Is there sugar in the Alzheimer's disease?

Epidemiological and immunohistochemical studies focus the interest on the contribution of carbohydrates in the pathophysiology of Alzheimer's disease. Diabetes mellitus increases the risk. In the extracellular (senile) plaques, which contain aggregates of amyloid proteins, and in the neurofibrillary tangles within the cytoplasm of neurons, advanced glycation end products were detected. It is discussed whether it is a cause or an effect of the Alzheimer's disease. The vascular origin of the lesions is also considered.     

Are γ-secretase and its associated Alzheimer's disease γ problems?

Presenilins (PS1 and PS2) and the amyloid-β precursor protein (AβPP) are the only known proteins as causing monogenic Alzheimer’s disease. AβPP is not the unique substrate of the γ-secretase complex. Presenilins are also implicated in the processing of Notch, an important developmental protein, which is thought to compete directly with AβPP for cleavage by γ-secretase.In the context of cleavages in alpha, beta and gamma and with the recent three-dimensional models of γ-secretase complex, a kinetic study of the sequential proteolysis of AβPP prompts us to think the possible existence of two entrance sites for substrate with only one exit site, a configuration depicting a lowercase gamma letter. The quantitative distribution of the cleavage products by the γ-secretase, mainly Aβ₄₀, Aβ₄₂ and Aβ₄₃, could be explained in the context of this hypothesis.Based on published results in the literature and the analyses of AβPP C99 fragment, highly abundant in Down’s syndrome patients, we propose that β- and γ-secretases can function as a supra-enzyme complex where AβPP substrate might be attached to the γ-secretase complex before β cleavage takes place. Different studies point that a small peptide sequence, showing homology in presenilins and AβPP, plays a pivotal role and that minor alterations in the sequence of AβPP protein limit the formation of C99 and also of Aβ₄₀ and Aβ₄₂.The model proposed could be of importance in future studies aimed at understanding the specific events involved in course of Alzheimer disease pathophysiology and also at studying of formation/deterioration of memory.     

Is M129V of PRNP gene associated with Alzheimer's disease? A case-control study and a meta-analysis

The methionine/valine (M/V) polymorphism at codon 129 within the prion protein gene (PRNP) represents a known risk factor for Creutzfeldt-Jakob disease (CJD). Few authors reported also the effects of this polymorphism on the risk of Alzheimer's disease (AD), although with controversial results. To better clarify this issue, we performed a novel case-control study and a meta-analysis of published association studies between PRNP and AD. Our findings argue against PRNP as a susceptibility gene for developing AD in the Italian population but support the hypothesis that the V allele influences cognitive performances. The meta-analysis, revealed that Caucasian subjects homozygous at codon 129 had a 1.3-fold increased risk [95% CI: 1.0-1.6, p = 0.05] of developing AD compared to heterozygous individuals. We also observed that MM genotype and M allele represent a risk factor for AD, independently from the ethnic background, providing a significant but modest association between this polymorphism and AD.     

Is knowledge of famous people disproportionately impaired in patients with early and questionable Alzheimer's disease?

Twenty-two patients with early dementia of Alzheimer's type (DAT) and 31 controls were administered tests of person-specific semantics (Experiment 1). DAT patients were impaired on all test components. In Experiment 2, 31 DAT patients, 28 questionable DAT (QDAT) patients, and 42 controls were administered the Graded Naming Test (GNT) and the newly designed Graded Faces Test (GFT), matched for difficulty with the GNT. DAT patients were impaired throughout but showed an advantage for naming objects over faces. The QDAT patients were impaired on the GFT only. Of the 7 QDAT patients who evolved to DAT within 1-2 years, 6 showed initial impairment on the GFT, whereas 17 of the nonconverters scored normally on the GFT. Results suggest greater and earlier vulnerability of person knowledge than general semantic knowledge in DAT.     

Brain atrophy and cognition: Interaction with cerebrovascular pathology?

