Disruption of the Sleep-Wake Cycle and Diurnal Fluctuation of β-Amyloid in Mice with Alzheimer's Disease Pathology

Aggregation of β-amyloid (Aβ) in the brain begins to occur years before the clinical onset of Alzheimer's disease (AD). Before Aβ aggregation, concentrations of extracellular soluble Aβ in the interstitial fluid (ISF) space of the brain, which are regulated by neuronal activity and the sleep-wake cycle, correlate with the amount of Aβ deposition in the brain seen later. The amount and quality of sleep decline with normal aging and to a greater extent in AD patients. How sleep quality as well as the diurnal fluctuation in Aβ change with age and Aβ aggregation is not well understood. We report a normal sleep-wake cycle and diurnal fluctuation in ISF Aβ in the brain of the APPswe/PS1δE9 mouse model of AD before Aβ plaque formation. After plaque formation, the sleep-wake cycle markedly deteriorated and diurnal fluctuation of ISF Aβ dissipated. As in mice, diurnal fluctuation of cerebrospinal fluid Aβ in young adult humans with presenilin mutations was also markedly attenuated after Aβ plaque formation. Virtual elimination of Aβ deposits in the mouse brain by active immunization with Aβ(42) normalized the sleep-wake cycle and the diurnal fluctuation of ISF Aβ. These data suggest that Aβ aggregation disrupts the sleep-wake cycle and diurnal fluctuation of Aβ. Sleep-wake behavior and diurnal fluctuation of Aβ in the central nervous system may be functional and biochemical indicators, respectively, of Aβ-associated pathology.     

Content of Autoantibodies to Bradykinin and β-Amyloid1-42 as a Criterion for Biochemical Differences between Alzheimer's Dementias

We measured serum content of autoantibodies to -amyloid protein A_1-42, its neurotoxic fragment A_25-35, vasopressin, bradykinin, thrombin, antithrombin III, ₂-macroglobulin, and angiotensin II in patients with various forms of Alzheimer's dementias, including presenile and senile dementias of the Alzheimer type. The ratio of antibradykinin and anti-A_1-42 autoantibody contents differed by 39% in these patients. Our results can be used for the development of a new biochemical method for differential diagnostics of dementias of the Alzheimer type.     

Silver Labeling of Alzheimer Neurofibrillary Changes and Brain β-Amyloid

Abstract

Alzheimer neurofibrillary changes and brain β-amyloid can be stained selectively by silver impregnation on tissue sections and (in the case of neurofibrillary proteins) on sodium dodecyl sulfate-polyacrylamide gels. The stain can be applied to frozen sections of tissue from 10–150 μm thick, to similarly thick polyethylene glycol sections, or to 5–15 μm thick paraffin sections. The technique can also be applied to routinely fixed autopsy material. The technique takes advantage of the physical development of nucleation sites, thereby permitting tight control of the entire procedure. It is less expensive than immunocytochemical techniques, and facilitates processing of large numbers of sections through entire hemispheres of the human brain. (The J Histotechnol 16:335, 1993)     

Transfer of the amyloid β and/or of β-amyloid precursor protein of the fetus with trisomy 21 to the maternal blood stream and its possible contribution to the pathogenesis of the maternal Alzheimer's Disease

Down Syndrome (DS) is the most frequent genetic pathology. It affects 1 out of every 800 newborn babies. Approximately between a 90% and a 95% of all the cases of DS are attributed to a trisomy in chromosome 21. One of the genes contained in this chromosome is the gene of β-amyloid precursor protein (βAPP). The metabolism of this protein yields, among others, the amyloid beta peptides made up of 40 amino acids (Aβ40) and 42 amino acids (Aβ42). The evidence that is derived from several sources - genetic, among them - suggests that the Aβ participates in the pathogenesis of Alzheimer’s Disease (AD).It is worth pointing at the fact that the transfer of cells, extracellular chromosomal material and some proteins from the fetus to the mother and vice versa has been widely described. The transfer rate from the fetus to the mother is higher when the mother is carrying a baby with trisomy 21. This has led to the hypothesis that sets forth that during the gestation of a baby with DS there is a greater fetomaternal transfer of cells and of products of the genes of chromosome 21 - among them, βAPP and its metabolites Aβ40 and Aβ42. It is possible to speculate on the possible contribution of the fetal components - among them, Aβ - to the higher risk of suffering AD, which has been reported in a subpopulation of women who have given birth to children with DS. On the other hand, the detection of the βAPP - mainly intracellular - and of the β amyloid peptides in maternal blood and urine during the early stages of gestation could be taken as a potential non invasive biochemical prenatal marker of DS.     

