Institute - NP neuritic plaque - SP senile plaque - TS total scoreAn erratum to this article can be found at     

Occurrence of acetylcholinesterase activity closely associated with amyloid β/A4 protein is not correlated with acetylcholinesterase-positive fiber density in amygdala of Alzheimer's disease

Summary To investigate the possible relationship between acetylcholinesterase (AChE)-containing fiber density and senile plaque density and between AChE-positive plaques and /A4 protein deposition, AChE histochemistry, the modified Bielschowsky's method and /A4 protein immunohistochemistry were performed on the amygdala of Alzheimer's disease (AD) and aged control cases. Abundant AChE-positive senile plaques were found in the amygdala and related structures in AD. These AChE-positive plaques were mainly of the primitive or diffuse type. In addition to senile plaques of typical morphologies a variety of AChE-positive structures were observed in the amygdala and related regions in AD. A comparison of serial sections stained alternatively with AChE histochemistry and /A4 protein immunohistochemistry has revealed that these AChE-positive structures with variable morphological appearances displayed /A4 protein immunoreactivity, indicating that AChE is localized in a variety of /A4 protein deposition including the diffuse plaque. Thus, it is suggested that AChE is present in some senile plaques at the earliest stage. However, there was no apparent correlation between the numerical density of AChE-positive fibers and senile plaque density. These findings suggest that the degeneration of cholinergic neurons is not attributed to the occurrence of AChE activity in /A4 protein.Supported in part by a research grant from the Ministry of Education, Science and Culture of Japan (No. 03670418, S. N.)     

Cardiacβ 2-adrenoceptors and the inotropic response to exercise in man

To find out what role, if any, ₂-adrenoceptors play in cardiac contractility, the heart rate, stroke volume and cardiac output of twelve healthy male and female volunteers (aged 18–28 years) were studied at rest (standing) and during two stages of treadmill exercise, 2 h after ingestion of propranolol (100 mg) or atenolol (100 mg) or a placebo, on different occasions, in a double-blind crossover manner. Cardiac output was measured by a carbon dioxide—rebreathing method. Atenolol and propranolol caused equal reductions in heart rate at rest, and in heart rate and cardiac output during exercise (p < 0.001, two-way analysis of variance). Neither atenolol nor propranolol had any significant effect on resting cardiac output, resting stroke volume or stroke volume during exercise. Since atenolol (100 mg) has been shown to be ₁-adrenoceptorselective, we conclude that cardiac inotropic function during exercise is largely ₁-adrenoceptor-mediated with little or no ₂-adrenoceptor involvement.     

Selective localization of gelatinase A,an enzyme degrading β-amyloid protein,in white matter microglia and in Schwann cells

Gelatinase A is an enzyme capable of cleaving soluble -amyloid protein (AP), and may function as an -secretase to produce secretory forms of amyloid precursor protein. We examined gelatinase A immunoreactivity in the brains and posterior roots of neurologically normal, lacunar stroke, Alzheimer disease (AD), amyotrophic lateral sclerosis, progressive supranuclear palsy and myasthenia gravis cases. The gelatinase A antibody stained only microglial cells in the white matter in all the brain tissues. In AD brain, the reactive microglia located in the center of classical senile plaques, as well as in other microglial cells in the gray matter, showed no immunoreactivity. Gelatinase A in white matter microglial cells may play a role in preventing local deposition of AP. In the posterior root, Schwann cells had positive immunoreactivity. As with other metalloproteases, gelatinase A in Schwann cells may play an antiproliferative role.     