We examined the interaction of brain atrophy and white matter lesions (WML) with cognitive functioning in 605 patients (mean age, 58 ± 10; 76% men) with atherosclerotic disease from the Second Manifestations of ARTerial disease-MR substudy (SMART-MR study). Automated brain segmentation was used to quantify volumes of brain tissue, cerebrospinal fluid, and WML on MRI. Total brain, ventricular, and cortical gray matter volume were divided by intracranial volume (ICV). Neuropsychological tests assessing executive functioning and memory performance were performed and composite scores were calculated. We observed that smaller total brain volume, larger ventricular volume, and smaller cortical gray matter volume (all as % of ICV) were associated with worse executive performance and that this association became stronger with presence of brain infarcts or severe WML volume (P-values for interaction <0.05). No interaction between measures of brain volume and cerebrovascular pathology on memory performance was observed. Our findings suggest that patients with cerebrovascular pathology on MRI may be more vulnerable to impairment in executive functioning related to global as well as focal brain atrophy.     

Is DNA repair compromised in Alzheimer's disease?

Mammalian cells utilize multiple mechanisms to repair DNA damage that occurs during normal cellular respiration and in response to genotoxic stress. This study sought to determine if chronic oxidative stress proposed to occur during Alzheimer's disease alters the expression or activity of DNA double-strand break repair or base excision repair proteins. Double-strand break repair requires DNA-dependent protein kinase, composed of a catalytic subunit, DNA-PKcs, and a regulatory component, Ku. Ku DNA binding activity was reduced in extracts of postmortem AD midfrontal cortex, but was not significantly different from the age-matched controls. Decreased Ku DNA binding correlated with reduced protein levels of Ku subunits, DNA-PKcs, and poly(ADP-ribose) polymerase-1. Expression of the base excision repair enzyme Ref-1, however, was significantly increased in AD extracts compared to controls. Ku DNA binding and DNA-PK protein levels in the AD cases correlated significantly with synaptophysin immunoreactivity, which is a measure of synaptic loss, a major correlate of cognitive deficits in AD. Immunohistochemical analysis suggested that DNA-PK protein levels reflected both number of neurons and regulation of cellular expression.     

Transthyretin and Alzheimer's disease: where in the brain?

Transthyretin (TTR), a carrier protein for thyroxine and retinol in plasma and cerebrospinal fluid (CSF), has been shown to bind the amyloid beta peptide. Accordingly, TTR has been suggested to protect against amyloid beta deposition, a key pathological feature in Alzheimer's disease (AD). Supporting this view are the reduced TTR levels found in CSF of patients with AD, as well as reports of altered TTR expression in the cortex and hippocampus of AD rodent models. Importantly, early characterization of TTR distribution revealed the choroid plexus as the site of TTR synthesis within the brain. To resolve this controversy we used precise laser microdissection technology to assay for TTR mRNA expression. Our results clearly demonstrate that TTR is not produced in the brain parenchyma of wild-type mice nor in two different transgenic mouse models of AD, suggesting that contamination by choroid plexus contributed to the recent results indicating TTR production in various brain regions. The relevance of TTR to AD should now take into consideration TTR production by the choroid plexus and its ability, in the CSF, to sequester the amyloid beta peptide.     

Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging?

For 70 years after Alois Alzheimer described a disorder of tangle-and-plaque dementia, Alzheimer's disease was a condition of the relatively young. Definitions of Alzheimer's disease (AD) have, however, changed over the past 30 years and under the revised view AD has truly become an age-related disease. Most now diagnosed with AD are elderly and would not have been diagnosed with AD as originally conceived. Accordingly, younger patients that qualify for a diagnosis of AD under both original and current Alzheimer's disease constructs now represent an exceptionally small percentage of the diagnosed population. The question of whether pathogenesis of the "early" and "late" onset cases is similar enough to qualify as a single disease was previously raised although not conclusively settled. Interestingly, debate on this issue has not kept pace with advancing knowledge about the molecular, biochemical and clinical underpinnings of tangle-and-plaque dementias. Since the question of whether both forms of AD share a common pathogenesis could profoundly impact diagnostic and treatment development efforts, it seems worthwhile to revisit this debate.     

Somatostatin,Alzheimer's disease and cognition: An old story coming of age?