A Phase 2 Multi-center,Open-label,Switch-over Trial to Evaluate the Safety and Efficacy of Abcertin? in Patients with Type 1 Gaucher Disease

Gaucher disease is a lysosomal storage disease for which enzyme replacement therapy has proven to be effective. A switch-over clinical trial was performed to evaluate the efficacy and safety of Abcertin® (ISU Abxis, Seoul, Korea) in subjects with type 1 Gaucher disease who were previously treated with imiglucerase. Five Korean patients with type 1 Gaucher disease were enrolled. Previous doses of imiglucerase ranged from 30 to 55 U/kg every other week. The same dose of Abcertin® was administered to all patients for 24 weeks. Primary efficacy endpoints were changes in hemoglobin levels and platelet counts, and the secondary efficacy endpoints included changes in liver and spleen volumes, serum biomarkers, skeletal status and bone mineral density (BMD). During the study period, no statistically significant changes were observed in all parameters including hemoglobin levels and platelet counts, liver and spleen volumes, skeletal status and BMD. Abcertin® administration was continued in three patients for another 24 weeks as an extension of the study. Hemoglobin levels and platelet counts were maintained in all three patients. In conclusion, the efficacy and safety of Abcertin® are similar to those of imiglucerase, and Abcertin® is an effective therapeutic agent for patients with type 1 Gaucher disease (Clinical Trial Registry No. {"type":"clinical-trial","attrs":{"text":"NCT02053896","term_id":"NCT02053896"}}NCT02053896 at www.clinicaltrials.gov).

Graphical Abstract

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A New Approach to the Differential Diagnosis of Patients with Parkinson’s Disease and Essential Tremor

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Regional Analysis of Spontaneous MEG Rhythms in Patients with Alzheimer’s Disease Using Spectral Entropies

Alzheimer’s disease (AD) is the most common form of dementia. Ageing is the greatest known risk factor for this disorder. Therefore, the prevalence of AD is expected to increase in western countries due to the rise in life expectancy. Nowadays, a low diagnosis accuracy is reached, but an early and accurate identification of AD should be attempted. In this sense, only a few studies have focused on the magnetoencephalographic (MEG) AD patterns. This work represents a new effort to explore the ability of three entropies from information theory to discriminate between spontaneous MEG rhythms from 20 AD patients and 21 controls. The Shannon (SSE), Tsallis (TSE), and Rényi (RSE) spectral entropies were calculated from the time-frequency distribution of the power spectral density (PSD). The entropies provided statistically significant lower values for AD patients than for controls in all brain regions (p < 0.0005). This fact suggests a significant loss of irregularity in AD patients’ MEG activity. Maximal accuracy of 87.8% was achieved by both the TSE and RSE (90.0%, sensitivity; 85.7%, specificity). The statistically significant results obtained by both the extensive (SSE and RSE) and non-extensive (TSE) spectral entropies suggest that AD could disturb long and short-range interactions causing an abnormal brain function.     

MEG Connectivity Analysis in Patients with Alzheimer’s Disease Using Cross Mutual Information and Spectral Coherence

Alzheimer’s disease (AD) is an irreversible brain disorder which represents the most common form of dementia in western countries. An early and accurate diagnosis of AD would enable to develop new strategies for managing the disease; however, nowadays there is no single test that can accurately predict the development of AD. In this sense, only a few studies have focused on the magnetoencephalographic (MEG) AD connectivity patterns. This study compares brain connectivity in terms of linear and nonlinear couplings by means of spectral coherence and cross mutual information function (CMIF), respectively. The variables defined from these functions provide statistically significant differences (p < 0.05) between AD patients and control subjects, especially the variables obtained from CMIF. The results suggest that AD is characterized by both decreases and increases of functional couplings in different frequency bands as well as by an increase in regularity, that is, more evident statistical deterministic relationships in AD patients’ MEG connectivity. The significant differences obtained indicate that AD could disturb brain interactions causing abnormal brain connectivity and operation. Furthermore, the combination of coherence and CMIF features to perform a diagnostic test based on logistic regression improved the tests based on individual variables for its robustness.     