Effect ofd,l-α-aminoadipate on the mediobasal hypothalamus and endocrine function in the rat

Summary Using the glutamate analog,d,l--aminoadipic acid (d,l-AA), experiments were conducted to examine the nature, extent, and specificity of its toxicity in the mediobasal hypothalamus and to determine its effect on endocrine homeostasis. Neonatal rats received daily injections ofd,l-AA (4 g/kg BW) on postnatal days 5–10 and were killed at various post-treatment intervals. Sex-matched littermates were given equimolar amounts of NaCl and served as controls. Treated rats killed 18 days post injection weighed slightly less than controls and had reduced testicular, ovarian, and uterine weights, but the differences were not statistically significant. Ind,l-AA treated rats serum and pituitary levels of TSH and PRL were comparable to control values. Pituitary content of LH ('s and 's) and FSH ('s), however, was lower (P<0.05) ind,l-AA treated rats than in controls, but serum levels were not significantly different. Distinct cytopathologic changes were evident in the arcuate nucleus and median eminence ofd,l-AA-treated rats killed at 2 and 6 h post injection only. By 12 h evidence of acute damage had largely disappeared. Both glial and ependymal cells underwent edematous swelling and necrosis, but neurons were largely unaffected. Evidence of reactive changes, such as gliosis, infiltration of microglia, and removal of debris, however, were not very conspicious. A random sample of mediobasal hypothalami of rats killed 18 days post injection failed to show any detectable lesion or residual effects of earlier pathology. Age at the time of exposure to the gliotoxin was found to be an important variable affecting both extent and duration of injury. The most deleterious effects were observed when the gliotoxin was administered in the form of a single injection on postnatal day 5 only. The results suggest that normal neuronal activity and endocrine homeostasis, specifically gonadotropin, may be irreversibly altered as a consequence of transient disruption of the glial compartment.Supported by grants from the Medical Research Council of Canada, the St. Boniface General Hospital, and Mrs. James A. Richardson Research Foundations     

Meningiomas with a non-meningotheliomatous component

Summary Seven cases of meningiomas with pseudopsammoma bodies have previously been described in the literature. Two additional cases are presented. Electron microscopy of the cells surrounding the pseudopsammoma bodies reveals an ultrastructure different from that of the meningotheliomatous cells. It is concluded that meningotheliomatous meningiomas with pseudopsammoma bodies are mixed tumours, including a non-meningotheliomatous component, the origin and significance of which is uncertain.     

The spatial patterns of β/A4 deposit subtypes in Alzheimer's disease

Summary The spatial patterns of diffuse, primitive, classic (cored) and compact (burnt-out) subtypes of /A4 deposits were studied in coronal sections of the frontal lobe and hippocampus, including the adjacent gyri, in nine cases of Alzheimer's disease (AD). If the more mature deposits were derived from the diffuse deposits then there should be a close association between their spatial patterns in a brain region. In the majority of tissues examined, all deposit subtypes occurred in clusters which varied in dimension from 200 to 6400 m. In many tissues, the clusters appeared to be regularly spaced parallel to the pia or alveus. The mean dimension of the primitive deposit clusters was greater than those of the diffuse, classic and compact types. In about 60% of cortical tissues examined, the clusters of primitive and diffuse deposits were not in phase, i.e. they alternated along the cortical strip. Clusters of classic deposits appeared to be distributed independently of the diffuse deposit clusters. Cluster size of the primitive deposits was positively correlated with the density of the primitive deposits in a tissue but no such relationship could be detected for the diffuse deposits. This study suggested that there was a complex relationship between the clusters of the different subtypes of /A4 deposits. If the diffuse deposits do give rise to the primitive and classic varieties then factors unrelated to the initial deposition of /A4 in the form of diffuse plaques were important in the formation of the mature deposits.Supported in part by the Alzheimer's disease Society of the UK     

