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.     

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.     

Analysis of TGF-β2 and TGF-β3 expression in the hydrocephalic H-Tx rat brain

Introduction Transforming growth factor- (TGF-) is an important cytokine with modulatory actions in the nervous system. The development of hydrocephalus in mouse models resulting from the overexpression of TGF-1 has previously been described, but the mechanism by which this occurs remains obscure.Methods In order to evaluate the role of TGF- in hydrocephalus, we used SYBR Green I-based real-time quantitative RT-PCR method and Western blot analysis to analyze the TGF-2 and TGF-3 mRNA and protein expressions in the cerebral cortex of the H-Tx rat, a model of congenital hydrocephalus.Results The hydrocephalic H-Tx rat expressed significantly higher TGF-3 levels than their normal siblings (p<0.01) at 7 and 14 days of age. This difference became insignificant when analyzed at 21 days of age. On the other hand, such a difference has not been observed in the TGF-2 levels in the hydrocephalic H-Tx rat.Conclusions These results suggest that TGF-2 and TGF-3 expression may be modulated differently in the hydrocephalus, and TGF-3 may contribute to the development of hydrocephalus in this rat model.     

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     

The effect of oxidative stress on amyloid precursor protein processing in cells engaged in β-amyloidosis is related to apolipoprotein E genotype

The reduced antioxidative defense in allele 4 carriers is suggested to contribute to -amyloidosis in Alzheimers disease and Downs syndrome. We studied the effect of oxidative stress on accumulation of amyloid- peptide (A) in vascular smooth muscle cells (SMCs) that are engaged in production of amyloid- in vivo. Previously, we found that oxidative stress caused by ferrous ions induced accumulation of A-apolipoprotein E deposits in lysosomes and was associated with a greater oxidative protein damage in 4 carriers. Here, we demonstrate that ferrous ions induce formation of A deposits also in vascular tunica media in organotypic cultures of whole brain vessels, suggesting the role of oxidative stress in development of vascular -amyloidosis. Cellular accumulation of A in SMCs treated with ferrous ions was associated with a greater accumulation of C-terminal amyloid precursor protein (APP) fragments in 4/4 than in 3/3 myocytes and reduced the amount of soluble APP in 3/3, but not 4/4, cultures. Antioxidant vitamin E prevented these effects, and, when applied alone, diminished the amount of APP C-terminal fragments and increased the amount of secreted APP in 3/3, but not 4/4, cells. C-terminal APP-immunoreactive material was accumulated in lysosomes partly with A- and N-terminal APP immunoreactivities. These results suggest that the increased accumulation of APP and its fragments in lysosomes may yield additional amounts of cellular A, particularly in 4 carriers. We hypothesize that the altered processing of APP in SMCs locally exposed to oxidative stress facilitates cellular deposition of A and contribute to the increased risk of development of -amyloidosis in 4/4 carriers.     

White matter amyloid in Alzheimer's disease brain

Amyloid -protein (A) deposits in the white matter were investigated by the double immunohistochemical staining for A and neuritic, glial or vascular components. Reactive astroglia and neurite abnormality were absent around A deposits in the white matter (w-A) even those with a core. The association of w-A with blood vessels was not consistent. Aggregates of activated microglia were found to be the sole but a consistent accompaniment of A deposits even in the absence of other components such as neuron, synapse, neurite abnormality and reactive astroglia, as observed in the white matter. This suggests that the aggregates of activated microglia most likely represent one of the factors promoting the process of A deposition.     

A simplified radioimmunological method for the determination of human β-endorphin in cerebrospinal fluid

Summary Human -endorphin-like immunoreactive substances ( _h -EI) in human cerebrospinal fluid (CSF) were determined radioimmunologically. The cross reactivity of the antibodies to human -endorphin ( _h -E) amounted to 40% for human -lipotropin ( _h -LPH) whilst it was less than 1% for leu-and metenkephalin, - and -endorphin, fraction I and II [5], substance P and -MSH. Prior to radioimmunological determination, an adsorbtion of _h -EI from CSF with silicic acid was carried out and followed by a desorbtion, using a mixture of aceton/hydrochloric acid. This method was chosen because the ratio of _h -LPH to _h -E in the desorbat can be shifted in favour of _h -E owing to the variation in recoveries r ( =33%, =64%). On the one hand, this enables a more specific determination of _h -E and, on the other hand, and separation of any peptidase than may be present [9]. An adsorbtion/desorbtion of 2 ml CSF suffices to prove the presence of 20–150 pg/ml (6–48 fmol/ml) of _h -EI.The CSF of 28 patients with various neurological diseases was examined and 24 of them had concentrations of 20–70 pg/ml _h -EI. The remaining four, which had concentrations less than 20 pg/ml, came from meningitis patients undergoing corticoid therapy.A purchasable RIA kit was tested for its determination of _h -E and was found to be unsuitable.

