Calcium in Alzheimer's disease pathogenesis: too much, too little or in the wrong place?

Our understanding of the molecular genetics and biochemical pathology of Alzheimer's disease has progressed tremendously in the past decade. The metabolism of amyloid beta-peptide is being unraveled, and specific anti-amyloid therapies are now in clinical trials worldwide. The precise biophysical structure of the amyloid beta-peptide that causes neuronal dysfunction remains under investigation, as does the interaction between amyloid peptides and tau hyperphosphorylation, but these two molecules likely play key roles in neuronal dysfunction in Alzheimer's disease. Despite these advances, the cell biology of neuronal dysfunction and cell death in the Alzheimer's disease brain remains poorly understood. This brief review will explore the role of calcium (Ca2+) in neuronal death occurring during Alzheimer's disease. The evidence for glutamate receptor-mediated Ca;2+ overload, or excitotoxicity, and other derangements of Ca2+ homeostasis in cell culture and animal models of Alzheimer's disease is reviewed. Finally, we raise the possibility that some of the neuronal death observed in Alzheimer's disease might be associated with a reduction in rather than an increase in cytosolic Ca2+ levels, an idea with potentially important therapeutic implications.     

Intrathecal baclofen in multiple sclerosis: too little, too late?

The majority of patients with multiple sclerosis (MS) have symptoms of spasticity that increasingly impair function as the disease progresses. With appropriate treatment, however, quality of life can be improved. Oral antispasticity medications are useful in managing mild spasticity but are frequently ineffective in controlling moderate to severe spasticity, because patients often cannot tolerate the adverse effects of increasing doses. Intrathecal baclofen (ITB) therapy can be an effective alternative to oral medications in patients who have a suboptimal response to oral medications or who cannot tolerate dose escalation or multidrug oral regimens. ITB therapy may be underutilized in the MS population because clinicians (a) are more focused on disease-modifying therapies rather than symptom control, (b) underestimate the impact of spasticity on quality of life, and (c) have concerns about the cost and safety of ITB therapy. Delivery of ITB therapy requires expertly trained staff and proper facilities for pump management. This article summarizes the findings and recommendations of an expert panel on the use of ITB therapy in the MS population and the role of the physician and comprehensive care team in patient selection, screening, and management.     

Alzheimer disease: are we intervening too late?

The affirmative position is argued in response to the question of whether intervention in the disease course of Alzheimer disease (AD) occurs too late. AD is not a singular, homogeneous disease, but rather a final common pathway or end-point that can be arrived at through multiple routes. As part of the affirmative argument, there is a delineation of two long-term trajectories leading to AD: (1) normal elderly progression to AD, and (2) depressed elderly progression to AD. In documenting normal elderly devolution into AD, two “normal” elderly pre-AD or prodromal stages are discussed: age-associated memory impairment (AAMI) and mild cognitive impairment (MCI). Data are provided evidencing significantly high conversion rates from these pre-AD stages to actual AD. Using the same paradigmatic approach that is used in documenting normal elderly decline into AAMI and MCI with eventual conversion to AD; there is explication of depressed elderly conversion to AD. The long-term, multiphasic disease progression of major depression without dementia to depressive dementia to final conversion to AD is brought into focus as another example of why intervention must occur prior to actual conversion to AD. Depression is defined as a cognitive syndrome and risk factor for AD requiring aggressive targeted intervention. AD does not just come suddenly out of nowhere. First intervention must occur during the pre-AD phases in an attempt to prevent, delay, and interrupt long-term neurodegenerative processes involved in both normal elderly and depressed elderly conversion to AD. A primary strategy proposed is to delay onset of AD. Population statistics indicate that if AD is delayed by a modest 1 year, there would be 9.5 million fewer cases by 2050, resulting in significant reduction in burden of disease. Data show early intervention with cognitive stimulation (mental exercise), physical exercise, aggressive treatment of AD risk factors and excess disability, psychotherapy, and other nonpharmacological interventions in combination with each other and/or with medications can result in delay of onset of AD. First intervention at time of diagnosis of AD is too late, when by definition, final conversion to AD has already occurred. When we have knowledge to successfully intervene earlier, why would we not want to do so.     

Chitosan-based nanoparticles in Alzheimer’s disease:messenger or message?

Cellulose is the most common natural(plant)polymer while its animal-kingdom close relative chitin comes in second.It is estimated that there are some 10 billion tons of chitin in the world(d’Ayala et al.,2008).Chitin may be described as cellulose with one hydroxyl group on each monomer replaced with an acetyl amine group.Chitin-producing organisms like protozoa,fungi,arthropods,and nematodes are often pathogens in other species.Despite the absence of endogenous chitin,mammals express chitinases(E.C 3.2.2.14)with enzymatic activity.     

Progress in Alzheimer’s disease

After more than one century from Alois Alzheimer and Gaetano Perusini’s first report, progress has been made in understanding the pathogenic steps of Alzheimer’s disease (AD), as well as in its early diagnosis. This review discusses recent findings leading to the formulation of novel criteria for diagnosis of the disease even in a preclinical phase, by using biological markers. In addition, treatment options will be discussed, with emphasis on new disease-modifying compounds and future trial design suitable to test these drugs in an early phase of the disease.     