In mammalian brain, the somatostatin (SRIF: somatotropin release-inhibiting factor) family is composed of two peptides: SRIF and cortistatin (CST), which interact with five different receptor subtypes, sst_1–5. This review summarizes the properties of these receptors, the involvement of somatostatinergic systems in Alzheimer's disease (SRIF/acetylcholine (Ach), SRIF/amyloid β peptides, and SRIF/tau interactions) and their role in cognition from early studies using cysteamine as an SRIF depleting substance to the use of subtype selective analogues and knockout mice, and modulation of synaptic plasticity. The current SRIF story illustrates how cognition and emotion are intimately integrated in brain function.     

Is mitochondrial DNA depletion involved in Alzheimer's disease?

Several studies have suggested that mitochondrial metabolism disturbances and mitochondrial DNA (mtDNA) abnormalities may contribute to the progression of the pathology of Alzheimer's disease (AD).In this study we have investigated whether the amount of mtDNA is modified in different brain regions (cerebellum, hippocampus and frontal cortex) of confirmed AD necropsies and in blood of living AD patients. We used a real-time PCR method to analyse the mtDNA relative abundance in brain regions from 12 AD and seven controls and from a group of blood samples (17 living AD patients and 11 controls). MtDNA from blood samples together with hippocampus and cerebellum brain areas did not show differences between controls and AD. However, AD patients showed a 28% decrease in the amount of mtDNA in the frontal cortex when compared to controls for this specific area. Since frontal cortex is a severely affected region in AD, our results support the hypothesis that mitochondrial defects may play a role in the pathogenesis of AD.     

Naming ability in patients with mild to moderate Alzheimer's disease: what changes occur with the evolution of the disease?

OBJECTIVES:

Naming deficit is a linguistic symptom that appears in the initial phase of Alzheimer''s disease, but the types of naming errors and the ways in which this deficit changes over the course of the disease are unclear. We analyzed the performance of patients with Alzheimer''s disease on naming tasks during the mild and moderate phases and verified how this linguistic skill deteriorates over the course of the disease.

METHODS:

A reduced version of the Boston Naming Test was administered to 30 patients with mild Alzheimer''s disease, 30 patients with moderate Alzheimer''s disease and 30 healthy controls. Errors were classified as verbal semantic paraphasia, verbal phonemic paraphasia, no response (pure anomia), circumlocution, unrelated verbal paraphasia, visual errors or intrusion errors.

RESULTS:

The patients with moderate Alzheimer''s disease had significantly fewer correct answers than did both the control group and the group with mild Alzheimer''s disease. With regard to the pattern of errors, verbal semantic paraphasia errors were the most frequent errors in all three groups. Additionally, as the disease severity increased, there was an increase in the number of no-response errors (pure anomia). The group with moderate Alzheimer''s disease demonstrated a greater incidence of visual errors and unrelated verbal paraphasias compared with the other two groups and presented a more variable pattern of errors.

CONCLUSIONS:

Performance on nominative tasks worsened as the disease progressed in terms of both the quantity and the type of errors encountered. This result reflects impairment at different levels of linguistic processing.     

Plasma β amyloid and the risk of Alzheimer's disease in Down syndrome

Extracellular deposition of amyloid beta peptide (Aβ) has been implicated as a critical step in the pathogenesis of Alzheimer's disease (AD). In Down syndrome (DS), Alzheimer's disease is assumed to be caused by the triplication and overexpression of the gene for amyloid precursor protein (APP), located on chromosome 21. Plasma concentrations of Aβ1-40 and Aβ1-42 were determined in a population based study of 506 persons with DS, who were screened annually for dementia. We used Cox proportional hazards models to determine the risk of dementia. Demented persons with DS have a significantly higher plasma Aβ1-40 concentration than the nondemented (p = 0.05). Those with the highest concentrations of Aβ1-40 and Aβ1-42 have a higher risk to develop dementia. The risk to develop dementia during follow-up (mean 4.7 years) increased to 2.56 (95% confidence interval, 1.39-4.71) for Aβ1-42 and 2.16 (95% confidence interval, 1.14-4.10) for Aβ1-40. High plasma concentration of plasma Aβ1-40 and Aβ1-42 are determinants of the risk of dementia in persons with DS.     