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Zusammenfassung Beta-human-Endorphin-like immunreaktive Substanzen ( _h -EI) im menschlichen Liquor (CSF) wurden radioimmunologisch bestimmt. Die Kreuzreaktivität des von uns eingesetzten Antikörpers gegen Beta-human-Endorphin ( _h -E) zum Beta-human-Lipoprotein ( _h -LPH) betrug 40%, während sie zu Leu- und Met-Enkephalin, Alpha- und Gamma-Endorphin, Fraktion I und II nach Terenius [10], Substanz P und Alpha-MSH geringer war als 1%. Vor der radioimmunologischen Bestimmung wurde eine Adsorption von _h -EI aus CSF an Kieselsäure mit anschließender Desorption mittels eines Gemisches aus Aceton/Salzsäure durchgeführt. Diese Methode wurde gewählt, weil sich dadurch das Verhältnis von _h -LPH zu _h -E im Desorbat zugunsten von _h -E aufgrund der unterschiedlichen Recoveries R ( =33%, =66%) verschob. Damit wird einerseits eine erhöhte Spezifität bei der Bestimmung von _h -EI und andererseits eine Abtrennung von eventuell vorhandenen Peptidasen erreicht. Eine Adsorption/Desorption aus 2 ml CSF genügt, um _h -EI von 20–150 pg/ml (6–48 fmol/ml) nachzuweisen.Patienten (n=28) mit verschiedenen neurologischen Erkrankungen wiesen Werte von 20–70 pg/ml auf. Vier Liquores unter 20 pg/ml stammten von Meningitis-Patienten, welche unter einer Corticoidtherapie standen.Ein käuflicher RIA-Kit wurde auf seine Eignung zur Bestimmung von _h -E untersucht und verworfen.

     

Glial reactions and the clearance of amyloid β protein in the brains of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type

Although the amyloid protein (A) E693Q mutation enhances A fibrillization in vitro and cerebral amyloid angiopathy (CAA) in vivo, brain parenchymal A deposition and tau pathology in hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) are limited. To evaluate whether clearance of A by glial cells may play a role in this regard, this immunohistochemical study of frontal cortex of 14 HCHWA-D autopsy brains was performed using double staining with glial markers and end-specific antibodies to Ax–42 (A42) and Ax–40 (A40). Tau pathology was also assessed. Numerous microglia and/or astrocytes carrying cytoplasmic A42⁺40^– granules were scattered among non-fibrillar (Congo red-negative) A deposits, i.e., clouds, fine diffuse plaques, and A42⁺40^– dense diffuse plaques. On the other hand, activated microglia and reactive astrocytes associated with fibrillar (Congo red-positive) A deposition, i.e., A42⁺40⁺ dense diffuse plaques and CAA invading the parenchyma, were virtually devoid of A granules. Tau pathology was scant and most frequently associated with CAA. These results suggest that relatively non-fibrillar parenchymal A deposits may be liable to glial clearance. A sequestration by glial cells may be a factor limiting the levels of neurotoxic soluble A oligomers in HCHWA-D brain.     

Microglial cells and amyloid β protein (Aβ) deposition: association with Aβ40-plaques

Two distinct species of amyloid protein (A) with different carboxyl termini, A₄₀ and A₄₂₍₄₃₎, are deposited in plaques in the brains of patients with Alzheimer's disease and Down's syndrome. The relationship between these two forms of A and microglial cells was investigated in 16 subjects with Down's syndrome ranging in age from 31 to 64 years. The amount of A₄₀ in plaques was low in persons under 50 years of age, even though high amounts of A₄₂₍₄₃₎ were present, but this former species increased after this age. Microglia were observed most commonly in plaques containing both A₄₀ and A₄₂₍₄₃₎ but less commonly in those with A₄₂₍₄₃₎ alone. The presence of microglial cells in plaques may be associated with the accumulation of A₄₀ and these cells may have a role in the production or processing of this particular molecular species.     

