Immunoinflammatory Aspects of Parkinson’s Disease

Neuroscience and Behavioral Physiology - This review analyzes immunological impairments in Parkinson’s disease (PD). We present data on neuroinflammation, with which cell degeneration in the...     

Peptide KED: Molecular-Genetic Aspects of Neurogenesis Regulation in Alzheimer’s Disease

Bulletin of Experimental Biology and Medicine - Neuroprotective peptides are promising candidate molecules for the treatment of Alzheimer’s disease (AD). Oral application of KED (Lys-Glu-Asp)...     

Selective Cell Death of Hyperploid Neurons in Alzheimer’s Disease

Aneuploidy, an abnormal number of copies of a genomic region, might be a significant source for neuronal complexity, intercellular diversity, and evolution. Genomic instability associated with aneuploidy, however, can also lead to developmental abnormalities and decreased cellular fitness. Here we show that neurons with a more-than-diploid content of DNA are increased in preclinical stages of Alzheimer’s disease (AD) and are selectively affected by cell death during progression of the disease. Present findings show that neuronal hyperploidy in AD is associated with a decreased viability. Hyperploidy of neurons thus represents a direct molecular signature of cells prone to death in AD and indicates that a failure of neuronal differentiation is a critical pathogenetic event in AD.Understanding the mechanisms underlying generation of neuronal variability and complexity remains a basic challenge to neuroscience. Structural variation in the human genome is likely to be one important mechanism for neuronal diversity and brain disease.¹ The genetic profile of a cell can be permanently altered by chromosomal aneuploidy (i.e., an abnormal number of copies of a genomic region). A combination of multiple different forms of aneuploid cells due to loss or gain of whole chromosomes (mosaic aneuploidy) giving rise to cellular diversity at the genomic level have been described in neurons of the normal and diseased adult human brain.^{2,3,4,5,6,7,8,9,10,11,12}Cells in normal individuals have basically been assumed to contain identical euploid genomes. Still, earlier hypotheses suggested that a number of mammalian somatic tissues are populated by polyploid cells. Adult neurons of mammals were assumed to be postmitotic cells characterized to some extent by a polyploid chromosome complement. Testing this hypothesis in the past through histochemical methods, however, yielded controversial results through technical limitations.^13,14 However, with the recent development of molecular cytogenic techniques, aneuploid cells in the normal developing and mature brain have clearly been identified, indicating that the maintenance of aneuploid neurons in the adult CNS is a widespread, if not universal, property of organization.^{2,3,4,5,6,7,8,9,10,11,12,15}Recent studies of the embryonic brain have shown that approximately one-third of the dividing cells that give rise to the cerebral cortex have genetic variability, manifested as chromosome aneuploidy.^3,7,12 Neurons that constitute the adult brain arise from mitotic neural progenitor cells in the ventricular zone, a proliferating region where aneuploid cells appear to be generated through various chromosome segregation defects initially.^3,10 While a portion of these aneuploid cells apparently die during development,^3,16,17 aneuploid neurons have been identified in the mature brain in all areas assayed^{2,3,4,5,6,7,8,9,10,11,12,15} indicating that aneuploidy does not necessarily impair viability.¹⁸ Aneuploid neurons in the adult have been shown to make distant connections and express markers associated with neural activity, which indicates that these neurons can be integrated into brain circuitry.^4,12Contrary to this physiological consequences of “low-level” aneuploidy potentially contributing to neuronal diversity, aneuploidy above a critical threshold might be detrimental. Genomic instability and imbalances in gene dosage associated with aneuploidy can lead to developmental abnormalities, decreased cellular and organismal fitness, and increased susceptibility to disease.^19,20Aneuploid cells have typically been associated with pathophysiological conditions such as cancer,²¹ and most aneuploid syndromes present brain phenotypes and show a high vulnerability for psychiatric disorders.²² Mental impairment is a characteristic feature of all recognizable autosomal aneuploidy syndromes.Recent studies have shown an increased rate of aneuploid neurons in Alzheimer’s disease (AD), schizophrenia, autism, and ataxia-telangiectasia.^2,5,23,24,25 So far, however, direct evidence for a pathogenetic role for neuronal aneuploidy in these disorders is lacking. In particular, it remains unclear whether neuronal aneuploidy affects cellular viability, thus contributing directly to neurodegeneration and cell death.Here, we analyzed the fate of hyperploid neurons at the conversion from preclinical to mild AD and during further progression to severe stages of the disease. We can show that neurons with a more-than-diploid content of DNA are increased in preclinical stages of AD and are selectively affected by cell death during progression of the disease. Present findings show that neuronal hyperploidy in AD is associated with a decreased viability and directly linked to cell death.     

Quantitative Evaluation of Links between Inflammatory Markers and Alzheimer’s Disease

Neuroscience and Behavioral Physiology - Objectives. To obtain quantitative assessment of the link between Alzheimer’s disease (AD) and inflammatory markers such as the enzymatic activity of...     

