Current Alzheimer Research - Volume 6, Issue 1, 2009

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Background: The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and protein levels, in the cerebrospinal fluid (CSF) of Alzheimer disease (AD) patients. Methods and Findings: AD patients aged 50-85 years were randomized to open-label treatment with oral rivastigmine, donepezil or galantamine for 13 weeks. AChE and BuChE activities were assayed by Ellman's colorimetric method. Protein levels were assessed by enzyme-linked immunosorbent assay (ELISA). Primary analyses were based on the Completer population (randomized patients who completed Week 13 assessments). 63 patients were randomized to treatment. Rivastigmine was associated with decreased AChE activity by 42.6% and decreased AChE protein levels by 9.3%, and decreased BuChE activity by 45.6% and decreased BuChE protein levels by 21.8%. Galantamine decreased AChE activity by 2.1% and BuChE activity by 0.5%, but increased AChE protein levels by 51.2% and BuChE protein levels by 10.5%. Donepezil increased AChE and BuChE activities by 11.8% and 2.8%, respectively. Donepezil caused a 215.2% increase in AChE and 0.4% increase in BuChE protein levels. Changes in mean AChE-Readthrough/Synaptic ratios, which might reflect underlying neurodegenerative processes, were 1.4, 0.6, and 0.4 for rivastigmine, donepezil and galantamine, respectively. Conclusion: The findings suggest pharmacologically-induced differences between rivastigmine, donepezil and galantamine. Rivastigmine provides sustained inhibition of AChE and BuChE, while donepezil and galantamine do not inhibit BuChE and are associated with increases in CSF AChE protein levels. The clinical implications require evaluation.

The role of cholesterol as a susceptibility factor or a protective agent in neurodegeneration and, more generally, in amyloid-induced cytotoxicity is still controversial. Epidemiological studies on the hypercholesterolemia-AD risk relation and some reports indicating a beneficial effect of statin therapy suggest cholesterol as a susceptibility factor in AD. The ApoE4 genotype as a prevalent genetic risk factor for AD and the function of ApoE as main cholesterol carrier in the brain also underlie a close cholesterol load-AD risk relation. Finally, cell biology evidences support a critical involvement of lipid raft cholesterol in the modulation of β- and γ-secretase cleavage of APP with altered Aβ production. However, little exchange does exist between circulating and brain cholesterol, the latter arising from endogenous synthesis. In addition, increasing evidence supports the idea that amyloid cytotoxicity in most cases is initiated by oligomer recruitment at the cell membrane with loss of membrane integrity, Ca2+ ingress into the cell, oxidative stress and apoptosis. In such a scenario, increased membrane cholesterol seems to be protective by disfavouring aggregate binding to the membrane. Recent findings also indicate that a reduction of cellular cholesterol favours co-localization of BACE1 and APP in non-raft membrane domains and hinders generation of plasmin, an Aβ-degrading enzyme. Finally, recent researches on Seladin-1, involved in cholesterol biosynthesis, show that modulation of membrane cholesterol affects Aβ generation and cell resistance against Aβ oligomer toxicity. These data confirm previous findings indicating a reduction of the cholesterol/ phospholipid ratio in aged and AD brains. The aim of this review is to critically discuss some of the main results reported in the recent years in this field supporting a role of cholesterol either as a susceptibility factor or as a protective agent in AD.

While anesthetics are indispensable clinical tools generally safe and effective, in some situations there is grown concern about selective neurotoxicity of these agents; the clinical significance is unclear as of yet. The mechanisms for inhalational anesthetics mediated cell damage are still not clear, although a role for calcium dysregulation has been suggested. For example, the inhaled anesthetic isoflurane decreases endoplasmic reticulum (ER) calcium concentration and increases that in the cytosol and mitochondria. Inhibition of ER calcium release, via either IP3 or ryanodine receptors, significantly inhibited isoflurane neurotoxicity. Neurons made vulnerable to calcium dysregulation by overexpression of mutated presenilin-1 (PS1) or huntingtin (Q-111) proteins showed enhanced apoptosis upon isoflurane exposure. Sevoflurane and desflurane were less potent than isoflurane in altering intracellular calcium, and produced less apoptosis. Short exposures to inhalational anesthetics may provide neuroprotection by preconditioning via a sublethal stress, while prolonged exposures to inhalational anesthetics may induce cell damage by apoptosis through direct cytotoxic effects.

The vast majority of the studies performed so far and aimed at elucidating DNA repair mechanisms has been performed in mitotic cells, such as transformed or cancer cell lines. Therefore, our understanding of DNA repair mechanisms in post-mitotic cells, such as neurons, remains one of the most exciting areas for future investigations. Markers of DNA damage, particularly oxidative DNA damage, have been largely found in brain regions, peripheral tissues, and biological fluids of Alzheimer's disease (AD) patients. Moreover, recent studies from our and other groups in individuals affected by Mild Cognitive Impairment provided evidence that oxidative DNA damage is one of the earliest detectable events within the progression from a normal brain to dementia. Almost one decade ago a decrease in the DNA base excision repair (BER) activity was observed in post mortem brain regions of AD individuals, leading to the hypothesis that the brain in AD might be subjected to the double insult of increased DNA damage, as well as deficiencies of DNA repair pathways. Subsequent studies have provided accumulating evidence of impaired DNA repair in AD. Moreover, functional variants and polymorphisms of DNA repair genes have been the focus of several cancer association studies, but only in recent years some of them have been investigated as possible AD risk factors. The few studies performed so far suggest that some variants might play a role in AD pathogenesis and deserve further investigations. Here, we summarize the current knowledge of DNA damage and repair in AD pathogenesis.