Potential role of transforming growth factor-β1 in terminating the immune response in patients with Guillain-Barré syndrome

T-cell activation and proinflammatory cytokines seem to be important in promoting the disease activity in Guillain-Barré syndrome (GBS). Transforming growth factor-1 (TGF-1) is a multifunctional peptide with potent immunosuppressive activity, and can therefore be considered a putative disease-limiting cytokine. We determined levels of soluble TGF-1 in the serum of 12 patients with GBS in serial investigations during the course of the disease, in 12 patients with other non-inflammatory neurological diseases (OND), and in 12 healthy control subjects. Levels of biologically active and total TGF-1 were significantly increased in patients with GBS compared with patients with OND and healthy controls. During the course of GBS, levels of TGF-1 peaked in the plateau phase before onset of recovery. During the recovery phase levels of TGF-1 decreased but still exceeded significantly the levels in patients with OND and healthy controls. The differences were more marked with biologically active than with total TGF-1. The temporal relationship between increased serum levels of TGF-1 and the end of the progressive phase indicates that TGF-1 has a role in terminating the pathological immune response in GBS. These findings suggest that TGF-1 may be important in recovery from GBS.     

GSK-3β in cerebrospinal fluid of schizophrenia patients

Summary. Cerebrospinal fluid contains proteins and metabolites of brain origin and was extensively studied in psychiatry in the 1970s with few definitive results. We have recently found 40% reduced protein levels of GSK-3 in schizophrenia in postmortem prefrontal cortex, but our attempt to develop a diagnostic marker using peripheral lymphocyte GSK-3 was not successful. In this study we aimed to find whether the reduction in brain GSK-3 is reflected in CSF of schizophrenia patients. We report a significant reduction in CSF GSK-3 protein levels in six schizophrenia patients compared to seventeen healthy subjects. Our results corroborate other studies in which CSF protein levels reflect the alteration found in these proteins in schizophrenia patients postmortem brain.     

Effects of interferon-γ, interleukin-1β, and tumor necrosis factor-α on the serotonin metabolism in the nucleus raphe dorsalis of the rat

Summary The effects of the cytokines interferon (IFN)-, interleukin (IL)-1, and tumor necrosis factor (TNF)- on the serotoninergic transmission in the nucleus raphe dorsalis (NRD) were studied after peripheral and central application. The studies were performed in the freely moving rat using differential pulse voltammetry with multicarbon fibre electrodes to study the extracellular levels of the serotonin (5-HT) metabolite 5-hydroxyindoleacetic acid (5-HIAA). The extracellular 5-HIAA levels were not changed in the NRD after peripheral application of rat recombinant IFN-, but elevated by the cytokines IL-1 and TNF-. After intracerebroventricular (i.c.v.) application the cytokines IFN-, IL-1 and TNF- stimulated the serotoninergic transmission in the NRD. Our data suggest that the effect of peripherally elevated cytokine concentrations on the serotonin metabolism in the NRD of the rat is cytokine-dependent. In this respect the T-cell and NK-cell cytokine IFN- acts clearly different when compared to the mainly macrophage-derived cytokines IL-1 and TNF-, and plays a different role in the communication between immune and central nervous system.     

Cerebral β amyloid deposition in patients with malignant neoplasms: its prevalence with aging and effects of radiation therapy on vascular amyloid

We examined immunohistochemically 123 autopsy brains from patients aged between 30 to 59, who died as a result of malignant neoplasms. Using antiserum to amyloid protein (A), we found that cerebral A deposits began in the subjects' fifth decade; its prevalence was 0%, 9.8% and 21.5% in the fourth, fifth and sixth decades, respectively. The major form of A deposition was diffuse-type plaques, although one third of the brains with A deposition showed amyloid angiopathy. Subpial A deposition is frequently associated with amyloid angiopathy. The prevalence of cerebral A deposits was about two times higher in the patients who had received brain radiation therapy (27.8%) compared to non-radiated patients (14.8%). Amyloid angiopathy was much more prominent (P<0.05) with radiation therapy (22.2%) than without (8.0%). We found that cerebral A deposition is dependent on aging, even in patients with malignant tumors and at beginning in their forties, and that brain radiation therapy is a possible risk factor of A deposition, especially in the form of amyloid angiopathy.     