Loss of perineuronal net N-acetylgalactosamine in Alzheimer’s disease

The perineuronal net (PN), a specialised region of extracellular matrix, is interposed between the neuronal cell surface and astrocytic processes. It is involved in the buffering of ions, in the development, stabilisation and remodelling of synapses and in the regulating the neuronal microenvironment particularly around the parvalbumin-positive GABAergic neurons. We have investigated the relative preservation of Wisteria floribunda agglutinin (WFA)-positive PNs and parvalbumin-positive neurons in Alzheimers disease (AD), and the relationship of WFA-positive PNs to parenchymal tau, amyloid -peptide (A) and MHC class II antigen (a marker of activated microglia), in paraffin sections of 100 cases with AD and 45 controls. The density of PNs that could be labelled with WFA, which binds to the N-acetylgalactosamine (GalNAc) residues of chondroitin sulphate proteoglycans, was reduced by about 2/3 in AD (P<0.001). In contrast, the density of parvalbumin-positive neurons did not differ significantly between AD and controls. Combined fluorescence imaging showed granular disintegration of WFA labelling around some parvalbumin-positive neurons. There was no significant difference in the amount of phosphorylated tau, A or MHC class II antigen in areas with and without WFA-positive PNs. In AD, there is marked loss of PN GalNAc that is not topographically related to neurofibrillary pathology, parenchymal A load or activated microglia. Although the parvalbumin-positive neurons themselves are relatively spared, the loss of PN GalNAc, which maintains a polyanionic microenvironment around neurons, is likely to impair the function of these inhibitory interneurons. This could in turn lead to increased activity of the glutamatergic and other neurons onto which they synapse.     

Up-regulation ofβ-adrenoceptors on circulating mononuclear cells after reduction of central sympathetic outflow by clonidine in normal subjects

Short term regulation of-adrenoceptors in peripheral blood mononuclear cells after sympathetic activation has been previously documented in normal individuals but changes after a central reduction in sympathetic activity are not known. We have studied-adrenoceptor number and affinity on peripheral blood mononuclear cells in normal subjects, before and after intravenous clonidine, an ₂-adrenoceptor agonist which lowers blood pressure predominantly by reducing central nervous system sympathetic outflow. After clonidine there was a decrease in plasma levels of noradrenaline and adrenaline, and an increase in growth hormone. There was up-regulation of-adrenergic receptors on peripheral blood mononuclear cells 30 and 60 min after clonidine which was related to the fall in blood pressure, noradrenaline and adrenaline levels and to the increase in growth hormone levels. The affinity of the receptors was decreased. Return to baseline values was observed after 2 h. Intracellular production of cAMP after isoproterenol stimulation demonstrated that the up-regulation was not functional. Our studies indicate short term up-regulation of-adrenoceptors in peripheral blood mononuclear cells after clonidine. These observations after a reduction in sympathetic activity may be of importance if they mirror the pattern of redistribution of adrenoceptors, which are present in a wide range of tissues.     

Amelioration of the cerebrovascular amyloidosis in a transgenic model of Alzheimer’s disease with the neurotrophic compound Cerebrolysin™

Summary. Increased production and reduced clearance of amyloid (A) plays a central role in the pathogenesis of Alzheimers disease (AD). We have recently shown that the neurotrophic peptide mixture Cerebrolysin (Cbl) has the ability of improving synaptic functioning and reducing amyloid deposition in a transgenic (tg) animal model of Alzheimers disease (AD). Since in AD, potentially toxic A aggregates accumulate not only around neurons but also in the blood vessels, then it is important to investigate whether bioactive compounds such as Cbl might have the capacity to ameliorate the age-related cerebral amyloid angiopathy (CAA) in tg models. To this end, tg mice expressing mutant human amyloid precursor protein (APP) under the Thy1 promoter were treated with Cbl or saline alone starting at 7 or 12 months of age for a total of three months. Neuropathological analysis with an antibody against A showed that Cbl decreased amyloid deposition around the blood vessels in a time dependant manner. These effects were accompanied by a reduction in perivascular microgliosis and astrogliosis and increased expression of markers of vascular fitness such as CD31 and ZO-1. No lymphocytic infiltration was observed associated with A in the vessels. Consistent with these findings, ultrastructural analysis showed that while in tg mice treated with saline alone there was an abundant accumulation of amyloid fibers in the vascular wall accompanied by thickening of the basal membrane and endothelial cell damage, in Cbl-treated mice there was considerable reduction in the subcellular alterations of endothelial and smooth muscle cells with preservation of basal membranes and intercellular junctions. Taken together, these results suggest that Cbl treatment might have beneficial effects in patients with cognitive impairment due to cerebrovascular amyloidosis by reducing A accumulation and promoting the preservation of the cerebrovasculature.     