Antiamnestic Effects of Antibodies to Glutamate in Experimental Alzheimer’s Disease

Experiments on rats showed that neurodegenerative brain damage caused by administration of neurotoxic fragment of β-amyloid protein Aβ_25-35 in a dose of 2 μg into Meynert giant cell nucleus leads to long-term memory impairment in rats. Intranasal administration of antibodies to glutamate in a dose of 300 μg/kg 1 h after damage restores learning capacity of the experimental animals in the conditioned passive avoidance paradigm.     

Brain atrophy in Alzheimer’s Disease and aging

Thanks to its safety and accessibility, magnetic resonance imaging (MRI) is extensively used in clinical routine and research field, largely contributing to our understanding of the pathophysiology of neurodegenerative disorders such as Alzheimer’s disease (AD). This review aims to provide a comprehensive overview of the main findings in AD and normal aging over the past twenty years, focusing on the patterns of gray and white matter changes assessed in vivo using MRI. Major progresses in the field concern the segmentation of the hippocampus with novel manual and automatic segmentation approaches, which might soon enable to assess also hippocampal subfields. Advancements in quantification of hippocampal volumetry might pave the way to its broader use as outcome marker in AD clinical trials. Patterns of cortical atrophy have been shown to accurately track disease progression and seem promising in distinguishing among AD subtypes. Disease progression has also been associated with changes in white matter tracts. Recent studies have investigated two areas often overlooked in AD, such as the striatum and basal forebrain, reporting significant atrophy, although the impact of these changes on cognition is still unclear. Future integration of different MRI modalities may further advance the field by providing more powerful biomarkers of disease onset and progression.     

Vesicular Acetylcholine Transporter Density and Alzheimer’s Disease

We have evaluated the vesamicol analogue meta-[¹²⁵I]iodobenzyltrozamicol {(+)-[¹²⁵I]MIBT} as a probe to assess cholinergic terminal integrity in the human temporal cortex. Saturation binding analysis, using 5-aminobenzovesamicol (ABV) to define nonspecific binding, revealed a high-affinity binding site with a K_d value of 4.3 ± 1.2 nM in the temporal cortex of the young control subjects. Similar affinity values were observed for (+)-[¹²⁵I]MIBT binding in aged control subjects (K_d = 3.4 ± 0.5 nM) and AD patients (K_d = 3.0 ± 0.8 nM). In contrast, Bmax values for young subjects, aged controls and AD patients were 31.2 ± 6.3, 17.0 ± 2.0 and 9.4 ± 1.6 pmol/g, respectively, clearly reflecting significant reductions in (+)-[¹²⁵I]MIBT binding site density with aging and age-related neuropathology. Moreover, the decrease in (+)-[¹²⁵I]MIBT binding was correlated with choline acetyltransferase activities (r = 0.72) in the AD temporal cortex. These results suggest that when selective ligands are used, the vesicular acetylcholine transporter can be a useful marker protein for assessing the loss of cholinergic projections in AD and related disorders.     

Future Therapeutics in Alzheimer’s Disease: Development Status of BACE Inhibitors

Alzheimer’s disease (AD) is the primary cause of dementia in the elderly. It remains incurable and poses a huge socio-economic challenge for developed countries with an aging population. AD manifests by progressive decline in cognitive functions and alterations in behaviour, which are the result of the extensive degeneration of brain neurons. The AD pathogenic mechanism involves the accumulation of amyloid beta peptide (Aβ), an aggregating protein fragment that self-associates to form neurotoxic fibrils that trigger a cascade of cellular events leading to neuronal injury and death. Researchers from academia and the pharmaceutical industry have pursued a rational approach to AD drug discovery and targeted the amyloid cascade. Schemes have been devised to prevent the overproduction and accumulation of Aβ in the brain. The extensive efforts of the past 20 years have been translated into bringing new drugs to advanced clinical trials. The most progressed mechanism-based therapies to date consist of immunological interventions to clear Aβ oligomers, and pharmacological drugs to inhibit the secretase enzymes that produce Aβ, namely β-site amyloid precursor-cleaving enzyme (BACE) and γ-secretase. After giving an update on the development and current status of new AD therapeutics, this review will focus on BACE inhibitors and, in particular, will discuss the prospects of verubecestat (MK-8931), which has reached phase III clinical trials.     

Antioxidant Status in Paranoid Schizophrenia and Alzheimer’s Disease

Neuroscience and Behavioral Physiology - Objective. To study measures of the plasma antioxidant profile in patients with paranoid schizophrenia and Alzheimer’s disease (AD). Materials and...     