Objective: To determine if a direct measure of instrumental activities of daily living (IADL) scale designed for use with dementia patients can detect differences between persons with mild cognitive impairment (MCI) and normal elderly control subjects (NC). Methods: This study used cross-sectional and longitudinal IADL scale data from MCI and NC subjects followed at an Alzheimer's Disease Center. Results: On a 52-point scale, MCI subjects (n = 30) scored significantly lower than NC subjects (n = 30) on the IADL scale (total score 47.17 vs. 48.77 points; t (58) = 2.34, p = .011) and its Memory subscale (5.27 vs. 6.6 points; t (58) = 3.29, p = .002).Examination of annualized IADL scale change scores revealed that 50% of MCI subjects had declined by one point, compared with 29% of NC. Conclusion: A direct IADL measure for dementia patients is able to detect small differences between MCI and NC and cross-sectionally and longitudinally, but does not distinguish between groups.

We obtained brain MRIs, plasma homocysteine levels and apolipoprotein E genotyping for 11 American Indian Alzheimer disease (AD) subjects and 10 Indian controls. We calculated white matter hyperintensity volume (WMHV), whole brain volume (WBV), and ratio of white matter hyperintensity volume to whole brain volume (WMHV/WBV). There were no significant differences between AD subjects and controls in gender, history of hypertension, diabetes, or history of high cholesterol, but hypertension and diabetes were more common among AD subjects. There was no difference between AD and control groups in age (range for all subjects was 61-89 years), % Indian heritage, waist size or body mass index. Median Indian heritage was 50% or greater in both groups. Range of education was 5-13 years in the AD group and 12-16 years in controls. Median plasma homocysteine concentration was higher in AD subjects (11 μmol/L vs. 9.8 μmol/L), but did not achieve statistical significance. Significantly more AD subjects had apolipoprotein Eη4 alleles than did controls (63% vs.10%). Neuroimaging findings were not significantly different between the 2 groups, but AD subjects had greater WMHV (median 15.64 vs. 5.52 cc) and greater WMHV/WBV ratio (median 1.63 vs. 0.65 %) and a far greater range of WMHV. In combined AD subjects and controls, WBV correlated with BMI and age. WMHV and WMHV/WBV correlated inversely with MMSE scores (p = 0.001, 0.002, respectively). In addition, WMHV correlated positively with % Indian heritage (p = 0.047).

Recent research findings provide evidence for Alzheimer's disease-related changes in brain diseases, such as normal pressure hydrocephalus and traumatic brain injury, and in glaucoma at the level of the retinal ganglion cells. This is a group of diseases that affect central nervous system tissue and are characterized by elevation of intracranial or intraocular pressure and/or local shear stress and strain. This strengthens the possibility that Alzheimer-type changes in these diseases may result at least in part from exposure of central nervous system tissue to elevated mechanical load. As activities or diseases with significant Valsalva effort can generate increased intracranial pressures, we hypothesize that individuals who frequently perform strong Valsalva maneuvers (e.g., long hours of repetitive heavy lifting, sequences of blows during the playing of a wind instrument, forceful and repetitive cough, bearing-down efforts during parturition) may be more susceptible to developing Alzheimer's disease. In this paper, we discuss three hypotheses about the mechanisms by which extensive use of the Valsalva maneuver might contribute to the neuropathogenesis of Alzheimer's disease: via mechanical stress-induced events in the hippocampus and/or via changes in the secretory process of the choroid plexus and/or via hemodynamic changes in cerebral blood flow. If confirmed, this hypothesis could have implications in clinical practice.

Investigations of alterations in brain asymmetry often focus on the planum temporale of patients with schizophrenia. Data also suggest changes in laterality of demented patients associated with a more marked impairment of the left hemisphere. Our study was performed on autoptic brain tissue of 84 patients, out of which there were 25 non-demented non-psychotic controls, 50 demented patients (34 Alzheimer disease, 9 multi - infarct dementia and 7 mixed-type dementia patients) and 9 people with schizophrenia. The plana temporalia were evaluated via a new volumetric method using dental resin matter. Areas, cortical thickness and volumes of the right and left planum temporale were evaluated without normalization to brain weight in 60 patients and with normalization in 24 people. In controls, a mild right/left laterality of areas, cortical thickness and volumes was found. Moreover, in control women the areas of the left planum temporale were smaller than those observed in control men. The shifts to left/right laterality of areas and volumes were found in all demented groups. In the more numerous Alzheimer group, the change in laterality of an area was associated with a mild decrease on the right and a mild increase on the left side. In contrast, marked but only bilateral area shrinkage as well as reduced cortical thickness and brain volumes were observed in schizophrenic patients.

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Commercial priorities have been identified as negative factors in drug development. We trace the problem to inattention to sound clinical pharmacology practices. When properly applied, clinical pharmacology and associated drug development sciences can, hand in hand, facilitate success in commercial drug development.

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