Astrocytes in Alzheimer’s disease

The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia. The astrocytes perform numerous functions, providing for the overall brain homeostasis, assisting in neurogenesis, determining the micro-architecture of the grey matter, and defending the brain through evolutionary conserved astrogliosis programs.     

Treatments in Alzheimer’s disease

Journal of Neurology -     

Positive argument for debate in J Neural Transmission: Alzheimer’s disease: are we intervening too late? Yes, by years if not decades

The ongoing debate as to whether we are or are not early enough in treatment for Alzheimer??s disease presents distinct vantage points. Points expressed range from stressing the need for early preventive measures to highlighting the failure of ??alternative?? therapies, and concluding that we are unfortunately doing all that we can at present. Herein, we stress the worth of nutritional intervention, and review why such studies are often inherently compromised. We conclude that considerable education is needed to advance lifestyle modifications early enough to obtain their optimal effect, and instead of positioning ??classical?? interventions against ??alternative?? interventions, the combinations of both may impart maximal benefit. The introduction of novel detection methods at the earliest indications of cognitive impairment may provide a window of opportunity for initiation of preventative approaches.     

Alzheimer’s disease,Huntington’s disease and cancer

Neurodegenerative disorders and cancer are two of the most common groups of conditions in our world. Some studies have proposed that neurodegenerative disorders may be protective of the development of cancer.We tested this hypothesis using two neurodegenerative disorders with different molecular pathophysiology – Alzheimer’s disease (AD) and Huntington’s disease (HD) – to see if the inverse relationship between cancer and neurodegeneration was generalizable. Five-year cancer incidence was determined in two large datasets: AD using the C-Path Online Date Repository (CODR) database (n = 6383) and HD using the ENROLL-HD database (n = 2608). Cancer incidence was determined in the populations and compared to normal population data for Australia, United Kingdom and the United States of America. Age-sex standardized rates of cancer were determined and expressed as 95% confidence intervals. We describe an age-sex standardized cancer rate of 1179.6/per 100,000 population to 1253.7/per 100,000 population in normal populations.The rate in AD was 815.2/per 100,000 population (95% CI 813.32–817.5/per 100,000 population) and for HD 1296.6/per 100,000 population (95% CI 1288–1308.2/per 100,000 population).We conclude that patients with AD have a reduced age-sex standardized rate of developing cancer not shared with HD, a finding that hints at different molecular mechanisms.     

Alzheimer’s disease

Conclusions It would appear, on the basis of this study, that Alzheimer's disease is a distinct clinicopathologic entity which, while not common, is not so rare as commonly believed.Finally, it is pertinent to emphasize that familiarity with the clinical picture will show that many more cases exist than have hitherto been suspected.     

Alzheimer’s disease

Psychiatric Quarterly - It would appear, on the basis of this study, that Alzheimer’s disease is a distinct clinicopathologic entity which, while not common, is not so rare as commonly...     

Statins: drugs for Alzheimer’s disease?

Summary. Evidences from cell culture experiments and animal studies suggest a strong link between cholesterol and Alzheimer’s disease (AD). This relationship is supported by retrospective epidemiological studies demonstrating that statin treatment reduced the prevalence of AD in patients suffering from hypercholesterolaemia. The alternative processing of the amyloid-precursor protein (APP) in the brain of AD patients leads to the production of the neurotoxic amyloid-beta protein (Aβ), a causative factor for AD pathology. In vitro, this mechanism is modulated by alterations in cellular cholesterol levels. Moreover, lowering cholesterol in animal experiments reduced the production of Aβ in most but not all studies. These findings led to prospective clinical trials of cholesterol-lowering statins in AD patients, even if many studies do not support elevated cholesterol levels in serum and brain as a risk factor for Alzheimer’s disease. Most of these studies were negative. Thus, up to date there is insufficient evidence to suggest the use of statins for treatment in patients with AD.     

Synaptic degeneration in Alzheimer’s disease

Synaptic loss is the major neurobiological substrate of cognitive dysfunction in Alzheimer’s disease (AD). Synaptic failure is an early event in the pathogenesis that is clearly detectable already in patients with mild cognitive impairment (MCI), a prodromal state of AD. It progresses during the course of AD and in most early stages involves mechanisms of compensation before reaching a stage of decompensated function. This dynamic process from an initially reversible functionally responsive stage of down-regulation of synaptic function to stages irreversibly associated with degeneration might be related to a disturbance of structural brain self-organization and involves morphoregulatory molecules such as the amyloid precursor protein. Further, recent evidence suggests a role for diffusible oligomers of amyloid β in synaptic dysfunction. To form synaptic connections and to continuously re-shape them in a process of ongoing structural adaptation, neurons must permanently withdraw from the cell cycle. Previously, we formulated the hypothesis that differentiated neurons after having withdrawn from the cell cycle are able to use molecular mechanisms primarily developed to control proliferation alternatively to control synaptic plasticity. The existence of these alternative effector pathways within neurons might put them at risk of erroneously converting signals derived from plastic synaptic changes into the program of cell cycle activation, which subsequently leads to cell death. The molecular mechanisms involved in cell cycle activation might, thus, link aberrant synaptic changes to cell death.