Positron emission tomographic studies on aromatic L-amino acid decarboxylase activity in vivo for L-dopa and 5-hydroxy-L-tryptophan in the monkey brain

Summary The regional brain kinetics following 5-hydroxy-L-(-11 C)tryptophan and L-(-11 C)DOPA intravenous injection was measured in twelve Rhesus monkeys using positron emission tomography (PET). The radiolabelled compounds were also injected together with various doses of unlabelled 5-hydroxy-L-tryptophan or L-DOPA. The radioactivity accumulated in the striatal region and the rate of increased utilization with time was calculated using a graphical method with back of the brain as a reference region. The rate constants for decarboxylation were 0.0070 ± 0.0007 (S. D) and 0.0121±0.0010min^–1 for 5-hydroxy-L-(-11C)tryptophan and L-(-11 C)DOPA, respectively. After concomitant injection with unlabelled 5-hydroxy-L-tryptophan, the rate constant of 5-hydroxy-L-(-11 C)tryptophan decreased dose-dependently and a 50 percent reduction was seen with a dose of about 4mg/kg of unlabelled compound. A decreased utilization rate of L-(-11 C)DOPA was seen only after simultaneous injection of 30 mg/kg of either L-DOPA or 5-hydroxy-L-tryptophan. This capacity limitation was most likely interpreted as different affinity of the striatal aromatic amino acid decarboxylase for L-DOPA and 5-hydroxy-L-tryptophan, respectively.     

Colocalization of prion protein and β protein in the same amyloid plaques in patients with Gerstmann-Sträussler Syndrome

Summary We examined paraffin-embedded brain sections from three patients with Creutzfeldt-Jakob disease (CJD) and four patients with Gerstmann-Sträussler syndrome (GSS) who also had protein deposits in the brains. Immunostaining using anti-prion protein (PrP) and anti- protein coupled with formic acid pretreatment, revealed PrP deposits and protein deposits, respectively. In all four GSS patients examined, sequential double immunostaining and single immunostaining in serial sections or simultaneous double immunofluorescence revealed the colocalization of PrP and protein in the same amyloid plaques. The plaques labeled with both antibodies were designated as -PrP plaques. Small kuru plaques of less than 15 m in diameter were rarely found to coexist with deposits. The percentages of -PrP plaques in larger kuru plaques were not constant among the four GSS patients. The colocalization patterns of both deposits were observed as being roughly of two types as follows: (1) diffuse protein deposits located around the PrP core; and (2) a protein core and PrP core simultaneously existing in one amyloid plaque. Under an electron microscope, we were able to confirm the presence of both protein and PrP in a single plaque in four GSS patients older than 60 years old. In contrast, no colocalization of either deposits was seen in the amyloid plaque core fractions of a young GSS patient who had no protein deposits, even at the electron microscopic level. Therefore, the colocalization of both proteins in a single plaque is believed to be age-related and incidental in GSS patients but suggests a similar morphogenesis of both amyloid deposits.Supported in part by a Grant-in-Aid for Scientific Research (02454245, 03454171) from the Ministry of Education, Science and Culture of Japan     

Transgenic BACE expression in mouse neurons accelerates amyloid plaque pathology

Summary. The cleavage of APP by BACE initiates the amyloidogenic process in Alzheimers disease (AD). We have generated transgenic mice expressing BACE and double transgenic mice expressing BACE and the Swedish mutations of APP (SwAPP) in neurons. BACE transgenic mice did not develop -amyloid plaques by age of 14 months, but showed intracellular -amyloid immunoreactivity that was co-localized with transgenic BACE in neurons. A levels were increased and AD-like pathology was accelerated in double transgenic mice expressing both BACE and SwAPP. At two months of age, early signs of extracellular A deposition and reactive astrocytes were found in double transgenic, but not in single transgenic mice. Furthermore, at four months, well defined -amyloid deposits surrounded by activated astrocytes could be detected in the double transgenic mice. We suggest that BACE overexpression is not sufficient to produce -amyloid plaques, but simultaneous expression of BACE and its substrate (SwAPP) leads to an accelerated amyloid plaque formation.     