Neuroinflammatory perspectives on the two faces of Alzheimer’s disease

Summary. The amyloid plaques in Alzheimers disease (AD) brains are co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that A deposits in AD brains are closely associated with a locally induced, non-immune mediated, chronic inflammatory response. Clinicopathological and neuroradiological studies show that activation of microglia is a relatively early pathogenic event that precedes the process of neuropil destruction in AD. Epidemiological studies indicate that polymorphisms of certain cytokines and acute-phase proteins that are colocalized with A plaques, are genetic risk factors of AD. Epidemiological studies have also shown that the use of classical nonsteroidal anti-inflammatory drugs (NSAIDs) can prevent the risk of AD but clinical trials with anti-inflammatory drugs in AD patients were negative. These findings indicate that anti-inflammatory agents can be helpful in the prevention but not in the treatment of AD. So, pathological, genetic and therapeutic studies suggest that inflammatory mechanisms are most likely involved in the early steps of the pathological cascade. In the autosomal dominant inherited forms of AD the primary factor is the increased production of A1–42 resulting into fibrillar A deposition that elicits a brain inflammatory response. The etiology of the sporadic forms is yet unknown but this subtype is considered to be heterogeneous and multifactorial in its pathogenesis. Here we review the evidence that inflammation related events could be a critical etiological factor in certain forms of the sporadic AD.     

Immunoreactivities of amyloid β peptide<Subscript>(1–42)</Subscript> and total τ protein in lumbar cerebrospinal fluid of patients with normal pressure hydrocephalus

Summary. Immunoreactivities of amyloid peptide_(1–42) (A42-IR) and total protein (TTIR) were measured in lumbar cerebrospinal fluid of 48 patients (12 patients in each group) with normal pressure hydrocephalus (NPH), vascular dementia (VD), Alzheimers disease (AD), Parkinsons disease without dementia (PD) and 24 controls (CON) using sensitive and specific enzyme immunoassays. TTIR in NPH was not significantly changed compared with VD, PD and CON, while NPH-A42-IR was significantly decreased compared with PD and CON. In AD, significant increases of TTIR and significant decreases of A42-IR were found. Using a TTIR by A42 plot, all NPH, PD, and CON samples were within the non-AD plot region. 92% of AD and VD samples were within the AD and non-AD area, respectively. We conclude that combined measurement of A42-IR and TTIR contributes to the differential diagnosis of NPH vs. AD and of AD vs. VD, respectively.     

Follow-up investigations in cerebrospinal fluid of patients with dementia with Lewy bodies and Alzheimer’s disease

Summary. Measuring proteins in cerebrospinal fluid (CSF) has gained wide acceptance for the differential diagnosis of dementia. Some groups have already extended these investigations in Alzheimers disease (AD) by asking how stable these markers are in follow-up analysis, if they depend on the stage of disease and whether they can be used to monitor the progression and biological effects of treatment. We evaluated 21 patients with dementia with Lewy bodies (DLB) and 19 patients with AD, on two occasions, with regard to levels of tau protein, tau protein phosphorylated at threonine 181 (p-tau), A42, A40 and S-100B protein, using a set of commercially available assays.Tau protein levels were lower in DLB in first and second LP compared to AD and decreased during course of both groups. P-tau levels were increased in AD and DLB and decreased during follow-up. A42 and A40 remained relatively stable during follow-up but we found a slight increase of the median A42 level in DLB, whereas in AD, A42 tends to decrease during follow-up. S-100B protein increased during follow-up in both diseases.The protein dynamics in DLB and AD are relatively similar. S-100B protein may be a useful marker for follow-up in neurodegenerative diseases but has to be analysed in longer follow-up periods. Tau protein may be used to differentiate between DLB and AD.Follow-up CSF analyses are of limited value for the differentiation of AD and DLB. We conclude that more specific markers have to be established for the differentiation and follow-up of these diseases.