Neuroanatomy of Down Syndrome in vivo: A Model of Preclinical Alzheimer’s Disease

Aging in Down syndrome (DS) is accompanied by neuropathological features of Alzheimer’s disease (AD). Therefore, DS has been proposed as a model to study predementia stages of AD. MRI-based measurement of grey matter atrophy is an in vivo surrogate marker of regional neuronal density. A range of neuroimaging studies have described the macroscopic neuroanatomy of DS. Recent studies using sensitive quantitative measures of region-specific atrophy based on high-resolution MRI suggest that age-related atrophy in DS resembles the pattern of brain atrophy in early stages of AD. The pattern of atrophy determined in predementia DS supports the notion that AD-type pathology leads to neuronal degeneration not only in allocortical, but also in neocortical brain areas before onset of clinical dementia. This has major implications for our understanding of the onset and progression of AD-type pathology both in DS and in sporadic AD.     

Model-based Quantification of Cerebral Hemodynamics as a Physiomarker for Alzheimer’s Disease?

Previous studies have found that Alzheimer’s disease (AD) impairs cerebral vascular function, even at early stages of the disease. This offers the prospect of a useful diagnostic method for AD, if cerebral vascular dysfunction can be quantified reliably within practical clinical constraints. We present a recently developed methodology that utilizes a data-based dynamic nonlinear closed-loop model of cerebral hemodynamics to compute “physiomarkers” quantifying the state of cerebral flow autoregulation to pressure-changes (CA) and cerebral CO2 vasomotor reactivity (CVMR) in each subject. This model is estimated from beat-to-beat measurements of mean arterial blood pressure, mean cerebral blood flow velocity and end-tidal CO2, which can be made reliably and non-invasively under resting conditions. This model may also take an open-loop form and comparisons are made with the closed-loop counterpart. The proposed model-based physiomarkers take the form of two indices that quantify the gain of the CA and CVMR processes in each subject. It was found in an initial set of clinical data that the CVMR index delineates AD patients from control subjects and, therefore, may prove useful in the improved diagnosis of early-stage AD.     

Calcium hypothesis of Alzheimer’s disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder caused by an increase in amyloid metabolism. The calcium hypothesis of AD explores how activation of the amyloidogenic pathway may function to remodel the neuronal Ca²⁺ signaling pathways responsible for cognition. Hydrolysis of the β-amyloid precursor protein (APP) yields two products that can influence Ca²⁺ signaling. Firstly, the amyloids released to the outside form oligomers that enhance the entry of Ca²⁺ that is pumped into the endoplasmic reticulum (ER). An increase in the luminal level of Ca²⁺ within the ER enhances the sensitivity of the ryanodine receptors (RYRs) to increase the amount of Ca²⁺ being released from the internal stores. Secondly, the APP intracellular domain may alter the expression of key signaling components such as the RYR. It is proposed that this remodeling of Ca²⁺ signaling will result in the learning and memory deficits that occur early during the onset of AD. In particular, the Ca²⁺ signaling remodeling may erase newly acquired memories by enhancing the mechanism of long-term depression that depends on activation of the Ca²⁺-dependent protein phosphatase calcineurin. The alteration in Ca²⁺ signaling will also contribute to the neurodegeneration that characterizes the later stages of dementia.     

The Cost of Crohn’s Disease

New biological medical therapies and innovative surgical approaches have revolutionised the care of patients with Crohn's disease. Until these innovations began to be utilised over the past decade, studies of the economics of Crohn's disease care were relatively scarce. Questions from both clinical and economic standpoints now arise over potential choices between medical and surgical approaches to patients with Crohn's disease. Initial economic studies suggested that the vast majority of costs in Crohn's disease were due to inpatient services and surgery. The large variance in cost data between patients resulted in a very small percentage of patients accounting for a disproportionately large percentage of the overall costs, with the bulk of costs, charges and reimbursements accrued by surgical cases. Studies suggest that surgery would need to result in a decreased utilisation of outpatient services in order to be 'cost-effective'. Evaluation of the clinical course of Crohn's disease suggests that the surgically-induced remission state is the longest remission state generally experienced by the patients, although sophisticated cost analysis fails to show enough of a remission benefit to offset the high costs associated with surgical procedures and post-operative convalescence. Bowel-sparing intestinal strictureplasty and minimally invasive laparoscopic surgeries have the potential to substantially decrease the costs associated with disease. These techniques need to be applied to a larger percentage of surgical Crohn's patients before the overall economic benefits can be fully assessed. Indirect costs and disability may account for most of the overall costs associated with Crohn's disease. Quality-of-life analyses have revealed that patients ill with Crohn's disease perform poorly, and the detrimental effects of medications or surgery may further increase disability in these patients. Future cost-utility studies may reveal the extent to which overall costs are affected by these issues. This review of the currently available literature on the economics of Crohn's disease suggests that medical therapy which can substantially reduce the utilisation of hospitalisations and surgery might be cost effective, even if the acquisition cost of the drug is high. However, broader application of specialised surgical techniques, together with the long post-operative remission state enjoyed by most Crohn's patients, may also offer a cost-effective long term approach to the disease. It is likely that both surgical and medical approaches will continue to be used in the treatment of Crohn's disease, with options for each patient being carefully considered on an individual basis.