Amyloid-Peptide Vaccinations Reduce β-Amyloid Plaques but Exacerbate Vascular Deposition and Inflammation in the Retina of Alzheimer’s Transgenic Mice

Alzheimer’s disease (AD) is pathologically characterized by accumulation of β-amyloid (Aβ) protein deposits and/or neurofibrillary tangles in association with progressive cognitive deficits. Although numerous studies have demonstrated a relationship between brain pathology and AD progression, the Alzheimer’s pathological hallmarks have not been found in the AD retina. A recent report showed Aβ plaques in the retinas of APPswe/PS1ΔE9 transgenic mice. We now report the detection of Aβ plaques with increased retinal microvascular deposition of Aβ and neuroinflammation in Tg2576 mouse retinas. The majority of Aβ-immunoreactive plaques were detected from the ganglion cell layer to the inner plexiform layer, and some plaques were observed in the outer nuclear layer, photoreceptor outer segment, and optic nerve. Hyperphosphorylated tau was labeled in the corresponding areas of the Aβ plaques in adjacent sections. Although Aβ vaccinations reduced retinal Aβ deposits, there was a marked increase in retinal microvascular Aβ deposition as well as local neuroinflammation manifested by microglial infiltration and astrogliosis linked with disruption of the retinal organization. These results provide evidence to support further investigation of the use of retinal imaging to diagnose AD and to monitor disease activity.Cerebral abnormalities including neuronal loss, neurofibrillary tangles, senile plaques with aggregated β-amyloid protein (Aβ) deposits, microvascular deposition of Aβ, and inflammation are well-known pathological hallmarks of Alzheimer’s disease (AD).^1,2,3 Despite the controversial evidence about the contribution of Aβ to the development of AD-related cognitive deficits, accumulation of toxic, aggregated forms of Aβ plays a crucial role in the pathogenesis of familial types of AD.^4,5 Overexpression of amyloid precursor protein (APP) in trisomy 21, altered APP processing resulting from mutations in APP, presenilin 1 (PS1), or 2 (PS2), and, as-of-yet unidentified other familial AD, related mutations, lead to Aβ deposition and Aβ plaques in the brain as well as cognitive abnormalities.^6,7 Therefore, to understand the molecular basis of amyloid protein deposition and to detect Aβ plaques in brain, parenchyma ante-mortem are currently among the most active areas of research in AD.Besides cognitive abnormalities, patients with AD commonly complain of visual anomalies, in particular, related to color vision,^8,9 spatial contrast sensitivity,¹⁰ backward masking,¹¹ visual fields,¹² and other visual performance tasks.^13,14,15,16 In addition to the damage and malfunction in the central visual pathways, retinal abnormalities such as ganglion cell degeneration,¹⁷ decreased thickness of the retinal nerve fiber layer,^18,19 and optic nerve degeneration^20,21 may, in part, account for AD-related visual dysfunction. Although intracellular Aβ deposition has been detected in both ganglion and lens fiber cells of patients with glaucoma, AD, or Down’s syndrome,^22,23,24,25 other typical hallmarks of AD have not yet been demonstrated. Interestingly, thioflavine-S-positive Aβ plaques were recently found in the retinal strata of APPswe/PS1ΔE9 transgenic mice²⁶ but not in the other animal models of AD. The current study used Tg2576 mice that constitutively overexpress APPswe and develop robust Aβ deposits in brain as well as cognitive abnormalities with aging.²⁷ We assessed the pathological changes in the retina of aged mice following different immunization schemes. We immunized Tg2576 with fibrillar Aβ42 and with a prefibrillar oligomer mimetic that gives rise to a prefibrillar oligomer-specific immune response. Both types of immunogens have been shown to be equally effective in reducing plaque deposition and inflammation in Tg2576 mouse brains.²⁸ In this study, we also used another prefibrillar oligomer mimetic antigen that uses the islet amyloid polypeptide (IAPP) instead of Aβ, but which gives rise to the same generic prefibrillar oligomer-specific immune response that also recognizes Aβ prefibrillar oligomers.²⁹ Aβ plaques and microvascular Aβ deposition were observed in the control Tg2576 mouse retinas. In contrast, Aβ and IAPP prefibrillar oligomer vaccinations differentially removed retinal Aβ deposits but exacerbated retinal amyloid angiopathy and inflammation as demonstrated by a significantly enhanced microglial infiltration and astrogliosis.     