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.     

Generalized gangliosidosis: Acid β-galactosidase deficiency with early onset,rapid mental deterioration and minimal bone dysplasia

Summary This report concerns a 3-month-old girl with rapidly progressive psychomotor retardation, hepatomegaly, vacuolated lymphocytes, minimal bone dysplasia and normal excretion of acid mucopolysaccharides. A deficiency of acid -galactosidase was demonstrated in isolated leucocytes and in a liver biopsy. The diagnosis of generalized gangliosidosis due to deficiency of -galactosidase was also based on the absence of the enzyme activity from cultured fibroblasts.The diagnosis was confirmed on autopsy at 16 months by typical histology, electron microscopy and biochemistry of the organs.-galactosidase deficiency has been demonstrated in various clinical conditions ranging from generalized gangliosidosis with severe mental retardation to clinical pictures resembling Morquio's disease and normal intelligence.The heterogeneity of the clinical manifestations in -galactosidase deficiency could be explained by different residual activities of a structurally mutated enzyme towards its various substrates.On sabbatical leave from the Department of Neurosciences, University of California, San Diego, La Jolla, California. In the Department of Pediatrics, University of Berne.     

The spatial patterns of β/A4 deposit subtypes in Down's syndrome

The spatial patterns of diffuse, primitive and classic /A4 deposits were studied in coronal sections of the hippocampus and adjacent gyri in 11 cases of Down's syndrome (DS) varying in age from 38 to 67 years. The objectives of the study were first, to compare the spatial patterns of /A4 deposits revealed in DS with those reported in cases of Alzheimer's disease (AD) and second, to study how the spatial patterns of /A4 deposits may develop in the tissue. The spatial patterns revealed in DS exhibited a number of similarities with those reported in AD: (1) the range and frequency of the different types of spatial pattern revealed were similar, (2) /A4 deposits occurred in clusters and in many cortical tissues, the clusters were distributed in a regular pattern parallel to the pia, (3) the clusters of diffuse and primitive /A4 deposits occurred in an alternating pattern along the cortex, and (4) the clusters of classic /A4 deposits were not correlated with the clusters of the diffuse and primitive deposits. Primitive deposits may develop from the diffuse deposits in regions of the cortex where extracellular paired helical filaments were formed. However, clusters of the classic /A4 deposits, which are formed in older cases, appear to develop independently of the diffuse and primitive deposits.Supported in part by the Alzheimer's Disease Society, UK     

Variability and heterogeneity in Alzheimer's disease with cotton wool plaques: a clinicopathological study of four autopsy cases

We describe three cases of early- (cases 1–3, 28–39 years) and one of late-onset (case 4, 76 years) Alzheimer's disease (AD) with 'cotton wool' plaques (CWPs) but without a family history indicating autosomal dominant inheritance. The early-onset cases, but not the late-onset case, showed remarkable aggression, disinhibition, and impulsiveness. Spastic paraparesis was observed in only one early-onset case. Hematoxylin-eosin-stained sections showed numerous CWPs, especially in the temporal cortex, in all cases. Bielschowsky-stained sections showed neurofibrillary tangles and minor neuritic changes surrounding the CWPs in three cases, but not in case 2. Gallyas-Braak-stained sections showed weak argyrophilia in homogeneous material of the CWPs in cases 2 and 4. Quantitative analysis demonstrated that A42 was deposited more predominantly than A40 in three cases. However, in case 2, approximately twice as much A40 as A42 was deposited. Tau immunostaining demonstrated neuritic changes in three cases, but not in case 2. -Synuclein-positive Lewy bodies (LBs) and astrocytic lesions containing non-A component of AD amyloid (NAC), a central fragment of -synuclein, were found in case 3. In conclusion, (1) a frontal lobe syndrome-like personality change may be one of the characteristic clinical features of early-onset CWP-AD, (2) the deposition pattern of A40 and A42 in CWP-AD is more variable than that of presenilin-1-linked cases, (3) A deposition can result in development of dementia without tau pathology, and (4) CWP-AD with LBs and several other neurodegenerative disorders with LBs share a common process involving -synuclein and NAC deposition.