Treatment of cognitive dysfunction associated with Alzheimer's disease with cholinergic precursors. Ineffective treatments or inappropriate approaches?

The observations of the loss of cholinergic function in neocortex and hippocampus in Alzheimer's disease (AD) developed the hypothesis that replacement of cholinergic function may be of therapeutic benefit to AD patients. The different approaches proposed or tested included intervention with acetylcholine (ACh) precursors, stimulation of ACh release, use of muscarinic or nicotinic receptor agonists and acetylcholinesterase (AChE) or cholinesterase (ChE) inhibition. Inhibition of endogenous ACh degradation through ChE inhibitors and precursor loading were treatments more largely investigated in clinical trials. Of the numerous compounds in development for the treatment of AD, AChE and ChE inhibitors are the most clinically advanced, although clinical trials conducted to date did not always confirm a significant benefit of these drugs on all symptom domains of AD. The first attempts in the treatment of AD with cholinergic precursors did not confirm a clinical utility of this class of compounds in well controlled clinical trials. However, cholinergic precursors most largely used such as choline and phosphatidylcholine (lecithin) were probably not suitable for enhancing brain levels of ACh. Other phospholipids involved in choline biosynthetic pathways such as CDP-choline, choline alphoscerate and phosphatidylserine clearly enhanced ACh availability or release and provided a modest improvement of cognitive dysfunction in AD, these effects being more pronounced with choline alphoscerate. Although some positive results cannot be generalized due to the small numbers of patients studied, they probably would justify reconsideration of the most promising molecules in larger carefully controlled trials.     

Is cutaneous malignant melanoma associated with the use of antibacterial soaps?

Since 1960, the incidence of melanoma has increased dramatically in Caucasians worldwide, and during the past decade has risen at a rate of 6% a year in the USA. A hypothesis regarding this increased incidence suggests that the prevalent use of antibacterial soaps that contain photosensitizing compounds may be a risk factor for the development of cutaneous malignant melanoma. These antibacterial soaps were introduced in the 1960s and compounds with photosensitizing properties are still present in various soaps throughout the industrialized world. The use of these antibacterial soaps, in combination with sun exposure, leads to free radical production in the skin. These free radicals are hypothesized to cause damage to melanocytes, leading to the development of melanoma. Various epidemiological findings regarding melanoma are consistent with this hypothesis. A significant reduction in the number of new cases of melanoma could be achieved if this hypothesis is correct.     

Is Epstein-Barr virus infection associated with the pathogenesis of microscopic colitis?

BackgroundEpstein-Barr virus (EBV) has been associated with inflammation in the colon, particularly in patients with inflammatory bowel disease (IBD). Even if a relevant plasmocytosis, similar to IBD, is present in microscopic colitis (MC), the frequency of EBV infection in this setting is unknown.ObjectivesWe aimed to compare the frequency of colonic EBV infection in patients with MC, ulcerative colitis (UC), and irritable bowel syndrome (IBS).Study designThe frequency of colonic EBV infection in biopsies of 30 patients with MC, 30 patients with UC, and 30 controls with IBS was retrospectively assessed. PCR was performed to detect viral EBV DNA in colonic biopsies. In situ hybridization was also performed to identify and localize EBV-encoded small RNA1 and 2 (EBERs) within cells.ResultsThe presence of EBV DNA was detected in 27 out of 30 MC patients, in 20 out of 30 UC cases, and in none of IBS group. The frequency of EBV DNA in MC was significantly higher compared with that reported in UC (90.0% vs. 66.7%, p = 0.03). EBERs+ cells were observed in 18 out of 30 MC patients, in only 3 out of 30 UC patients (60.0% vs. 10.0%, p < 0.001), and in none of IBS group.ConclusionsEBV infection is almost always detectable in the colonic mucosa of patients with MC. Further studies are necessary to confirm this association and to clarify the role of EBV in MC and, more generally, in colonic inflammation.