Does the Presence of Anti-CCP Autoantibodies and Their Serum Levels Influence the Severity and Activity in Rheumatoid Arthritis Patients?

This study aims to investigate the association of the presence and of the titer of autoantibodies against cyclic citrullinated peptides (aCCP), with clinical manifestations and disease activity in a cohort of patients with rheumatoid arthritis (RA). From January 2000 through December 2005, 135 patients were diagnosed with RA at the Rheumatology Unit of our hospital. Demographic, clinical, laboratory, and therapeutic parameters were evaluated in all patients at study entry and at every follow-up visit. Positivity in aCCP and also their levels were determined for all patients. At the end of the study, we reevaluated the above parameters, dividing patients into aCCP positive and aCCP negative. From 135 patients, 53.3% were aCCP positive. The majority of aCCP-positive patients were males (p < 0.001), positive to rheumatoid factor (p < 0.001) and current smokers (p < 0.05). At diagnosis, aCCP-positive patients presented with higher tender joint counts (p < 0.001) and swollen joint counts (p < 0.001), and exhibited more active disease, expressed by higher disease activity scores for 28 joints (DAS-28) (p < 0.001). At the end of the study, aCCP-positive patients also displayed more active disease, with higher DAS-28 (p < 0.001), and more severe disease, as this was indicated by the higher radiological Larsen score (p < 0.001). The serum levels of aCCP were not found to be associated with disease activity and severity. In early RA, the presence of aCCP is associated with increased disease activity and severity. This was found to be independent of circulating levels of aCCP.     

Intracerebral Production of Tumor Necrosis Factor-α, a Local Neuroprotective Agent, in Alzheimer Disease and Vascular Dementia

The local pattern of proinflammatory cytokine release was studied in Alzheimer disease (AD) and vascular dementia (VAD), by measuring intrathecal levels of IL-1, IL-6, TNF-, and its naturally occurring antagonists, soluble TNF receptors I and II. The cytokine levels were related to neuronal damage, as measured by the intrathecal tau concentration, to cerebral apoptosis assessed by levels of Fas/APO-1 and bcl-2, and to clinical variables. In vitro analysis was performed to study the effect of TNF- on the production of bcl-2, an antiapoptotic factor, by human neuronal cells. Patients with both AD and VAD displayed significantly higher intrathecal levels of TNF- compared to controls. In addition, patients with AD showed significantly negative correlations between the intrathecal levels of TNF- and the levels of Fas/APO-1 as well as of tau protein. The level of bcl-2 in supernatants of TNF--exposed cultures of human neuronal cells was up to three times higher than in control supernatants. Our study demonstrates intrathecal production of TNF- in patients with dementias, suggesting that this cytokine may have a neuroprotective role in these neurodegenerative conditions as evidenced by negative correlations between this cytokine and (i) levels of intrathecal Fas/APO-1 and (ii) levels of tau protein, both parameters closely related to brain damage. Our in vitro data suggest that TNF- exerts its neuroprotective effect by stimulating neuronal cells to express bcl-2, a molecule which downregulates apoptosis.     

β-Amyloid 42/40 ratio and kalirin expression in Alzheimer disease with psychosis

Psychosis in Alzheimer disease differentiates a subgroup with more rapid decline, is heritable, and aggregates within families, suggesting a distinct neurobiology. Evidence indicates that greater impairments of cerebral cortical synapses, particularly in dorsolateral prefrontal cortex, may contribute to the pathogenesis of psychosis in Alzheimer disease (AD) phenotype. Soluble β-amyloid induces loss of dendritic spine synapses through impairment of long-term potentiation. In contrast, the Rho guanine nucleotide exchange factor (GEF) kalirin is an essential mediator of spine maintenance and growth in cerebral cortex. We therefore hypothesized that psychosis in AD would be associated with increased soluble β-amyloid and reduced expression of kalirin in the cortex. We tested this hypothesis in postmortem cortical gray matter extracts from 52 AD subjects with and without psychosis. In subjects with psychosis, the β-amyloid(1-42)/β-amyloid(1-40) ratio was increased, due primarily to reduced soluble β-amyloid(1-40), and kalirin-7, -9, and -12 were reduced. These findings suggest that increased cortical β-amyloid(1-42)/β-amyloid(1-40) ratio and decreased kalirin expression may both contribute to the pathogenesis of psychosis in AD.